Volume 18 Issue 3
Peer Reviewed
From OEL to Commercial Supply:
Designing Robust High-Potency Oral Solid Manufacturing
Automated Print Inspection in Pharmaceutical Packaging: From Batch Release to Data-Driven Quality Control
Rethinking CNS Drug Development:
From Symptom Control to Durable Brain Health
Alternative Drug Delivery Routes:
Opportunities, Challenges and How to Overcome Them CDMO
Subsection page 12
Sponsor Company:
Injectables
Subsection page 44
Neurodegenerative Diseases Subsection page 54
Nasal & Pulmonary Subsection page 64
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Contents 04
Editor’s Letter
TALKING POINT 06
DIRECTOR: Mark A. Barker BUSINESS DEVELOPMENT: Anthony Stewart anthony@senglobalcoms.com MANAGING EDITOR: Alice Phillips alice@senglobalcoms.com EDITORIAL ASSISTANTS: Melissa Canver melissa@senglobalcoms.com Carla Devine carla@senglobalcoms.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com
Taking Risk Out of Device Development Through Regulatory Strategy
Sandra Schaerer and Karolina Snajdarova of Ypsomed examine how early regulatory strategy can help prevent device development from becoming a bottleneck in pharmaceutical programmes. 10
Annex 1 in Practice: Building a Stronger Contamination Control Strategy
The Pharma Conversations Podcast features Jim Polarine of STERIS, exploring how Annex 1 is reshaping contamination control in sterile manufacturing. CDMO 16
An Integrated State-of-the-Art Site for ADC DS and DP, from IND to Commercial Supply
BSP Pharmaceuticals’ Aldo Braca highlights an integrated approach to ADC manufacturing within a single facility and quality system. 20
Innovative Formulations and Processing Technologies for Oral Drug Delivery
Sander van den Ban of Almac Pharma Services explores how advanced formulation and processing technologies are helping overcome challenges in oral drug delivery. 24
From OEL to Commercial Supply: Designing Robust High-Potency Oral Solid Manufacturing
FINANCE DEPARTMENT: Akash Sharma accounts@senglobal.com
David O’Connell of PCI explores how toxicology, process engineering and containment can be integrated from the outset to maintain product quality and support early development through to commercial supply.
COVER IMAGE: iStockphoto ©
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AI in Lyophilised Product Development: Opportunities and Limitations
AI is beginning to support lyophilisation development by helping teams structure protocols, explore cycle parameters and organise technical information. Drawing on insights from Sam Woodyard, Erin Kuhn and Dr. Kevin Ward of Biopharma Group. PACKAGING 34
Automated Print Inspection in Pharmaceutical Packaging: From Batch Release to Data-Driven Quality Control
Dr. André Schwarz of EyeC explores how automated print inspection data can go beyond batch release documentation to identify recurring defects. 40
Child-Resistant Packaging: Balancing Safety, Adult Access and Product Performance
Aaron Small of Silgan Dispensing explores the growing role of child-resistant packaging in pharmaceuticals.
2026 Senglobal Ltd./Volume 18 Issue 3 – Autumn – 2026
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 1
Contents INJECTABLES 44
72
The Elastomeric Stopper as Part of a System: Building Confidence Through Worst-Case Scenario Testing
Edouard Pagnoud of Aptar Pharma explores how worst-case testing, lifecycle evaluation and system-level data can help manufacturers strengthen USP <382> qualification. 46
The Global Harmonisation of Contamination Control Strategy Regulations and Enforcement
Lauren Orme of West Pharmaceutical Services examines how global regulators are increasingly aligning on stricter, risk-based contamination control standards for sterile manufacturing. 52
Redrawing the Delivery Map: How Microneedle Patches Could Transform Patient-Centric Drug Delivery
Kindeva’s Andrew Riso explores how microneedle array patches could reshape the delivery of biologics by reducing injection-related barriers. NEURODEGENERATIVE DISEASES 54
Mass Spectrometry Imaging Drives Research into Parkinson’s Disease
Dr. Per Andrén and Dr. Michael Easterling of Bruker Daltonics explore how mass spectrometry imaging is revealing molecular changes linked to Parkinson’s disease and L-DOPA-induced dyskinesia. 56
Rethinking CNS Drug Development: From Symptom Control to Durable Brain Health
CONNECTA’s Dr. Josep Prous Jr. examines how CNS drug development is shifting from symptom control towards therapies designed to deliver lasting improvements. 60
Translating Clinical Evidence to Advance N2B Drug Development
Julie Suman and Reenal Gandhi of Aptar examines how more consistent nasal targeting and integrated device–formulation development could help a more reliable strategy for CNS drug delivery. NASAL & PULMONARY 64
Keeping Pace with Increasing Complexity in Pharmaceutical Analytics
A&M STABTEST’s Regina Ohmer explores how increasingly complex medicines are changing the demands placed on pharmaceutical analytics. 68
Why Is the Nasal Route Redefining Systemic and CNS Drug Delivery?
Elsie Thomas and Sophie Conte of Nermera explore advances in formulations and device technology are expanding its use across emergency, neurological and CNS therapies.
When the Ground Shifts, So Must the Materials
Yann Treguier and Sophie Versavaud from Victrex examine how PFAS restrictions and propellant changes are reshaping pharmaceutical material requirements. 78
The Upcoming Inhaled Biologics Therapies: A Data-Driven Analysis of the Inhaled Biologics Clinical Pipeline
Philippe Rogueda of Merxin explores emerging therapies and the growing opportunity for portable inhalers. 82
From Molecule to Market, Faster: Solving Nasal Drug Delivery's Biggest Development Bottlenecks
Bespak’s Chris Hirst is joined by Nikki Whitfield of Upperton and Deborah Jones of Resyca to explore how integrated formulation, device and manufacturing expertise can help overcome challenges in nasal drug delivery. 86
Beyond Propellant Replacement: A More Intelligent Development Pathway for Low-GWP pMDIs
Joanne Mather of Proveris explores a smarter approach to developing low-GWP pMDIs, focusing on formulation, device performance and aerosol behaviour. 92
A Pioneer's Path to Transition: How HFO-1234ze(E) Is Shaping the Future of Sustainable Pressurised Metered Dose Inhalers
Nilesh Wagh, Sandeep Mukhi and Rahul Parakhia of Solstice Advanced Materials explore how HFO-1234ze(E) is enabling the transition to lower-GWP pMDIs. 96
Soft Mist Inhalers: Enabling the Next Generation of Complex Inhaled Therapies
Nicolas Buchmann at Resyca highlights how soft mist inhalers could expand the use of inhaled medicines beyond traditional drugs, particularly for newer therapies. EVENTS & EXHIBITIONS 100 CPHI Milan APP NOTES 12
Leading Innovation in TIDES
Aurisco’s Rafael Antunes examines how advances in manufacturing and regulation are bringing generic oligonucleotide and peptide medicines closer to market. 75
Alternative Drug Delivery Routes: Opportunities, Challenges and How to Overcome Them
Jon Lenn, Jon Volmer and Charles Evans of MedPharm explore the expanding nasal drug delivery beyond local treatments into systemic and CNS therapies.
Advertisers Index Page 67 Page 23 Page 59 & BC Page 5 Page 85 Page 29 Page 19 Page 101 Page 102 Page 47 IFC Page 51 IBC
A&M STABTEST GmbH Almac Group Aptar Bachem Inc. Bespak Limited Biopharma Process Systems Ltd BSP Pharmaceeuticals S.p.A CPHI Milan DDL Gerresheimer EyeC GmbH Kindeva Krutz Temax
2 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Page 81 Page 43 Page 49 Page 31 Page 27 Page 89 Page 99 Page 3 Page 91 Page 35 Page 37 Page 9
Merxin Ltd Nemera Nipro Novo Nordisk PCI Pharma Services Proveris Scientific LLC Resyca Silgan Dispensing Systems Solstice Advanced Materials Alcami Woolcool Ypsomed
Autumn 2026 Volume 18 Issue 3
HiMark® CR
Simple // Secure HiMark® CR Nasal Pump is a sleek, effective solution that meets realworld needs of consumers and drug manufacturers. • • •
Independently certified for child-resistance Designed and tested to ensure ease of use for seniors Developed based on extensive consumer feedback and testing
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 3
Editor's Letter Welcome to the Autumn 2026 issue of IPI. With CPHI Milan just around the corner, this edition arrives at an exciting time of year for the pharma sector, as companies, researchers and technology providers prepare to come together and share the latest developments. This issue is packed with articles with a specific focus on CDMO, Injectables, Mental Health, and Nasal & Pulmonary. One of the highlights of this issue is a feature from Almac Pharma Services exploring the latest approaches to oral drug delivery and how innovative formulation and processing technologies are helping developers overcome challenges such as poor solubility, bioavailability and complex drug substance properties. The article looks at advances including amorphous solid dispersions, spray drying, hot melt extrusion, particle engineering and liquid-filled capsules, while highlighting the importance of Quality by Design, process understanding, scalability and patient-centric formulation. It also considers how integrating formulation science, analytical capability and manufacturing expertise from an early stage can help reduce development risk and support the efficient progression of oral medicines from early clinical development through to commercialisation.
emphasises the importance of lifecycle-based evaluation, ensuring closure performance remains robust from sterilisation and storage through to point of use, while providing manufacturers with the system-level data needed to make informed packaging decisions and build robust, riskinformed qualification strategies. A favourite of mine in this issue is a contribution from Bruker Daltonics, exploring how mass spectrometry imaging (MSI) is helping researchers better understand Parkinson’s disease and levodopa-induced dyskinesia (LID). I found the research particularly fascinating because it uses advanced imaging to reveal what is happening at a molecular level across different areas of the brain, offering new clues into why some patients develop this debilitating side effect.
challenges of alternative drug delivery routes, with a particular focus on nasal delivery. What makes this particularly interesting is the way it looks beyond the formulation itself to consider how the drug, device and biology of the nose all interact to determine where and how effectively a medicine is delivered. The piece also explores MedPharm’s innovative preclinical models and how these can help developers better understand formulation performance, reduce uncertainty and make more informed decisions earlier in the development process. I hope you enjoy this Autumn issue of IPI, and for those attending CPHI Milan, I hope you have a great show. As always, thank you to all our contributors for sharing their expertise and insights with our readers.
Another highlight of this issue is a contribution from MedPharm, exploring the opportunities and
Alice Phillips, Editorial Manager
Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research, Center of MCH, Astana, Kazakhstan
Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy
Steve Heath, Head of EMEA – Medidata Solutions, Inc Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories
Catherine Lund, Vice Chairman, OnQ Consulting
Jagdish Unni, Vice President – Beroe Risk and Industry Delivery Lead – Healthcare, Beroe Inc.
Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research
In our Injectables section is a feature from Aptar Pharma exploring how elastomeric vial stoppers should be evaluated as part of the complete Container Closure System under USP <382>. It highlights the value of worst-case testing across factors such as needle gauge, repeated piercing, sterilisation, stopper hardness and geometry to understand their combined impact on piercing force, fragmentation, self-sealing and container closure integrity. The feature also
Editorial Advisory Board
Deborah A. Komlos, Principal STEM Content Analyst, Clarivate Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organisation (WHO) Expert in ethics 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation Maha Al-Farhan, Chair of the GCC Chapter of the ACRP
Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB
Autumn 2026 Volume 18 Issue 3
Leading partner in TIDES
Bachem is a leading, innovation-driven company specializing in the development and manufacture of peptides and oligonucleotides. The company, which has over 50 years of experience and expertise, provides products for research, clinical development, and commercial applications to pharmaceutical and biotechnology companies worldwide and offers a comprehensive range of services. Bachem operates internationally with its headquarters in Switzerland and production sites in Europe and the US. The company is listed on the SIX Swiss Exchange. www.international-pharma.com
Scan to visit the Bachem homepage INTERNATIONAL PHARMACEUTICAL INDUSTRY 5
Talking Point
Taking Risk Out of Device Development Through Regulatory Strategy Sandra Schaerer and Karolina Snajdarova are Regulatory Affairs Managers at Ypsomed. We spoke with them about where programmes actually slow down on the device side, and what a different approach looks like. Device development isn't usually where sponsors expect their programme to stall, but it often does. Why? Sandra Schaerer: Because the risk tends to be invisible until it isn't. Sponsors understandably focus first on the molecule, formulation, and clinical strategy, and the device gets treated as something you sort out later. The issue is that "later" is exactly when your options narrow. If you discover a regulatory gap when the design is already fixed, closing it means creating additional documentation, repeating verification work, adding usability and bridging studies, and losing time. That is why regulatory thinking needs to start early, while there's still room for flexibility in the device and submission strategy. What does that early regulatory involvement look like in practice? Sandra Schaerer: We run what we call a regulatory radar, continuously tracking global regulatory requirements and authorities’ feedback, and contributing to standards like the ISO 11608 series, so that when requirements change, we’ve anticipated them rather than absorbed them. For sponsors, that means fewer late surprises, stronger device documentation, and submissions that behave more predictably. This is especially important in fast-moving market areas such as biologics, biosimilars, GLP-1s, peptides, and therapies shifting toward at-home administration. That predictability and readiness have real commercial value.
Figure 1: Regulatory activities and competences at Ypsomed
devices. When the device platform is already well characterised and supported by validation and verification evidence, manufacturing experience, expertise in risk management and human factors, and is also based on current regulatory requirements, a new project doesn’t need to start development from scratch.
GLP-1s and peptide therapies are driving significant demand right now. What does Ypsomed bring to that part of the market?
It also means that when something shifts, whether a formulation moves to a higher viscosity or a fill volume change, you're not creating a compliance burden on top of an already complex programme. You're working within a known platform context.
Sandra Schaerer: Something that shapes how we work across the whole pen business, not just one part of it. For our reusable pen platforms, YpsoPen and ServoPen, we hold full legal manufacturer responsibility. This means we deal directly with notified bodies and competent authorities, are responsible for certifications and approvals, as well as for the entire device lifecycle. Branding customisation is, of course, determined by the customer.
And then there's the weight of track record. More than 40 years of self-injection experience, over 80 combination products, and devices that already support more than eight million people across multiple therapeutic areas. Regulators and patients have seen these devices perform. That's not just a credential. It's a form of de-risking that no amount of documentation alone can replicate.
In volume terms, though, most of the pen programmes we support are integral combination products like UnoPen or YpsoMate autoinjectors. That's the more typical model, and it's where the depth of our own experience from reusable pens pays off. Because we've lived the full regulatory lifecycle from the inside, we know what authorities look for, where submissions tend to meet resistance, and
So the starting point is getting ahead of regulatory risk. What's the foundation that actually makes that possible? Sandra Schaerer: The foundation is the use of well-established and mature platform 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Figure 2: Ypsomed’s portfolio consists of 15 platforms, supporting 80+ combination product launches Autumn 2026 Volume 18 Issue 3
Regulatory & Talking Marketplace Point the pre-developed autoinjector early in the clinical trial, which may eliminate the need for a PK bridging study. This allows you to reach the market sooner and with lower overall spending. Figure 3: MIDBA approach enabling omission of a dedicated PK bridging study between manual injection and autoinjector
how to structure documentation to anticipate that. Our partners on combination product programmes benefit from that knowledge directly. It's built into how we approach the device-related part of the submissions, input on regulatory strategy, risk management evidence, verification and validation data, human factors input, labelling support, and lifecycle impact assessments. This distinction is important. We do not replace the MAH or the customer’s regulatory responsibility, but we help ensure that the device part is ready, consistent, and aligned with the relevant regulatory expectations. The foundations of that expertise were built over more than 40 years in diabetes care. Bringing insulin delivery and connected diabetes solutions to market required us to navigate approvals, lifecycle management, risk management, human factors requirements, post-market surveillance, and evolving regulatory expectations across multiple jurisdictions. That experience now informs how we support today's GLP-1 and peptide programmes, from clinical development through commercialisation. Moving to autoinjectors, traditionally timelines here can stretch. Is that still true? Karolina Snajdarova: It doesn't have to be. With pre-configured clinic-ready devices that are already pre-qualified and pre-verified, you can cut a standard development window in half to around six months. The lengthy device development timelines stop being what holds up your clinical submission. Because the devices cover the wide range of fill volumes and viscosities, you can enter Phase IIb easily, then pick or switch between devices as the formulation evolves. At the cost of a Phase IIb or III programme, that kind of flexibility matters enormously. But the timeline is only part of the story. The less-discussed cost-related aspect is the PK bridging study. Under the traditional model, introducing an autoinjector late in development requires a pharmacokinetic study to bridge the manual injection used early in the trial to the autoinjector. Short development timelines enable the use of www.international-pharma.com
There's a specific bridging approach that takes this further in the EU. What does MIDBA change for a sponsor? Karolina Snajdarova: MIDBA, the moleculeindependent device bridging approach qualified by the CHMP (Committee for Medicinal Products for Human Use), is one of the most significant regulatory advancements in recent years. In the EU, under specific conditions, you may omit a dedicated PK bridging study between manual injection and an autoinjector altogether for new monoclonal antibodies. Instead, you may use PK comparability data from reference monoclonal antibodies. This scientificallyjustified and evidence-based approach supports efficiency, time-to-market, and patient access to innovative treatments. The validity of the MIDBA has been demonstrated using the YpsoMate 2.25mL and 1.0mL autoinjector and with omalizumab and gantenerumab as reference mAbs. The pharmaceutical companies using the YpsoMate platforms can leverage this approach with reduced regulatory uncertainty to lower development burden, and shorten the development timelines for new drug products. Applying the MIDBA to a different autoinjector and/or changing any of the proposed specifications need to be supported by additional data and/or justification, along the lines presented for YpsoMate 2.25 and 1.0 in the qualification opinion. Sponsors using alternative platforms may therefore
need to establish an additional reference evidence base before leveraging a MIDBAbased strategy across similar mAbs. And what exactly are the specific conditions which need to be met in order to omit a dedicated PK bridging study? Karolina Snajdarova: The qualification opinion for MIDBA clearly defines the conditions that must be met for MIDBA to be accepted. When transitioning from manual injection to an autoinjector, the monoclonal antibody, dose and formulation, injection volume (0.5–2 mL), and injection site(s) must remain unchanged. The exposed needle length was determined as an additional potential factor that influences the outcome of the pharmacokinetic (PK) comparability study and must remain between 4 and 8 mm. The monoclonal antibody must demonstrate slow absorption after subcutaneous (SC) injection and have similar physicochemical properties to at least one reference mAb. MIDBA is a good example of the kind of efficient, scienceled approach with the potential to influence future global regulatory frameworks and facilitate acceptance of similar approaches in other markets. Which brings us to the geography question. Regulatory requirements may differ from market to market. How do you maintain a consistent approach while navigating different regions? Sandra Schaerer: The principle is the same in every region: get ahead of requirements rather than react to them. What changes is the regulatory landscape, and that's where local expertise becomes critical. China is a good example. Success there requires more than understanding global regulatory principles.
Figure 4: Ypsomed‘s “two wings” framework in China INTERNATIONAL PHARMACEUTICAL INDUSTRY 7
Talking Point You also need people on the ground who understand local requirements, expectations, and regulatory processes. Our local regulatory team helps multinational companies translate global development programmes into submissions that meet Chinese requirements, while supporting Chinese companies as they prepare products for international markets. That local commitment extends beyond regulatory expertise. In June 2025, we opened our manufacturing facility in Changzhou, built to global standards and certified to ISO 13485 by TÜV SÜD. Together with our local teams, it demonstrates our long-term investment in supporting customers in one of the world's most important pharmaceutical markets. The same model applies across our global network. We combine local regulatory
knowledge with globally consistent quality and development standards, helping partners coordinate programmes across the US, Europe, China, Japan, and other markets without having to navigate each region in isolation.
regulatory thread from concept to end of life means you're not absorbing surprises. A footprint that now spans Europe, Asia, and, from 2027, a US site at Holly Springs means you're not re-engineering your approach for each market.
So if you pull all of this together, platforms, regulatory strategy, methodology, global footprint, what's the single thing a senior leader should take from it?
What partners ultimately rely on is the combination: depth of collaboration and expertise, the insight that comes from running a high volume of submissions, and the agility to implement new requirements quickly. In a market that never stands still, that's what turns complexity into opportunity.
Sandra Schaerer: That the device should not become a bottleneck in a development programme. Everything we've talked about is in service of the same idea: make the device predictable, so you can focus on the drug development. Proven platforms mean you're not re-proving fundamentals. A continuous
Karolina Snajdarova Karolina Snajdarova is Regulatory Affairs Manager, Associate Director and Team Lead Autoinjectors at Ypsomed. She is responsible for regulatory affairs for the company’s autoinjector platforms and provides strategic regulatory support for customer-specific projects, including global registration activities, and supports a variety of corporate strategic initiatives. Karolina holds a Master's degree in Chemistry for Medical Applications. She has a strong background in analytical chemistry and extensive regulatory expertise in various product categories. Email: karolina.snajdarova@ypsomed.com
Sandra Schaerer Sandra Schaerer is Regulatory Affairs Manager at Ypsomed, supporting strategic regulatory projects for pen injectors and drug–device combination products. Her regulatory career began in the pharmaceutical sector, preparing CTDs and managing medicinal product submissions, before expanding into MedTech. Her expertise spans MDR CE marking, Article 117 assessments, FDA CFR regulations, and global market registrations. With a background in chemistry and bioprocess engineering, she now focuses on lifecycle management, technical documentation, and guiding cross-functional teams. Email: sandra.schaerer@ypsomed.com
8 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Autumn 2026 Volume 18 Issue 3
13049199-MSTR-en/V01
Making the complex feel straightforward.
Over 40 years dedicated to selfcare and self-injection solutions. More than 80 combination products and 24 indications served, covering both originators and biosimilars. Improving the quality of life of over 8 million people around the globe. Over 130 large, medium and small biopharma and biotech customers worldwide. Scalable business models for clinical trials and full-scale production. 100% electricity from renewable sources since 2021.
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Talking Point
Annex 1 in Practice:
Based on an interview with Jim Polarine, Principal Consultant, STERIS The revised EU GMP Annex 1 has rapidly become one of the most influential regulatory updates in sterile medicinal product manufacturing. Its impact is global, its expectations far reaching, and its interpretation still evolving. In a recent episode of the Pharma Conversations podcast, we sat down with Jim Polarine, Principal Consultant at STERIS one of the industry’s most respected voices on contamination control, to explore how organisations are navigating Annex 1 in real world environments.
European cGMP manufacturing sites particularly in Ireland and Belgium are described as early adopters of EU Annex 1 with strong CCS maturity. Many have already embedded risk based thinking into their operations. In contrast, United States (U.S.) facilities face a steeper learning curve. Annex 1 introduces concepts not historically emphasised in Food and Drug Administration (FDA) centric environments, including: • •
Integrated risk-based decision making and frequent utilisation of risk assessments Expanded environmental monitoring expectations Enhanced gowning requirements Deeper CCS integration
Several themes repeatedly emerged: the criticality of a robust contamination control strategy (CCS), the growing maturity gap between regions, the importance of a robust risk assessment, and the operational challenges that continue to surface in cGMP (current Good Manufacturing Practices) drug and device manufacturing facilities. What follows is a comprehensive analysis of the key takeaways from Jim’s insights offering a practical, experience driven perspective on Annex 1 implementation today.
• •
CCS Is No Longer a Document – It’s a Mindset Contamination control strategy is the backbone of Annex 1. It is not a checklist, not a binder on a shelf, and not a regulatory afterthought. It is a holistic, cross functional framework that must integrate every aspect of sterile manufacturing.
Annex 1 expects risk assessment to be embedded in:
Organisations that excel in CCS share several traits:
Large multinational companies tend to excel here, using structured methodologies to identify worst case scenarios and optimise validation scope. Smaller organisations, however, often struggle with either overtesting due to fear of non compliance or under testing due to lack of expertise.
• • •
Cross departmental ownership Continuous improvement culture Data driven decision making
A CCS must be a living system that is reviewed, challenged, and refined regularly. The organisations that treat CCS as a culture rather than a compliance exercise are the ones seeing the strongest outcomes. A Growing Global Maturity Gap One of the most interesting insights from Jim’s perspective is the regional disparity in Annex 1 readiness. 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY
This difference is not about capability; it’s about mindset shift. Annex 1 requires organisations to move from a compliance driven approach to one that is proactive, science based, and risk oriented. Risk Assessment: The Heart of Annex 1 If CCS is the backbone, risk assessment is the heartbeat.
• • • • •
Although residues on non-product contact surfaces are not considered a major risk, a residue management strategy is an important part of Annex 1. Residues can: • • • • •
Contribute to particulate contamination Interfere with biodecontamination Jim highlighted the need for: Routine rinsing with WFI or 70% IPA Documented residue management strategies
This is an area where many organisations are still adapting and where regulators are increasingly focused. Personnel: The Largest Source of Contamination Operators remain the number one contamination risk. Annex 1 reflects this reality with heightened expectations for: • •
Gowning Behaviour
Process design Environmental monitoring Cleaning and disinfection Material transfer Validation strategies
Jim’s advice is clear: invest in training. Risk assessment is not just a regulatory expectation; it is a tool for smarter, more efficient operations. Residue Management: The Silent Contamination Risk Residue management has become a major focus under the revised Annex 1. Autumn 2026 Volume 18 Issue 3
Regulatory & Talking Marketplace Point • • •
Movement Training Qualification
A key change is the requirement for sterile gowning in Grade B areas supporting isolators or Restricted Access Barrier Systems (RABS), a departure from previous norms which included scrubs or non-sterile gowning. Jim shared examples of how minor behavioural lapses can escalate contamination risk, reinforcing that training is not optional; it is foundational. Material Transfer: The Hidden Weak Link Material transfer is responsible for a significant proportion of contamination events, yet it is often inadequately designed. Jim highlighted recurring issues:
mental monitoring (EM), particularly in Grades C and D. Jim emphasised two major shifts: 1.
2.
Trend analysis over point data Organisations must identify potential bioburden patterns early before they reach Grade A/B cleanrooms. This includes more identification of bioburden in the Grade C and Grade D cleanrooms. Increased focus on lower grade areas Contamination rarely originates in Grade A areas; it migrates from elsewhere.
Jim also pointed to rapid microbiological methods (RMMs). While adoption is still limited, regulatory acceptance is growing, and technology is advancing quickly.
Carts and trolleys moving between uncontrolled and controlled areas Inadequate cleaning protocols Poorly defined transfer pathways Inconsistent disinfection practices
Isolators, RABS, and the Complexity of Modern Containment Advanced containment technologies reduce operator intervention but they introduce new challenges.
Annex 1 expects organisations to treat material transfer with the same rigor as aseptic processing and many are only now recognising the extent of this gap.
The most misunderstood requirement: cleaning before Vaporised Hydrogen Peroxide (VHP) bio decontamination.
• • • •
Legacy Facilities: When Infrastructure Becomes the Risk Ageing facilities face structural and mechanical challenges that can undermine even the strongest CCS, including: • • • • •
Degraded surfaces Compromised seals Outdated HVAC systems Water ingress Mold outbreaks These issues are real, recurring, and costly.
Annex 1 forces organisations to confront a difficult question: Is continued operation viable without significant investment? For resource constrained companies, Jim recommends prioritising these areas: • • • •
Critical infrastructure repairs Enhanced maintenance Targeted risk assessments Interim mitigation strategies
Environmental Monitoring: A More Proactive Era Annex 1 expands expectations for environwww.international-pharma.com
This raises questions about: • • • •
Compatible cleaning agents Residue management Equipment integrity Cycle development
Emerging technologies like UV disinfection offer promise but come with limitations such as shadowing. UV is best viewed as a complementary tool, not a replacement for common biodecontamination methods such as Vaporised Hydrogen Peroxide (VHP).
Practical Prioritisation for Resource Limited Organisations Not every organisation has the budget of a multinational. Jim offered pragmatic guidance for smaller companies: Start with the highest impact areas: 1. 2. 3. 4. 5.
Personnel training Gowning Material transfer Environmental monitoring Infrastructure repairs
These foundational elements deliver the greatest risk reduction for the time and resources invested. The Future of Annex 1: Continuous Evolution Annex 1 is a positive force that elevates standards and drives better science. But it is not static. Updates and clarifications will continue, and industry groups like Parenteral Drug Association (PDA) will play a critical role in shaping interpretation and sharing best practices. Annex 1’s future will be shaped by: • • • •
Technological innovation Regulatory evolution Industry collaboration Continuous learning
Conclusion Jim Polarine’s insights reveal an industry in transition that is moving from compliance driven behaviours to science based, risk oriented, and holistic contamination control. Annex 1 is challenging, but it is also transformative. Organisations that embrace its principles are not just meeting regulatory expectations; they are building stronger, safer, and more robust cGMP drug and device manufacturing operations.
Process Mapping: The Foundation of a Strong CCS Organisations cannot build an effective CCS without deep process understanding. Process mapping enables teams to: • • • •
Identify contamination risks Define critical control points Align controls with real world operations Eliminate blind spots
This is especially important in complex manufacturing environments where interactions between steps can create hidden risks.
Jim Polarine Jim Polarine is a Principal Consultant, Technical Services at STERIS Corporation, widely recognised as one of the leading global experts in contamination control, cleaning and disinfection, disinfectant validation, and microbial excursions in sterile manufacturing.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 11
Application Note
Leading Innovation in TIDES
Aurisco, the first USFDA inspected generic oligonucleotide API manufacturer is innovating in enzymatic ligation, hybrid solid and liquid phase synthesis, GLP-1 peptide recombinant and SPPS technologies, flow-photochemistry and much more. Aurisco Pharmaceutical, a leading global oligonucleotide and peptide (TIDES) and small molecule API manufacturer, recently announced that its site in Yangzhou, China has passed the USFDA inspection this June as the first generic Oligonucleotide API manufacturer in the world. The USFDA preapproval inspection for Inclisiran Sodium API covered cGMP compliance inspection for oligonucleotides, GLP-1 peptides. A New Era in Oligonucleotides Aurisco’s announcement marks more than a corporate milestone; it signals a new era for oligonucleotides. As of August 25, 2026, FDA had approved 24 oligonucleotide medicines, including 12 ASOs and 8 siRNAs, yet no generic oligonucleotide had been approved in the US. However, Paragraph IV competition is intensifying: Leqvio (inclisiran) has one ANDA filed, alongside two Spinraza (nusinersen) ANDAs and one Amvuttra (vutrisiran) ANDA. Generic oligonucleotides are moving closer to US patients. Oligonucleotides are short, synthetic DNA or RNA strands designed to bind specific genetic sequences and regulate gene
expression. Antisense oligonucleotides (ASOs) bind targeted RNA to modify its processing or function, whereas small interfering RNAs (siRNAs) promote RNA degradation and gene silencing. GalNAc conjugation enables efficient, targeted delivery to liver cells. Their sequencebased mechanisms make oligonucleotides a powerful therapeutic platform for genetic and rare disorders, as well as increasingly prevalent diseases. To help generic companies develop safe and affordable versions of these medicines, USFDA has published 18 product-specific (draft) guidances (PSGs) for generic oligonucleotide drug products with 2 additional planned for February 2027. Most PSGs follow a common regulatory approach that allows applicants to request a waiver of in vivo bioequivalence studies based primarily on demonstrating API sameness and manufacturing-process robustness. Patisiran is the principal exception because its formulation incorporates the siRNA within a complex lipid nanoparticle delivery system. The Importance of the API Pre-ANDA meetings are fundamental to ensure the regulatory strategy is adequate and data provided by the API manufacturer is sufficient. Besides Q1/Q2 formulation sameness. the USFDA requires: • •
Side-by-side comparative characterisation of at least three test and three RLD batches; Confirmation of primary sequence and chemical structure;
• • • •
• •
Comparison of diastereomeric composition; Evaluation of phosphorothioate-tophosphodiester ratios, where applicable; Orthogonal methods such as MS/MS, NMR, LC and duplex melting temperature; Physicochemical characterisation using CD, FTIR, DSC, SEC and SV-AUC or validated alternative analytical methods, as appropriate; Comparative impurity profiling; Immunogenicity and inflammation-risk assessment.
The ANDA holder and API manufacturer should be able to provide comprehensive method validation data to demonstrate the adequacy (e.g., sensitivity, resolution and discriminative power) of the selected methods in demonstrating the sameness between the test and reference product. The demonstration of resolution of the analytical methods and comparative impurity profiling requires the synthesis and characterisation of a significant number of potential process impurities. When solid-phase synthesis is used, each step can generate at least N-1 and N+1 impurities, on top of degradation impurities. As such, an ASO may require over 50 impurity standards, and a siRNA may require over 100 impurity standards to be synthetised and characterised. Behind every oligonucleotide DMF there is a ton of analytical work. Another challenge for generics is the access and cost of the RLD batches to support the API and FDF development and sameness
cGMP Oligonucleotide Manufacturing at Yangzhou Aurisco 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Autumn 2026 Volume 18 Issue 3
Application Note Active Ingredient or revised
RLD
Modality
Dosage form/route
PSG issued or revised
PSG_NDA
Nusinersen sodium
Spinraza
ASO, 21-MOE phosphorothioate
Intrathecal solution
Feb 2022
209531
Eteplirsen
Exondys 51
PMO antisense oligonucleotide
IV solution
Nov 2022
206488
Patisiran sodium
Onpattro
Lipid nanoparticle-formulated siRNA
IV solution
Nov 2022
210922
Inotersen
Tegsedi
ASO; 21-MOE phosphorothioate
Subcutaneous solution
Nov 2022
211172
Golodirsen
Vyondys 53
PMO antisense oligonucleotide
IV solution
Feb 2023
211970
Viltolarsen
Viltepso
PMO antisense oligonucleotide
IV solution
Feb 2023
212154
Givosiran sodium
Givlaari
GalNAc-conjugated siRNA
Subcutaneous solution
May 2023
212194
Casimersen
Amondys 45
PMO antisense oligonucleotide
IV solution
May 2023
213026
Lumasiran sodium
Oxlumo
GalNAc-conjugated siRNA
Subcutaneous solution
Aug 2023
214103
Vutrisiran sodium
Amvuttra
GalNAc-conjugated siRNA
Subcutaneous solution
Aug 2023
215515
Inclisiran sodium
Leqvio
GalNAc-conjugated siRNA
Subcutaneous solution
May 2023;
214012
Tofersen
Qalsody
ASO, 21-MOE phosphorothioate
Intrathecal solution
Nov 2023 (rev)
215887
Nedosiran sodium
Rivfloza
GalNAc-conjugated siRNA
Injectable solution
Aug 2024
215842
Eplontersen
Wainua
GalNAc-conjugated ASO; 21-MOE phosphorothioate
Subcutaneous solution
Aug 2024
217388
Avacincaptad pegol sodium
Izervay
PEG-conjugated RNA aptamer
Intravitreal solution
Nov 2024
217225
Fitusiran sodium
Qfitlia
GalNAc-conjugated siRNA
Subcutaneous solution
Feb 2026
219019
Imetelstat sodium
Rytelo
Lipid-conjugated ASO phosphorothioate
Powder for IV solution
May 2026
217779
Olezarsen
Tryngolza
GalNAc-conjugated ASO; 21-MOE phosphorothioate
Subcutaneous solution
May 2026
218614
Donidalorsen
Dawnzera
GalNAc-conjugated ASO; 21-MOE phosphorothioate
Subcutaneous solution
Aug 2026
219407
Plozasiran
Redemplo
GalNAc-conjugated siRNA
Subcutaneous solution
Planned Feb 2027
219947
demonstrations. In certain oligos, the sourcing of 3 vials of 3 independent batches can easily exceed USD1.5M, a significant upfront investment that deters smaller generic companies. NEW Oligo Synthesis Platform Most approved oligonucleotide medicines still target rare or ultra-rare diseases but www.international-pharma.com
improving knowledge of disease mechanisms is expanding their potential into larger cardiovascular, degenerative and metabolic indications. Inclisiran and vutrisiran illustrate this shift toward substantially larger patient populations. These indications will require greater manufacturing capacity, lower costs, and more sustainable production technologies.
Enzymatic ligation emerges as an alternative to fully solid-phase synthesis for long and complex oligonucleotides. Short, chemically synthesised fragments are joined using ligases or polymerases, avoiding cumulative coupling inefficiencies, declining yields, and increasing impurity burdens associated with conventional solid-phase synthesis. Assembling shorter high-purity fragments can improve final INTERNATIONAL PHARMACEUTICAL INDUSTRY 13
Application Note product quality, scalability, and manufacturing robustness while reducing synthesis cycles and purification demands. This approach can also improve sustainability. Conventional oligonucleotide synthesis consumes substantial quantities of acetonitrile, activators, oxidants, and protecting-group reagents. Fewer chemical coupling cycles can reduce solvent consumption, process mass intensity, and hazardous waste. Progress in enzyme engineering, template-directed ligation, and enzymatic error correction is expanding the industrial applicability of hybrid chemical-biological processes. To combine chemical synthesis with enzymatic ligation, Aurisco is developing intelligent design and directed evolution methods for non-natural nucleic acid ligases. Its scientists use AI-assisted enzyme design to enable recognition and ligation of modified phosphorothioate-containing substrates, while optimising ligase expression and production for reactions conducted at high substrate concentrations. These capabilities will support efficient manufacturing of increasingly long, modified, and structurally complex therapeutic oligonucleotides at commercially relevant scale while improving product consistency and reducing environmental burdens across the overall manufacturing global lifecycle. Continuous Flow Phosphoramidite Synthesis A key contributor to the COGS of oligonucleotide medicines is the phosphoramidite cost. Due to the inherent inefficiency of standard solid-phase synthesis and extensive purification, each kilo of a 20mer ASO consumes between 5kg and 15kg of amidites and siRNAs require double of that. Leveraging years of experience in the development of flow-chemistry processes, Aurisco has developed continuous flow process technology and equipment to efficiently manufacture customized amidites, eliminating the use of expensive catalysts, bases and reducing the consumption of expensive reagents, solvents and water. With increased yields and reduced cycle-times, continuous flow is the most sustainable and cost-efficient way to manufacture phosphoramidites. Synthetic and Recombinant Peptide Synthesis Platforms Recent advances in structural biology, recombinant biologics, and new synthetic and analytic technologies have significantly accelerated the discovery process. As of March 2024, there were 119 peptides with 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY
FDA approval for therapeutic or diagnostic purposes, with six approved in 2025 alone with more than 150 peptides in clinical trials and another 400–600 peptides in preclinical studies. The choice between recombinant and synthetic peptide manufacturing has significant implications for development timelines, production capacity and costs, environmental sustainability, and the regulatory approval pathways applicable to both innovative and generic products. Recombinant synthesis uses biotechnology to introduce a plasmid containing DNA encoding a semaglutide precursor into host cells such as S. cerevisiae or E. coli. The engineered host translates the recombinant DNA into the intended peptide chain. The resulting intermediate is then recovered and purified using biochemical, chromatographic, and filtration techniques that remove biological contaminants and process-related byproducts. This recombinant route, selected by Novo Nordisk for commercial semaglutide production, supports efficient biosynthesis followed by downstream purification. In solid-phase peptide synthesis (SPPS), amino acids are sequentially added to a peptide chain anchored to a solid resin. After the first amino acid is attached, repeated protection, deprotection and coupling cycles extend the sequence. Each cycle removes an Fmoc or Boc protecting group to expose the reactive amine, which is coupled with the next protected amino acid. Once the target sequence is complete, the peptide is cleaved from the resin and purified. Hybrid processes use SPPS to produce shortmers and then combine them into the final peptide by liquid-phase peptide synthesis (LPPS). Eli Lilly uses this kind of route to produce tirzepatide at commercial manufacturing scale. Generic GLP-1 Peptides Generic peptides require extensive characterisation of primary and secondary structure, oligomeric and aggregation states, and biological activity to demonstrate sameness with the reference listed drug (RLD). Primary amino acid sequence and disulfide-bond positions are critical for establishing drug-substance sameness. Generic formulations are usually qualitatively and quantitatively identical to the RLD because new excipients may alter stability and promote dimers, higher-order aggregates, or other species that could affect efficacy, safety, and immunogenicity. Peptides exhibit predominantly random-coil conformations
with varying proportions of alpha-helices or beta-sheets. Because structural organisation can influence biological activity, secondary structure should be evaluated during comparative characterisation. However, many peptides are highly conformationally flexible, and their higher-order structures are governed primarily by thermodynamic equilibrium rather than kinetic folding. Consequently, when a generic peptide has the same amino acid sequence and an equivalent qualitative and quantitative formulation, its higher-order structure can generally be inferred to match that of the RLD. The USFDA Guidance for Industry “ANDAs for Certain Highly Purified Synthetic Peptide Drug Products That Refer to Listed Drugs of rDNA Origin” defines requirements for generic synthetic peptides referencing recombinant DNA-derived drugs. For semaglutide, FDA has issued PSGs for oral and injectable generics, including the possibility of waiving in vivo bioequivalence studies for the injectable product. The principal challenge is demonstrating comparable quality and safety because manufacturing may introduce impurities absent from the reference product. The July 2026 revised semaglutide PSG_209637 requires sameness to be demonstrated at release and at the end of shelf life, emphasising control of APIrelated and non-API-related impurities. This revision may favour recombinant semaglutide because recombinant production can reduce process-related impurities and lower the risk of higher-order structural changes and aggregation during storage. These controls are particularly important because peptide-related impurities often closely resemble the active peptide in sequence and physicochemical properties, making them difficult to detect, characterise, quantify, and control throughout the product lifecycle. Beyond analytical comparison of peptiderelated impurities and the primary and secondary structures of the generic and RLD, FDA may require comparative in vitro studies, animal studies, clinical pharmacokinetic and pharmacodynamic equivalence studies, or clinical trials to establish the safety and effectiveness of a synthetic peptide. In vitro bioassays linking structure to activity are essential for characterising higherorder structure and biological function in complex peptides. Biological activity may be assessed through animal-based, cell-based, biochemical, or immune-response assays, particularly when confirmatory evidence is needed to demonstrate sameness. FDA’s tirzepatide PSG recommends comparative Autumn 2026 Volume 18 Issue 3
Application Note
assessment of secondary structure, oligomeric and aggregation states, and biological activity. If clinical evidence is necessary, submission under section 505(b) of the FD&C Act may be required. Outside the US, some generic peptides may follow biosimilar pathways, requiring high similarity in manufacturing quality, biological activity, clinical safety and efficacy, and immunogenicity. EMA guidance requires applicants to quantify differences between chemically synthesised and recombinant peptides and demonstrate comparability using a broad panel of side-by-side analytical methods applied to the synthetic product and the EU-sourced recombinant reference product. The overall evidence package
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must therefore integrate physicochemical characterisation, functional testing, impurity assessment, and, where justified, targeted comparative clinical confirmation studies. Conclusion The generic landscape in new modalities such as peptides and oligonucleotides is changing fast and companies like Aurisco are leading the way, offering demonstrated experience, regulatory knowledge and compliance in the manufacturing of peptide and oligonucleotide APIs for both generic and innovators. Using modern facilities and advanced science, Aurisco is a CDMO collaborating with the best pharmaceutical companies in the world and with regulators to make new and generic medicines accessible to patients.
Rafael Antunes Rafael Antunes is the Vice President of
Marketing and Business Development of Aurisco Pharmaceutical in Europe. He has over 20 years of Pharma Industry Experience, working in International European and Chinese, Generic and CDMO companies. Broad experience in multiple roles in Process Chemistry R&D, Tech-Transfer, Scale-up, Pilot-Scale and Commercial cGMP Manufacturing, Procurement, Management, Product Development and Licensing and Business Development. Strong Scientific and Business Management backgrounds and relevant HSE, Quality and Regulatory experience. Has been a qualified cGMP and ISO14001 auditor and participated as industry representative in RX360 and EFCG (European Fine Chemicals Group – a pharma industry CDMO lobby group, member of the broader European Chemical Industry Council (CEFIC). He represented the EFCG at USFDA GDUFA II implementation meetings and Regulatory Science meetings. Championed the adoption of Science Based targets (SBTi), Ecovadis Sustainability ranking and joined the Sustainable Procurement Pledge (SPP).
INTERNATIONAL PHARMACEUTICAL INDUSTRY 15
Subsection: CDMO
An Integrated State-of-the-Art Site for ADC DS and DP, from IND to Commercial Supply Antibody-Drug Conjugates (ADCs) represent one of the most powerful and complex classes of cancer therapies ever developed – combining the precision of a monoclonal antibody with the potency of a cytotoxic payload. Their multi-step, hazardous manufacturing process has made specialist ADC CDMO manufacturing one of the fastest-growing and most technically demanding segments in pharmaceutical outsourcing – and a critical strategic priority for both large pharma and emerging biotech sponsors. The global ADC contract manufacturing market reached an estimated USD 11.08 billion in 2026 and is projected to expand to approximately USD 29.65 billion by 2035, at a CAGR of 11.56%, according to Towards Healthcare (2026). The market is expanding steadily, fuelled by rising oncology therapies, expanding clinical pipeline, sustained commercial revenue from approved products, increasing R&D investment from both large pharma and emerging biotech, and the emergence of next-generation ADC technologies – including site-specific conjugation, bispecific ADCs, and novel payload classes – that demand more advanced CDMO platforms. The availability of CDMOs that genuinely understand protein engineering, conjugation technologies, and next-generation ADC formats is far more limited than generalpurpose biologics capacity – and that scarcity is what positions specialist CDMOs as strategic partners rather than commodity suppliers. The complexity of ADCs creates several manufacturing challenges. Traditionally, producing an ADC required multiple CDMOs, multiple quality systems, multiple technology transfers, and multiple regulatory inspections – across different sites, different countries, different standards. As the first CDMO in the world to offer a fully integrated supply chain for ADCs under a single roof and a single quality system, BSP 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY
delivers Drug Substance and Drug Product manufacturing in seamless operational continuity. At its Latina, Italy site, BSP Pharmaceuticals has addressed a significant industry bottleneck in ADC manufacturing: a fragmented supply chain. The site co-locates drug substance (DS) conjugation and drug product (DP) fill-finish within a single facility under one quality system. This eliminates multiple inter-site transfers, reduces cold chain risks, improves traceability, accelerates batch release and regulatory preparedness, enhances worker safety when handling highly potent compounds, and shortens time to market. The result is a more resilient and efficient supply chain that supports the production of lifesaving oncology therapies. Consolidating Conjugation and Fill-finish at One Site Founded in 2006, BSP Pharmaceuticals is an Italian contract development and manufacturing organization (CDMO) specialising in the production of oncology, cytotoxic, and immunotherapy drugs for pharmaceutical and biotechnology partners. It operates from investigational new drug to commercial supply. The company currently manufactures 13 of the 19 ADCs approved for the commercial market and provides service support for more than one hundred bioconjugated clinical programmes. Traditionally, the critical steps needed to manufacture an ADC are managed in separate, often geographically distant sites, resulting in a highly fragmented supply chain. Monoclonal antibodies are shipped from one facility, the linker-payload complex is shipped from another, and conjugation occurs at a third site. This DS is shipped again to a fill-finish facility to produce the DP. Each handover runs the risk of cold chain interruption, transportation problems, and delays that affect product integrity and delivery to patients. The Latina facility consolidates conjugation and fill-finish operations within a single facility, which represents a fundamental shift in the structure of ADC supply chains. It is unusual to have a fully integrated supply chain for commercialscale DPs as complex as ADCs, making the
Latina unique in the industry. Monoclonals, cytotoxin-linkers, and intermediates are protected from exposure risks, handling complexity, and extended storage. Cold chain logistics are streamlined, while on-site storage as low as -80oC eliminates the need to move temperature-sensitive materials between sites. All critical components are received at one site, which means fully packaged DP is produced and shipped through a unified supply chain. “Inter-site transfers of highly potent, cytotoxic intermediates introduces exposure risk, cold chain challenges, and the potential for quality deviations during transit,” said Aldo Braca, Chief Executive Officer and President. “By housing both steps at Latina, end-to-end integration compresses the overall manufacturing cycle, strengthens batch traceability, and gives us a unified point of accountability for the entire ADC production process.” A Single Quality System for DS and DP A single quality management system (QMS) across the entire manufacturing process delivers full traceability, improved compliance, and faster batch release, while harmonised documentation reduces complexity and drives higher quality outcomes. “Co-locating drug substance and drug product operations creates a continuous quality oversight loop that simply isn't achievable when the two steps are separated,” said Aldo Braca. “QC teams can monitor critical quality attributes – conjugation efficiency, drug-to-antibody ratio, aggregation levels – and immediately apply those insights to the downstream fill-finish process without the delays inherent in inter-site communication.” Any out-of-trend result detected at the DS stage can trigger a real-time review before the material advances, preventing quality risks from propagating. Shared analytical infrastructure also avoids the need to repeat or transfer testing between sites, reducing variability in results. “Ultimately, the proximity of drug substance and drug product operations fosters a culture of integrated quality ownership, where every team member Autumn 2026 Volume 18 Issue 3
Subsection: CDMO understands how their work connects to the final product delivered to patients,” said Aldo Braca. Accelerated Regulatory Pathway When DS and DP operations are split across multiple sites, regulatory agencies must inspect and approve each location separately. Each site requires its own set of manufacturing authorisations, SOPs, and QMS. Coordinating across those different regulatory frameworks adds considerable overhead and risk. By integrating DS and DP manufacturing, the Latina facility streamlines regulatory pathways for fast-track approvals, reduces post-approval changes, and speeds commercial readiness. “At Latina, inspectors can assess the full manufacturing journey in a single visit, from conjugation through final fill-finish,” said Aldo Braca. “There is one integrated quality system, one unified set of batch records, and one accountable manufacturing team. This transparency simplifies the inspection process for authorities, accelerates responses to queries, and reduces the likelihood of cross-site inconsistencies being flagged. It also streamlines CMC dossier preparation and post-approval change management, since changes affecting both drug substance and drug product can be addressed in a single regulatory submission.” Safety by Design The cytotoxic payloads used in conjugation are among the most hazardous substances handled in pharmaceutical manufacturing, and those handled at the Latina site have an occupational exposure limit (OEL) below 10 nanograms per cubic meter. Every transfer of these materials between facilities introduces occupational exposure risk, packaging complexity, transport hazards, and emergency response challenges across multiple jurisdictions.
Accelerated Time-to-Market One of the most significant timelines in ADC drug development is the period between clinical batch release and first patient dosing, or between regulatory submission and commercial launch. Any inefficiency in manufacturing, such as delays at batch handover, inter-site shipping, redundant QC testing, and misaligned release schedules, directly compounds patient wait times. The resilience of the Latina supply chain reduces these delays and has meaningful impacts on time to market. “Thanks to Latina's integrated supply chain, we have eliminated many of these points of inefficiency,” said Aldo Braca. “Batch release decisions are made with full visibility across both drug product and drug substance, without waiting for material to arrive from a remote site. This allows a faster, more agile response to demand fluctuations or clinical trial schedule changes. For innovative oncology therapies where urgency is critical, the ability to reduce cycle time without compromising quality is not just a competitive advantage, it is a patientcentred imperative.” BSP Pharmaceuticals has shown that the production of complex ADCs can be dependable and efficient while addressing one of the most critical challenges in oncology manufacturing. “The expansion of the Latina site establishes a new standard for supply chain resilience and rapid product delivery,” said Aldo Braca. “For patients and partners alike, it means a more reliable, predictable supply of complex, life-saving therapies.”
What makes BSP truly unique is the design and operation of its fully integrated manufacturing site, which combines integration, flexibility, scalability, and technological depth in a way that is unparalleled in the industry. The site offers an integrated system that ensures seamless coordination between development, drug substance manufacturing, conjugation, drug product manufacturing, fill finish, storage, cold chain management and quality control. This integration delivers multiple benefits: optimised material flows, enhanced product safety, and significant reductions in working capital, allowing clients to achieve faster, safer, and more costefficient pathways to market. The co-location of development laboratories, quality control facilities, and GMP manufacturing at multiple scales allows for a smooth scale-up process. Scientists and technical experts work in close collaboration, ensuring that every step of the journey from formulation development to commercial supply is aligned and optimised. This integrated approach minimises handover gaps, quickens FDA approval, one inspection for DS and DP, reduces costs, accelerates timelines, and increases the probability of success for complex bioconjugates and nextgeneration modalities. Flexibility of scale is another cornerstone of BSP’s offering, which provides a broad range of capacities that can adapt to the evolving needs of its partners. For conjugation, BSP has implemented scales from 40 grams up to 15 kilograms of mAb, enabling both small-scale clinical projects and large-scale
“The design of the Latina plant confines the handling of HPAPI-conjugated intermediates to one containment-engineered environment with a highly trained workforce operating under a unified safety management system,” said Aldo Braca. “There is one containment strategy, one spill response protocol, one set of engineering controls – all optimised for ADC-specific hazards.” This consolidation dramatically reduces the number of touchpoints where exposure incidents could occur and enables a more proactive, coherent approach to occupational health across the entire production chain. www.international-pharma.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 17
Subsection: CDMO commercial production under one roof. This range of options demonstrates BSP’s ability to serve projects at every stage from early clinical batches to global commercial launches without requiring technology transfers to multiple facilities, optimising both timelines and budgets for clients. Whether a customer requires toxicology batches, small-scale GMPequivalent runs, or full commercial production, BSP provides a continuum of services that ensures consistency, quality, and speed. A critical enabler of this success is BSP’s internal technology transfer structure. Dedicated teams oversee projects from early development through PPQ, ensuring that knowledge, processes, and quality standards flow seamlessly across phases. This reduces the risk of scalability issues that often arise when products move from early to late stages, protecting both clients and patients from delays or failures. The company’s commitment to innovation is also evident in its approach to risk-sharing in product development. By lowering the barriers to entry for promising therapies, BSP ensures that more breakthrough products can advance to clinical testing and ultimately to patients: a tangible support from BSP to projects that carry high levels of scientific and financial uncertainty. BSP not only fosters innovation but also strengthens long-term partnerships built on trust, transparency, and shared objectives. To back this vision, BSP’s Board has approved a €700 million financed expansion plan, adding four new conjugation suites and 4 drug product filling lines. By 2030, DS
capacity will increase (to over 4,700 Kg mab/ year), while DP capacity will reach over 155 million units annually. These investments will support ADCs, liposomes, RNA-based onco-vaccines, and advanced polypeptides, reinforcing BSP’s role as a global leader in oncology, immunotherapy, CNS and type 2 diabet therapeutics. BSP Pharmaceuticals combines scientific excellence, operational flexibility, and a collaborative spirit. Its fully integrated and scalable site, extensive technical capabilities, innovative risk-sharing approach, and unwavering commitment to patient safety
clearly set BSP apart. By enabling faster, safer, and more efficient development and commercialisation of critical oncology and specialty medicines, BSP not only advances the biopharmaceutical industry, but also contributes to the global mission of improving patient outcomes. REFERENCES 1. 2.
https://pharmasource.global/content/antibodydrug-conjugates-adc-contract-manufacturingmarket/ https://www.towardshealthcare.com/insights/ antibody-drug-conjugates-adcs-cmo-andcdmo-market-sizing
Aldo Braca Aldo is the President and founder of BSP Pharmaceuticals since 2006, year of the incorporation of the company. He is a member of the Advisory Board of "PM & Partners", a private equity firm specialised in investing in small and middle-sized companies. Aldo has been President of Patheon Europe, a subsidiary of Patheon Inc., since 2010 and developed the company in Europe starting from 1999. Aldo is trained as an Industrial Chemist. He is a graduate of Advanced Management Program at the Harvard Business School.
18 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Autumn 2026 Volume 18 Issue 3
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 19
Subsection: CDMO
Innovative Formulations and Processing Technologies for Oral Drug Delivery Oral drug delivery remains one of the most important and widely adopted routes of administration in pharmaceutical development. Tablets and capsules continue to offer clear advantages in terms of patient acceptance, convenience, stability, scalability and cost-effective manufacture. Yet the science behind oral dose development has changed significantly. Today’s oral medicines are increasingly expected to do more than deliver an active ingredient in a conventional immediate-release format. They must overcome solubility and bioavailability limitations, support challenging drug substance properties, enable modified or targeted release, align with paediatric and patient-centric needs and transition efficiently from early clinical supply to commercial-scale manufacture. This evolution is being driven by the changing nature of pharmaceutical pipelines. Many contemporary small molecule candidates present formulation challenges, particularly poor aqueous solubility, limited permeability, complex solid-state behaviour or potency-related handling requirements. Poor solubility remains one of the most persistent barriers in drug development, making early understanding of API characteristics essential to maximising solubility, stability and therapeutic impact. At the same time, the industry is seeing increased interest in more complex oral dosage forms, including modified-release systems, paediatric-friendly presentations, liquid-filled capsules, amorphous solid dispersions and other enabling technologies designed to improve in vivo performance. For drug developers, the key question is no longer simply whether a compound can be made into a tablet or capsule. It is whether the selected formulation and process are sufficiently robust, scalable and clinically appropriate to support the product across its lifecycle. That requires a development strategy that integrates formulation science, material understanding, process engineering, analytical capability and regulatory foresight from the outset. 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Oral Delivery Remains Central – But Expectations Are Rising The continued dominance of oral solid dosage forms reflects their practical value. They are generally easier for patients to take than injectable therapies, comparatively stable during storage and distribution and suitable for large-scale production. However, the simplicity perceived by patients often masks the complexity involved in development and manufacture. As pipelines have shifted towards more challenging molecules, the oral dosage form has had to become more sophisticated. Recent industry analysis points to sustained growth in oral solid dose development, with innovation focused on improving drug efficacy, adherence and manufacturability through advanced delivery systems, modified-release technologies and formulation platforms that address bioavailability challenges. The sector is also seeing increased demand for CDMO support across formulation development, testing, analytical services, clinical supply and manufacturing as companies seek specialist expertise to manage greater technical complexity. In practical terms, this means oral dose development must balance speed with scientific depth. Early clinical programmes often require rapid delivery of fit-for-purpose formulations for first-in-human studies, while later-phase programmes require deeper product and process understanding, control strategies and scale-up pathways. The most successful programmes are those in which these requirements are not treated as separate phases, but as part of a continuous development pathway. The rise of targeted therapies and precision medicines is reshaping oral dose manufacturing. As products are increasingly developed for smaller patient populations, commercial volumes are often significantly lower than those associated with traditional blockbuster drugs. In response, manufacturers are adopting more flexible, small-scale production models, often utilising equipment and technologies traditionally associated with development-phase manufacturing. CDMOs have been at the forefront of this transition, investing in flexible infrastructure,
advanced processing technologies and contained high-potency capabilities that enable the efficient manufacture of small-volume, high-value medicines while supporting seamless progression from development to commercial supply. Bioavailability Enhancement: Addressing a Critical Development Challenge One of the most prominent areas of innovation in oral drug delivery is bioavailability enhancement. A high proportion of new chemical entities present poor aqueous solubility, which can limit absorption and make it difficult to achieve therapeutic exposure through conventional formulations. In these cases, simple blending, granulation and compression may not be sufficient. Instead, more advanced formulation strategies may be required to improve dissolution rate, maintain supersaturation, stabilise amorphous forms or enhance absorption. Amorphous solid dispersions, spray drying, hot melt extrusion, particle engineering, lipid-based systems and liquidfilled capsules are among the technologies increasingly used to address solubility and exposure challenges. Industry commentary has highlighted amorphous solid dispersions prepared through spray drying or hot melt extrusion as important tools for improving solubility and bioavailability in oral solid dosage development. These technologies are not interchangeable; each has advantages, constraints and development implications. Selection should be based on compound properties, target dose, stability profile, manufacturability, clinical objectives and commercial considerations. For example, spray drying can be valuable where rapid solvent removal is needed to generate an amorphous dispersion with improved dissolution characteristics. Hot melt extrusion may be suitable where the API and polymer system can withstand thermal and mechanical processing. Liquid-filled capsules, semi-solid-filled hard capsules and non-sterile oral liquids can provide efficient early-phase solutions for poorly soluble compounds, particularly where speed to clinic is a priority. Particle size reduction or other particle engineering Autumn 2026 Volume 18 Issue 3
Subsection: CDMO techniques may be appropriate where dissolution rate, content uniformity or downstream processability are limiting factors. The scientific challenge lies not only in selecting a technology, but in understanding the formulation system. Polymer selection, drug loading, residual solvent control, physical stability, recrystallisation risk, dissolution behaviour and scale-up feasibility must all be considered. The formulation must be robust enough to support clinical supply, but also capable of evolving into a commercially viable product. Processing Technologies: Where Formulation Meets Manufacturability Innovative formulation design must be matched by appropriate processing technology. Oral drug delivery success depends on the ability to manufacture a product reproducibly, at the right quality, and at the required scale. This is particularly important for complex formulations, highly potent compounds or products requiring tight control of critical quality attributes such as dissolution, assay, content uniformity, impurity profile, stability or release performance. Traditional oral solid dose processes, including blending, granulation, compression, encapsulation and coating, remain essential. However, the level of process understanding required has increased. Developers must understand how material attributes and process parameters influence product performance. This deeper understanding has also enabled the incorporation of novel and functional excipients that can enhance product performance while maintaining robust and reproducible manufacturing processes.
masking, moisture protection, enteric release or modified-release performance. Encapsulation may provide flexibility during early development, especially where dose range exploration is required. For potent compounds, contained processing and appropriate facility design are central to operator safety, product quality and crosscontamination control. Quality by Design and the Move Towards Deeper Product Understanding The regulatory and scientific direction of travel is clear: quality should be built into the product and process, not tested in at the end. ICH Q8(R2) provides a framework for pharmaceutical development and describes how greater understanding of formulation and manufacturing sciences can support flexible regulatory approaches. The FDA’s Q8(R2) guidance further describes the principles of Quality by Design, including the value of development knowledge and process understanding. For oral dosage forms, Quality by Design begins by defining the Quality Target Product Profile. What should the product do? What dose, release profile, stability, presentation and patient requirements must it meet? From there, developers identify critical quality attributes and assess which material attributes and process parameters may influence them. Design of experiments, risk assessment, predictive modelling and analytical characterisation can then be used to build a more complete understanding of the product and process.
This includes properties such as particle size distribution, polymorphic form, flowability, glass transition temperature, compressibility, moisture sensitivity and excipient compatibility. It also includes process variables such as mixing time, granulation endpoint, drying conditions, compression force, coating parameters and environmental controls.
This approach is particularly valuable when dealing with complex oral formulations. For a bioavailability-enhanced product, for example, the critical quality attributes may include amorphous content, dissolution profile, residual solvent, particle morphology, impurity formation and physical stability. For a modified-release tablet, they may include release rate, coating uniformity, tablet hardness, friability and robustness under different physiological conditions. For a highly potent product, containment, cleaning strategy and cross-contamination control become central to the development plan.
Advanced processing approaches can help address specific development challenges. Wet granulation may improve flow and content uniformity for low-dose products. Dry granulation can be advantageous for moisture- or heat-sensitive compounds. Coating technologies can support taste
A QbD approach does not necessarily mean longer timelines. In many cases, it can reduce risk by identifying potential failure points earlier, avoiding repeated reformulation and supporting more efficient scale-up. The value is in making development decisions based on scientific evidence rather than trial and error.
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Analytical Science as an Enabler of Oral Dose Innovation Analytical capability is often the unsung enabler of successful oral drug delivery. Innovative formulations require robust methods to characterise both the API and finished dosage form. This may include solidstate characterisation, assay and impurity testing, dissolution method development, stability studies, content uniformity, residual solvent analysis, water content, particle size analysis and physical characterisation of intermediate materials. For amorphous solid dispersions, analytical science is essential to confirm amorphous form, detect recrystallisation, monitor stability and understand dissolution behaviour. For modified-release formulations, discriminatory dissolution methods are critical to link in vitro performance with product quality and, where possible, in vivo behaviour. For paediatric formulations, analytical methods must often support dose flexibility, taste-masking assessment, stability and compatibility with administration routes. For potent compounds, analytical procedures must be aligned with containment and safe handling requirements. Patient-Centric Formulation: Beyond Manufacturability Innovation in oral drug delivery is not solely about overcoming technical development barriers. It is also about improving the patient experience. Patient-centric dosage form design considers how the medicine will be used in real life, including swallowability, dose burden, taste, dosing frequency, packaging, administration with food or liquids, and suitability for paediatric, geriatric or other specialist populations. Modified-release technologies can reduce dosing frequency and support adherence. Mini-tablets, multiparticulates, oral liquids or sprinkle formulations may help paediatric or dysphagic patients. Taste masking can be decisive for adherence, particularly in children. Smaller tablet size, improved coating or alternative capsule formats may make a meaningful difference for patients managing chronic therapy. The challenge is that patient-centric features must be scientifically and commercially feasible. A formulation that is ideal for the patient but unstable, difficult to manufacture or hard to scale will struggle to progress. Conversely, a formulation that is easy to manufacture but poorly suited to patient needs may not deliver the intended INTERNATIONAL PHARMACEUTICAL INDUSTRY 21
Subsection: CDMO therapeutic benefit in practice. The optimum development strategy therefore considers patient use, product performance and manufacturing reality together. This is especially important for products intended to move from early phase to commercialisation. Early development formulations may be fit for initial clinical assessment, but developers should maintain a view of the likely commercial presentation. Decisions around excipients, capsule versus tablet, liquid versus solid, release profile and packaging should be informed by the long-term target product profile wherever possible. Scalability: Designing with the End in Mind A recurring challenge in oral drug delivery is the transition from small-scale development to larger-scale GMP manufacture. A process that works well at laboratory scale may behave differently when batch size, equipment geometry, mixing dynamics, drying efficiency or compression speed changes. Scale-up risk can be particularly significant for complex formulations, low-dose products, poorly flowing materials, moisture-sensitive APIs or modified-release systems. Where precision medicines is driving towards lower commercial volume this is influencing how scalability is defined. Rather than simply increasing batch size, developers must ensure processes remain robust across smaller manufacturing scale and equipment. Flexible equipment platforms and process design are enabling efficient production for targeted therapies, orphan medicines and other lower-volume products, while maintaining the quality, control and supply reliability expected of commercial manufacture. Designing with scalability in mind does not mean over-engineering early clinical formulations. It means making informed choices that preserve future options. For example, selecting excipients with a strong regulatory and supply track record, understanding whether a process is likely to be transferable, choosing analytical methods capable of supporting later-phase control strategies, and documenting development rationale clearly. The Role of Partnership in Modern Oral Dose Development As oral formulations become more complex, the role of the CDMO is also changing. Sponsors are not simply looking for capacity; they are looking for scientific input, problem22 INTERNATIONAL PHARMACEUTICAL INDUSTRY
solving, regulatory awareness and practical manufacturing experience. The most effective partnerships are built around transparent technical dialogue. This includes early discussion of molecule properties, clinical objectives, dose projections, formulation risks, timelines, regulatory expectations and commercial ambitions. A capable CDMO should be able to challenge assumptions constructively. Is an immediate-release capsule sufficient for first-in-human studies, or is an enabling technology required? Is the selected bioavailability approach scalable? Are there stability risks that should be addressed before GMP manufacture? Is the analytical method sufficiently discriminatory? Can the process accommodate future dose strengths? Are there containment implications? What data will be needed to support regulatory submissions? These questions are not barriers to progress; they are safeguards against avoidable development risk. In oral drug delivery, speed is important, but speed without scientific understanding can create costly delays later. A disciplined development strategy can support both efficiency and robustness. Looking Ahead: A More Integrated Future for Oral Drug Delivery The future of oral drug delivery will be shaped by continued innovation in formulation science, processing technologies, data-driven development and patient-centric design. Artificial intelligence, predictive modelling and digital tools are expected to play a greater role in formulation screening and process optimisation, although these tools will need to be grounded in high-quality experimental data and practical manufacturing knowledge. However, the fundamentals will remain the same. A successful oral medicine must deliver the right dose, at the right rate, with
consistent quality, in a form that patients can use and manufacturers can reliably produce. Innovation is valuable when it solves a real development or patient problem. The goal is not complexity for its own sake, but purposeful formulation and process design. For companies developing oral medicines, the opportunity lies in integrating enabling technologies earlier, applying QbD principles pragmatically and selecting experienced development partners with the scientific and operational capability to support the product across its lifecycle. As pipelines continue to challenge conventional formulation approaches, this integrated model will become increasingly important. Advances in formulation science and processing technology are enabling developers to address increasingly complex molecules while delivering robust, scalable and patient-centric oral medicines. Oral drug delivery has always been central to pharmaceutical development. What is changing is the level of science required to make oral delivery work for today’s molecules and tomorrow’s patients. Through advanced formulation technologies, robust processing strategies and lifecycle-focused development, the industry can continue to expand what is possible through the oral route – delivering medicines that are not only manufacturable, but meaningful for the patients who depend on them.
Sander van den Ban Director I Operations, Manufacturing, Almac Pharma Services
Autumn 2026 Volume 18 Issue 3
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Subsection: CDMO
From OEL to Commercial Supply: Designing Robust High-Potency Oral Solid Manufacturing Highly potent APIs are becoming more significant across the pharmaceutical development pipeline. Market estimates vary, but the direction is consistent: the global HPAPI market hit around USD 29.87 billion in 2025 and forecasts growth to USD 48.29 billion by 2033[RG1.1], driven by demand for targeted medicines, oncology therapies and other potent molecules.1 For oral drug products, however, the challenge is not simply to handle HPAPI safely. Whether the intended medicine is a tablet, capsule, or liquid formulation, success depends on integrating toxicology, formulation science, process engineering, containment and lifecycle planning from the outset. An isolator, negative-pressure suite or stated occupational exposure band (OEB) may be an important part of the answer. None, in isolation, demonstrates that a product can be manufactured safely, reproducibly and at commercial scale. The more meaningful test is whether the proposed operating model protects people, prevents crosscontamination, preserves critical quality attributes and remains practical through development, technology transfer and routine supply. Starting With Exposure Containment discussions often begin with an OEB designation, such as OEB 4 or OEB 5. Although useful as an operational shorthand, OEBs are not universally harmonised across the industry and should not replace compound-specific assessment.
daily exposure (ADE), is relevant to the assessment of product carryover, crosscontamination and cleaning limits in multiproduct facilities. The no-observedeffect level may contribute to defining an acceptable daily exposure where appropriate toxicology data are available.
features. This risks missing the broader point: containment is the demonstrated performance of the complete operating system.
These distinctions have practical implications. Two products within the same broad OEB may require different containment strategies because they differ in batch size, particle characteristics, powder flow, dose, route of administration, process route and handling requirements. A fine, cohesive and electrostatically charged powder handled through multiple open transfers presents a different risk profile from a material processed through closed charging and transfer systems.
• •
A robust new-product-introduction process should therefore assess the molecule before it reaches the manufacturing floor. The review should bring together toxicology, pharmacology, OEL and PDE data, proposed batch size, formulation route, equipment requirements and operational tasks. A risk assessment can then identify where material could be released, where product may be retained, and what controls are required before development or manufacture begins. Containment as an Operating System For potent products, containment is often described in terms of equipment or facility
Exposure and cross-contamination risks should be assessed across four principal pathways:
• •
Airborne transfer of dust or aerosol. Mechanical transfer through equipment, materials or movement between areas. Personnel transfer, including garments, gloves and movement patterns. Product retention on contact surfaces, seals, components or difficult-to-clean locations.
The highest risks frequently occur at interfaces between operations. Material receipt, dispensing, charging, transfer, sampling, discharge, cleaning, maintenance and waste handling can all create exposure opportunities, even when the principal unit operation is enclosed. Primary containment should be positioned as close as possible to the material source. Suitable equipment operates under negative pressure and is designed to prevent release during normal processing. Secondary containment is then provided by the surrounding facility, including airmanagement systems, pressure cascades, airlocks, access controls, cleaning and decontamination areas, and appropriate filtration.
The starting point is the occupational exposure limit, or OEL: the average airborne concentration of an API considered acceptable over a defined period, commonly an eight-hour time-weighted average. The OEL defines the exposure outcome that a control strategy must achieve. It does not prescribe a particular piece of equipment, room classification or facility layout. Other toxicological limits also inform manufacturing decisions. Permitted daily exposure (PDE), also known as acceptable 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY
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Subsection: CDMO granule-size distribution, fines and final tabletability. Development must therefore establish conditions that produce not simply acceptable granules, but a consistent final dosage form with the required hardness, friability, disintegration, dissolution and content uniformity.
This layered model is more robust than relying on a negative-pressure room alone. It also provides a framework for evaluating what happens if containment is breached. Air handling, dust collection, room segregation and safe material flow are important, but their purpose is to support the primary barrier, not to substitute for it. The strategy must account for normal and abnormal operations. It is not enough to assess a process while equipment runs as intended. Teams should consider foreseeable interventions: material charging, sampling, container changes, clearing a blockage, responding to alarms, replacing components, cleaning and maintenance. A process that is technically enclosed but routinely requires manual intervention may introduce operational weakness. PPE remains important for work within a controlled environment and for response to a system failure. It should not, however, be treated as the primary containment barrier during normal operations. Where potency demands a high level of control, engineering and process design must do the bulk of the protective work.
charge, cohesiveness and flowability influence dusting, segregation and material hold-up. For low-dose products, containment must also protect blend uniformity and avoid transfer steps that increase segregation risk. Roller compaction illustrates the connection between formulation, process design and containment. In this drygranulation route, a powder blend is compacted between counter-rotating rollers into a ribbon, then milled into granules for tableting, encapsulation or sachet filling. It can be valuable where direct compression is unsuitable and wet granulation creates stability concerns, particularly for moisturesensitive, heat-sensitive or poorly flowing materials. Its integration with contained feeding, sealed transfer and milling can also reduce open powder handling. However, enclosure alone does not make the process robust. Compaction force, roller gap and speed, feed rate and milling conditions affect ribbon density,
The risk profile for oral liquids is different. They can improve administration and dosing flexibility, but may be more vulnerable to degradation and microbial growth, increasing demands on formulation design, preservation, packaging compatibility and dose accuracy. With potent APIs, the greatest containment risk is often at charging and wetting: once the material is fully wetted, airborne exposure potential is substantially reduced. Fine powders can disperse during transfer, and static charge may intensify dusting. Poorly controlled liquid addition can cause splashing or aerosolisation, while particle size, hydrophobicity and wettability can delay dispersion or cause clumping. Contained charging and closed processing must therefore be designed alongside order of addition, mixing energy, wetting rate and vehicle selection to achieve safe dispersion without compromising product quality or manufacturability. Building Containment into QbD Quality by Design provides a useful structure for integrating these decisions. It begins with the quality target product profile and identifies the critical quality attributes that the finished medicine must achieve. Development work then determines the critical process parameters that affect those attributes and establishes a proportionate control strategy.
Oral Formulation Changes the Risk Profile For oral products, formulation choice determines where and how containment must perform. The aim is not only to prevent material release, but to do so while maintaining the critical quality attributes of the finished medicine. For solid oral dosage forms, key risk points include dispensing, blending, milling, granulation, compression or encapsulation, sampling and cleaning. Fine powders can become airborne during charging and discharge, while particle size, electrostatic www.international-pharma.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 25
Subsection: CDMO For a high-potency programme, containment must sit within this framework. Early formulation and process studies should identify not only whether a product is technically feasible, but also where dust may be generated, what material-handling steps are required, where manual intervention may occur, how samples can be obtained and how equipment can be cleaned. This approach can reduce the risk of developing a process that performs well in a laboratory but cannot be transferred safely or efficiently into a contained manufacturing environment. Process analytical technology can help where inline or real-time information reduces the need to open equipment. Automation and programmable adjustments can also reduce manual intervention, provided the process is well understood and teams can manage deviations. The technology alone is not the strategy. Its value lies in delivering relevant process information and enabling timely control of conditions that affect both product quality and containment performance. For roller compaction, structured designof-experiments work can define how compaction force, roller gap, roller speed and feed conditions affect ribbon properties, granule attributes and final-tablet performance. This creates a stronger basis for establishing a design space and identifying the parameters that must remain under control as a process moves towards largerscale manufacture. Designing for Transfer and Commercial Supply A development batch conducted safely does not prove that a process is commercially sustainable. Scale-up may change material quantities, feed behaviour, dust load, transfer routes, cleaning burden and the practical nature of interventions.
and exposure potential. Identifying these differences early makes it possible to determine whether process parameters, equipment arrangements or operating procedures need to change before batches are executed at the receiving site. Cleaning is particularly important in multiproduct facilities. Potent materials may remain on product-contact surfaces, seals, transfer assemblies or inaccessible areas of equipment. A sound cleaning strategy begins during new-product assessment and is informed by toxicology, product characteristics, equipment design and the risk of carryover to the next product. Appropriate swab and rinse sampling methods, cleaning verification and lifecycle validation provide the evidence that the strategy remains effective. The aim is not necessarily to require a dedicated facility for every potent product. It is to establish whether the facility, equipment train, cleaning programme and operating procedures can provide an appropriate, demonstrable level of control.
Containment therefore needs to be addressed explicitly during technology transfer. The transfer package should cover more than formulation composition, manufacturing instructions and analytical methods. It should capture material flow, equipment interfaces, containment-critical steps, sampling requirements, cleaning rationale, waste handling and anticipated deviations.
Questions That Matter A stated OEB capability is only a starting point for sponsor due diligence. The questions that determine whether a manufacturing strategy is truly robust are more specific:
A gap analysis is valuable before transfer begins. Differences in equipment geometry, feeder design, vessel size, transfer routes and cleaning access can alter powder behaviour
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26 INTERNATIONAL PHARMACEUTICAL INDUSTRY
•
Has the compound been assessed using appropriate toxicological and pharmacological information before site acceptance? How will the OEL be translated into controls across dispensing, transfer, processing, sampling, cleaning and waste?
• • • • •
Does the process protect both operator safety and the product’s critical quality attributes? How are routine and non-routine interventions managed? What evidence supports containment performance at the intended scale and for comparable operations? How will containment-critical knowledge transfer from development into clinical and commercial manufacturing? How are cleaning, carryover and multiproduct risk managed over the product lifecycle?
High-potency oral manufacturing is not defined by an OEB label, a facility claim or one item of containment equipment. It is defined by the ability to translate toxicological requirements into a repeatable manufacturing system: one that protects operators, preserves product quality and remains viable from the first development batch through commercial supply. REFERENCES 1.
High Potency Active Pharmaceutical Ingredients Market (2026 – 2033) https://www. grandviewresearch.com/industry-analysis/highpotency-active-pharmaceutical-ingredientshpapi-market
David O’Connell Director, Scientific and Technical Affairs at PCI Pharma Services.
Autumn 2026 Volume 18 Issue 3
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Subsection: CDMO
AI in Lyophilised Product Development: Opportunities and Limitations Artificial intelligence (AI) is beginning to influence many aspects of pharmaceutical development, including areas once thought too specialist or product-specific for generic digital tools. In lyophilisation (also known as freeze-drying), AI can already help teams frame protocols, suggest first-pass cycle parameters and organise early technical thinking more quickly. That makes it useful, particularly when a project is still taking shape and development teams are deciding what to test first. Yet freeze-drying remains a process governed by formulation behaviour, critical temperature data, equipment characteristics and product quality requirements that cannot be inferred reliably from pattern recognition alone. For scientists working on biologics, vaccines, peptides and other sensitive products, the key question is not whether AI has a role, but what are its limitations. Used well, it can support the early stages of development. Used uncritically, it can create false confidence in outputs that still require experimental confirmation and expert interpretation. Why AI is Entering Lyophilisation Process Development Artificial intelligence has entered pharmaceutical workflows because it offers the speed research and development teams are keen to harness. AI can save valuable time by summarising information quickly, organising technical ideas into a useful framework, and generating draft protocols and project reports. As a niche part of this drug development workflow, freeze-drying is no exception. Lyophilisation projects involve recurring questions around cycle design, formulation options, analytical methods, equipment choice and scale-up strategy, so it is unsurprising that AI is now being tested as a practical support tool in this area. When asking current AI Large Language models, a scientist can receive a draft cycle, a list of analytical considerations or a summary of typical formulation factors within seconds.
While AI can help structure analysis and identify patterns in the information available, it does not yet understand how a specific formulation behaves under freeze concentration or where a true process limit lies for lyophilisation. “What matters in freeze-drying is not whether a lyophilisation cycle looks plausible, but whether it stands up to product-specific data, experimental testing and the realities of scalable manufacture,” confirms Dr Kevin Ward. Where AI Can Genuinely Help For that reason, the real value of AI is not to completely replace the role of scientists, but to act as a tool to increase efficiency in the R&D workflow. The strongest use case for AI in freeze-drying is at the front end of development, where it can help a team create a sensible starting framework before experimental work begins. That might include drafting protocols, creating Gantt charts for
project timelines, generating a list of common excipients for formulation development, or suggesting a rough first-pass cycle concept for discussion. It can also help non-specialists understand the terminology and ask more informed questions before speaking with scientists, engineers or CDMO partners. That can be especially useful in cross-functional teams, where discussions often involve people from formulation, analytical, manufacturing and regulatory backgrounds. Even so, its role needs to stay in proportion. AI works best as a tool for early thinking, communication and preparation. It is far less reliable when its outputs are treated as evidence-based conclusions. Why Freeze-Drying Remains ProductSpecific In early development, AI is most useful as a practical starting point: it can help teams move faster, but it cannot replace scientific
However, these useful responses should not be confused with scientific understanding. 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY
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Subsection: CDMO judgment. That matters in lyophilisation, where plausible outputs can be accepted too quickly if they are not rigorously tested, and where the knowledge base is niche and not readily available online. Freeze-drying remains highly product-specific, with the physicochemical behaviour of each formulation shaping what kind of cycle is safe, robust and commercially viable. Monoclonal antibodies, peptides and vaccines may all require lyophilisation for stability, but they cannot be developed using identical process. Even with a purposebuilt formulation, confident cycle design still depends on understanding the thermal properties of the mix and its associated critical temperatures such as collapse temperature, eutectic melting and glass transition. Without that data, the process window is inferred rather than defined. That is why analytical techniques such as Freeze-Drying Microscopy (FDM) – Lyostat analysis – and Modulated Differential Scanning Calorimetry (MDSC) remain central to development: they provide productspecific data rather than generalised assumptions. They help establish suitable product temperatures during the freezedrying process; whether additional annealing steps are required for largely crystalline systems; and what margin may exist between a robust process and a risky one. Equally important is the empirical evaluation that follows lyophilisation. Cake appearance, residual moisture and reconstitution behaviour are core indicators of whether the chosen process has produced a usable and stable product. AI models can describe these considerations but cannot replace the experimental work required to define them for a novel formulation. This limitation goes to the heart of why lyophilization remains a hands-on scientific discipline rather than a text-generation exercise. Formulation, Scale-Up and Regulatory Limits The same principle applies to formulation development. Though AI can be a useful copilot in the earliest stages of cycle thinking, formulation work is where that role narrows considerably. A wide range of excipients are used to modify certain aspects of a liquid formulation to make it ‘lyo-ready’, with a goal of improving functionality, stability, mechanical strength and solubility in the dry state. Formulation design requires an understanding of molecular behaviour, excipient interactions, physical stability, chemical stability and how the product must perform after drying and reconstitution. How these excipients interact with the liquid 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY
formulation is extremely product specific, and current AI systems lack the intricate knowledge to design these formulations from scratch. A proposed formulation may sound plausible in theory but prove unsuitable once tested because it protects one quality attribute while compromising another; supports acceptable cake structure while introducing problems in reconstitution; or appears stable under only specific conditions. These problems cannot be resolved reliably through generic pattern matching but depend on data, interpretation and trade-offs. Formulation development therefore remains rooted in laboratory work and expert review, with AI-generated formulation suggestions treated with caution. Unlike a broad process outline, a formulation recommendation can imply a level of precision and suitability that simply has not been earned. Another area where AI reaches its limits is equipment and scale-up. Freeze-drying happens on real systems with their own behaviour, constraints and performance characteristics. Not all freeze-dryers operate in the same way, and those differences become increasingly important when a process moves from laboratory feasibility to pilot, clinical or GMP manufacture. Shelf heat transfer, condenser capacity and chamber pressure all influence how a cycle performs in practice. A generic cycle may look technically possible but still fail to deliver the desired balance of product quality, reproducibility and efficiency when transferred to a specific machine or different laboratory environment. This is one of the clearest examples of the gap between plausibility and robustness. An AI-generated cycle may include temperatures
and pressures that appear sensible at first glance and even avoid obvious technical errors. Yet if it cannot account for the behaviour of a given system, it cannot reliably predict how long drying will take, how evenly the load will behave, or whether product temperature will track safely through the critical parts of the cycle. All of these variables will change at different scales, with larger batch sizes having different thermal properties (greater thermal lag and longer drying times), meaning a cycle developed for 1000 vials may not be suitable for a batch of 10000 vials. Predictions can be made by machine learning models to determine additional drying times/ temperature changes, but these conditions will always need to be validated in real-world environments. Differences in equipment type and batch size affect throughput, cost, transferability and confidence in the process. A development team needs a cycle to perform consistently and do so within an acceptable commercial framework. That level of judgment still depends on experience, data and equipmentspecific understanding. Regulatory and quality considerations reinforce the same conclusion. One of AI’s most convincing traits is that it can produce language that sounds polished, structured and professional. In technical and regulated environments, that can be helpful for drafting and organisation but can also be misleading. AI models do not always distinguish well between robust scientific information and weaker source material, especially as peer-reviewed literature in the field of lyophilisation is not as abundant as other sections of the pharmaceutical industry. The result can be inconsistency, overconfidence Autumn 2026 Volume 18 Issue 3
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 31
Subsection: CDMO or recommendations that require substantial correction. In pharmaceutical development, regulators and quality teams are interested in whether the underlying process understanding is real, traceable and supported by data. Documentation is only as strong as the development logic behind it. This is particularly relevant in areas such as CMC (Chemistry, Manufacturing, and Controls) strategy, analytical validation planning and technology transfer. AI may assist with drafting internal text or helping teams structure a submission narrative, but it does not remove the need for scientific ownership. Development decisions must still be justified through evidence and process choices understood in context. Transfer activities must still reflect what the product and equipment have actually shown in practice. In that sense, AI can speed up the packaging of information, but it cannot replace the responsibility carried by scientists, engineers and quality professionals. The more regulated the environment, the more important that distinction becomes. A Practical Comparison: AI Machine Learning Model Versus Expert Design A useful way to assess these boundaries is through direct comparison. In a case study ChatGPT 4 was prompted as follows: “Simulate a freeze-drying cycle trace for a 10% Dextran solution in a DIN10R Vial with a 2ml fill and present as a graph”. The output was then directly compared to a recipe designed by experienced lyophilisation scientists for the same concentration, fill volume and container size.1 The comparison is valuable because it moves the discussion away from abstract debate and into a real development scenario. Instead of asking whether AI can provide recommendations about the freeze-drying process, it asks whether AI can fully simulate a cycle that is genuinely efficient and robust in practice.
Figure 1: Graph showing cycle designed at Biopharma Group
Based on that comparison, the answer is nuanced. The AI-generated output was not worthless: on the contrary, it provided a reasonable starting point and included viable shelf temperatures and chamber pressures. This is significant, as it shows that AI can already contribute something useful at the beginning of a project. It can produce a shape for discussion, and in some cases that may save time. Where the limitations became more obvious was in the detail that separates a draft from a development-ready process. In the case study, the simulated recipe was less reliable in its representation of product temperature change over time, the length of the secondary drying step and the overall cycle duration. Those issues impact directly on cycle efficiency, process confidence and how practical the recipe would be in a real setting. This can also lead to product failure by providing process parameters that are not just inefficient, but unsuitable for the specific product being freeze-dried.
Figure 1: Graph showing simulate freeze-drying cycle conditions using ChatGPT 4 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The reported outcome was that the expert-designed cycle produced visually excellent cakes using a process approximately half the length of the simulated AI cycle. That is the most telling part of the exercise. It suggests that AI can help establish a starting framework, but not yet the kind of optimised, experimentally informed process that experienced scientists can create when working from data and practical understanding. Put another way, the AI cycle was plausible, but the expert cycle was purposeful. “Efficiency matters in lyophilisation,” emphasises Dr. Ward. “A cycle that is unnecessarily long can affect capacity, cost and commercial viability. For a development team, the difference between a workable concept and an efficient, scalable process is often where the real value lies.” The case study also highlights a broader lesson. AI is most convincing when it produces outputs that are close enough to good practice to look dependable. That is precisely why disciplined use matters. When a result is broadly reasonable, the temptation is to move forward without sufficient challenge. In highly specialised development work, this is where risk begins. The real danger is that AI can generate answers that appear sufficiently credible to delay the moment when deeper scientific scrutiny is applied. Where AI Fits Today A more productive way forward is therefore neither uncritical enthusiasm nor blanket rejection. AI should be used in lyophilisation in proportion to what it can genuinely do Autumn 2026 Volume 18 Issue 3
Subsection: CDMO well. At present, that means helping teams begin faster, structure ideas more clearly and prepare for experimentation more efficiently. It does not mean bypassing formulation studies, critical temperature
determination, empirical cycle development or equipment-specific review. A sensible workflow is AI-assisted rather than AIdirected. The tool can support preparation and communication, but scientific decisions
should remain firmly anchored in data-led human judgment. Viewed in that light, current machine learning models already have a meaningful place in freeze-drying cycle development. It can reduce friction at the start of a project and make some technical tasks more accessible. At the same time, lyophilisation remains a product-specific, evidence-driven process in which performance, quality and transferability cannot be secured through generic outputs alone. For all the progress AI has made, there is still no substitute for the combination of analytical testing, practical development knowledge and critical scientific interpretation that robust freeze-drying requires. REFERENCES 1.
‘Leveraging AI as a tool for freeze-drying process development’ at https://biopharmagroupcdmo. com/articles-resources/leveraging-ai-as-a-toolfor-freeze-drying-process-development/
Sam Woodyard Sam Woodyard is a Research Scientist at Biopharma Group, specialising in freezedrying formulation, cycle development, project management and pre- and postlyophilisation analysis.
Erin Kuhn Erin Kuhn is Head of Pharma R&D Sales at Biopharma Group, supporting pharmaceutical companies with the handling, processability and scalability of liquid and freeze-dried formulations.
Dr. Kevin Ward Dr. Kevin Ward is Director of R&D at Biopharma Group, with extensive experience in freeze-drying process development, formulation support and analytical characterisation across pharmaceutical applications.
www.international-pharma.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 33
Packaging
Automated Print Inspection in Pharmaceutical Packaging – From Batch Release to Data-Driven Quality Control Pharmaceutical packaging occupies a critical position in the product lifecycle. From both a regulatory and quality control perspective, it is a critical component of the finished medicinal product. Errors in labelling, content information, 1D/2D codes, or Braille embossing can trigger product recalls and, in severe cases, directly endanger patient safety. Incorrect codes can also compromise traceability systems for medications throughout the supply chain, with significant downstream implications for pharmacovigilance and serialisation compliance. Against this backdrop, automated print inspection systems have become the established standard in modern pharmaceutical packaging, replacing time-consuming and error-prone manual visual inspection. These systems deliver standardised, reproducible inspection results and are capable of simultaneously assessing print image integrity, code legibility and grading, and Braille embossing compliance in a single pass. Beyond efficiency gains, they generate comprehensive, audit-proof inspection reports. The inspection data accumulated by these systems represents a largely underutilised asset that, when systematically consolidated and analysed, can yield significant insights into process quality, recurring defects, and systemic risks. Regulatory Framework Any use of automated inspection data within a pharmaceutical quality context must be grounded in the applicable regulatory framework. Two primary regulatory instruments define the requirements for computer-based inspection systems and their data outputs: In Europe, EU GMP Annex 11 and Annex 15 are most directly applicable. Annex 15 requires that quality-critical systems and processes be formally qualified (for systems) and validated (for processes), with supporting documentation maintained on a risk-based basis. Packaging quality characteristics must be reproducibly present and systematically tested. Annex 11 governs computer-based systems, including complete and consistent 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY
data recording, traceability, protection against unauthorised access or alteration, regular data backup, and the maintenance of an audit trail. Inspection decisions and batch release actions must be documented in an auditproof manner. Inspection reports, typically stored as PDF files immediately upon test completion, satisfy these requirements by default, though digital backup of extensive reports is advisable. In the United States, 21 CFR Part 11 (in effect since 1997) sets out the equivalence of electronic records and signatures with their paper-based counterparts. Key requirements applicable to inspection systems include system validation (§11.10(a)), access controls (§11.10(d)), audit trails (§11.10(e)), sequential use of test steps and status indicators (§11.10(f)), and documented user training and qualification (§11.10(i)). A significant regulatory gap is identified: neither Annex 11 nor 21 CFR Part 11 explicitly addresses the procedures for retrospective analysis or secondary use of inspection data. This gap represents both a limitation and an opportunity, as there is substantial analytical potential between regulatory minimum requirements and datadriven quality assurance. Types of Data Generated Modern automated print inspection systems operate on the principle of digital comparison: a camera or scanning line captures the actual printed image, which is compared pixel by pixel against a pre-approved digital template (the "golden master"). Deviations exceeding defined tolerance thresholds are flagged for user evaluation or automatically rated as failures depending on system configuration. All systems generate several structured categories of data. Understanding the analytical potential of inspection data requires first mapping the categories of records produced by modern print inspection systems. •
Unit-level inspection records include a unique identifier (item or batch number), an automatically generated timestamp, an overall pass/fail result, results for each inspected feature (artwork, codes, Braille), any deviations between the approved template and the inspected sample, and quantitative measurements
such as code grading values and Braille dot heights. •
Batch-level reports aggregate individual unit tests and include count data (total samples, rejection rates, error type frequencies) as well as trend data. For example, how rejection rates increased progressively across a batch, at what points errors occurred most frequently, and how error types changed over the inspection run.
•
Audit trail and event logs record system start/stop events, user actions, parameter changes, and modifications to inspection configurations. Although primarily required for regulatory purposes, this contextual data is critical for analysing anomalies and nonconformities.
•
Pixel-level difference data is generated through digital comparison of an approved print template (the "golden master," typically a structured PDF) against the captured print image. The raw data of high value for root cause analysis shows not only the occurrence of a deviation but its precise location and magnitude.
•
Quantitative code quality metrics are reported in accordance with ISO/IEC 15416 (linear barcodes) and ISO/IEC 15415 (2D codes), providing graded assessments (A to F) for parameters such as modulation, decodability, and print quality. Braille inspection systems generate analogous quantitative outputs, including dot height deviations, grid conformity, and geometric measurements.
Retrospective Analysis: Opportunities and Application Areas The systematic cross-batch analysis of inspection data is not conceptually novel. Statistical process control (SPC) has been standard practice in semiconductor manufacturing and other high-volume, highly automated sectors for decades. Its application to pharmaceutical packaging inspection data, however, has been limited despite the availability of a suitable data foundation. Several factors contribute to Autumn 2026 Volume 18 Issue 3
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Packaging this gap: inspection systems have historically been optimised as approval tools rather than analytical platforms; the necessary data infrastructure has only recently been established as companies transition from manual to automated inspection; and the methodological frameworks for analysing this data within a GMP context are not yet widely embedded in quality management practice.
can be linked to change events such as supplier changes, maintenance intervals, or process modifications. 3.
Once these conditions are addressed, retrospective analysis opens several concrete opportunities: 1.
2.
Identification of recurring defects: Statistical evaluation across batches can distinguish systematic error patterns (e.g., consistent legibility failures for a specific code type or print deviations in a defined region of a carton) from random process variation. Assessment of process stability: Continuous evaluation of quantitative measurement variables, such as code print quality grades or Braille dot height measurements, over extended time periods allow determination of whether a packaging line is operating within its qualified process limits. Deviations correlated with specific time points
36 INTERNATIONAL PHARMACEUTICAL INDUSTRY
4.
Support for qualification and validation: Installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification (PQ) are required during initial system of qualification. Retrospective inspection data from routine production can provide supporting evidence of sustained process performance within PQ parameters, strengthening both initial validation and periodic revalidation. Systematic ongoing data evaluation expands the evidentiary base compared with relying solely on discrete revalidation batches. Risk Assessment and CAPA Support: Failure Mode and Effects Analysis (FMEA) in packaging processes is typically qualitative. Inspection data enables quantitative estimation of defect occurrence frequencies, providing an empirical basis for risk prioritisation. Corrective and Preventive Action (CAPA) effectiveness can similarly be objectively demonstrated by showing a statistically significant reduction in the frequency of the addressed failure mode following implementation.
Analytical Methodology The analysis described above can be conducted using a range of statistical and data management approaches. Method selection must be appropriate to the data type, the analytical question, and the regulatory context. For pass/fail data, statistical process control methods are the primary tool. It is suited to statistical process control methods, enabling scrap rate calculations over time and differentiation between special-cause events and natural process variability. Commoncause variation can only be reduced through systematic process improvement; specialcause events require targeted investigation and, where appropriate, CAPA. Quantitative measurements (code grades, Braille dot heights, pixel deviations) enable the calculation of sample statistics for comparison against specification limits, enabling assessment of whether processes are operating within specification limits and whether trends toward the specification boundary are emerging. The temporal structure of inspection data is of particular methodological importance. Inspection data is time-bound, and trends can only be identified if the temporal context
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 37
Packaging is preserved and incorporated into the analysis.
applicable to blood products and certain biologics.
In some cases, calculating rates is the method of choice, for instance, when output volumes vary between batches or time periods; absolute defect counts must be normalised to total units inspected to permit valid comparisons.
A general implementation pathway is described in five steps:
Finally, data quality considerations must be addressed explicitly. Inspection data generated under GMP conditions is generally of high quality, given the requirements of Annex 11 and 21 CFR Part 11. However, events such as maintenance, reference file updates, or changes to inspection parameters may introduce discontinuities in the measurement series. A rigorous analysis incorporates this contextual information and adjusts interpretations accordingly.
1.
Inventory of existing inspection data across systems
2.
Formulation of a specific research question before analysis begins
3.
Data preparation, including retrieval, supplementation with contextual metadata (batch, line, product, time period, change events), and format conversion – often the most time-consuming step
4.
Statistical analysis interpreted within the context of inspection conditions, treating identified correlations as hypotheses
requiring further root cause investigation rather than as proof of causation 5.
Documentation of analysis results in accordance with Good Documentation Practice (GDP)
Limitations A balanced assessment of retrospective inspection data analysis requires acknowledging its inherent limitations. First, inspection systems can only detect what they are configured to inspect. If inspection parameters or tolerance thresholds are not appropriately set for the relevant risks, the resulting data – however voluminous – cannot provide a complete picture of process performance. Data analysis cannot compensate for deficiencies in system configuration.
Infrastructure and Implementation Practical implementation of data analysis depends on several infrastructure conditions. Inspection data must remain accessible and analysable beyond the batch release period, which is not always the case – some systems store data locally in proprietary or archive-optimised formats unsuitable for cross-batch analysis. Integration into databases and the use of standardised data formats are prerequisites. Regulatory data retention requirements must also be satisfied throughout: in Europe, records must typically be retained for at least one year after the product's expiration date, with longer periods
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Packaging Second, statistical analysis identifies correlations, not causes. Detecting a recurrent defect pattern of the data is the beginning of an investigation, not its conclusion. Root cause analysis requires process expertise, contextual knowledge, and targeted investigation; data analysis can direct and support this process, but cannot replace it. Third, the validity of retrospective analysis depends on data continuity and consistency. Changes in inspection systems, modifications to inspection parameters, or incomplete archiving can introduce discontinuities in time series data that limit the interpretability and comparability of results across time periods. Conclusion Automated inspection systems satisfy established regulatory requirements for audit-proof documentation of print quality, codes, and Braille in pharmaceutical packaging. The structured data these systems generate, however, exceeds its current use as a documentation and batch release tool. When systematically aggregated, temporally organised, and analysed using appropriate statistical methods, this data can support identification of systematic error patterns, objective process stability assessment, qualification and validation activities, and empirically grounded risk management. The primary gap is not in available data, but in the systematic transition from archiving to active analysis, a transition expected to gain regulatory and operational importance as pharmaceutical production continues to digitise and as regulatory focus on data integrity and continuous improvement intensifies.
Dr. André Schwarz Dr. André Schwarz is Director of Marketing, Documentation & Validation Support at EyeC GmbH, a Hamburg-based provider of print inspection systems. He studied German language and literature, political science, and law in Marburg/Lahn, and earned his doctorate in modern German literature from Philipps University. After working as a journalist in online and print media, he joined EyeC in 2016 as Technical Writer and computer system validation expert, taking on his current role in 2022.
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Packaging
Child-Resistant Packaging: Balancing Safety, Adult Access and Product Performance Child-resistant packaging is an important consideration in the development and commercialisation of certain pharmaceutical products. Its fundamental purpose is to make access significantly difficult for young children while allowing adults to use the package properly. Despite declining birth rates in many developed markets, demand for child-resistant packaging continues to grow. Industry analysts have pointed to a phenomenon sometimes described as “risk concentration per household”, where fewer children may be exposed to a growing number of potentially hazardous products within the home.1 Growing Demand for Child-Resistant Packaging Industry experts and market data point to a phenomenon known as "risk concentration per household," where there are fewer children in the household, but households now contain a greater number of prescription medications, OTC products, cannabis-related products, and other potentially hazardous substances.1 The primary drivers include: •
Multi-generational households that increase interaction between children and medications and other products used by older adults
•
Expanding regulations that continue to broaden the categories requiring childresistant packaging
•
The emergence of look-alike products such as cannabis edibles and concentrated household products, and
•
Growing expectations for sustainable and user-friendly packaging solutions.
Pharmaceuticals account for a substantial share of the child-resistant packaging market, while North America remains one of the most established markets for child-resistant packaging due to its long-standing regulatory framework.2 Together, these developments have made packaging strategy an increasingly important consideration for pharmaceutical manufacturers. 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Regulatory Expansion Across Product Categories Over the past decade, the scope of products subject to child-resistant packaging requirements has continued to expand in several markets. While prescription medicines have long been associated with safety packaging measures, regulatory authorities are increasingly evaluating additional product categories based on risk profiles, active ingredients and potential for accidental ingestion. This trend is particularly visible in consumer healthcare products, cannabisderived formulations and certain highconcentration products. As new therapies are introduced and self-administration becomes more common, packaging is expected to contribute not only to product protection but also to risk mitigation. For pharmaceutical companies, this evolving regulatory environment creates new challenges. Packaging decisions that were traditionally made late in the development process are increasingly being considered earlier, helping companies anticipate future requirements and avoid costly redesigns after product launch. Strategic Considerations for Packaging Development To address growing regulatory complexity while maintaining efficiency in product development, pharmaceutical companies are increasingly evaluating packaging solutions earlier in the development process. Considerations often extend beyond the packaging component itself and include device engineering, regulatory requirements, manufacturing capabilities and quality management systems. Early collaboration among development stakeholders can help reduce risk, facilitate compliance activities and support more efficient market introduction. Collaboration Across the Development Process As pharmaceutical products and drugdevice combinations become increasingly complex, packaging development often requires collaboration across multiple disciplines. Engineering, regulatory affairs,
manufacturing, project management and quality teams may all contribute to the design, qualification and commercialisation process. This multidisciplinary approach can help ensure that packaging systems meet performance, safety and regulatory expectations while supporting overall product development objectives. As drug-device combinations become increasingly sophisticated and regulatory requirements continue to increase, greater coordination between technical, regulatory and manufacturing functions is often required. Packaging components are no longer considered standalone elements but are assessed as part of the overall patient experience, product safety profile and lifecycle management strategy. Navigating Regulatory Requirements Regulatory requirements for pharmaceutical packaging continue to evolve across markets and product categories. As a result, companies must ensure that packaging and delivery systems are appropriately tested, documented and manufactured throughout development and commercialisation. This requires a strong understanding of safety-sensitive applications, evolving regulatory requirements, submission documentation, testing methodologies, and, where applicable, bioequivalence and compatibility considerations. Supply Chain and Manufacturing Considerations From a manufacturing perspective, supply chain security remains an important consideration for pharmaceutical companies. Whether for prescription medicines or OTC healthcare products, consistent product availability depends on reliable sourcing, manufacturing continuity and sufficient production capacity. Manufacturers are therefore increasingly evaluating supplychain resilience, operational flexibility and quality-system robustness when selecting packaging components and suppliers. Recent disruptions to global supply chains have further increased attention on manufacturing resilience and continuity planning. Pharmaceutical manufacturers Autumn 2026 Volume 18 Issue 3
Packaging are increasingly evaluating geographic manufacturing footprints, business continuity plans and raw material sourcing strategies when selecting component suppliers. The ability to maintain consistent quality while supporting demand fluctuations has become an important differentiating factor within the pharmaceutical packaging sector. Sustainability Considerations In parallel with safety requirements, pharmaceutical companies are facing growing pressure to improve the environmental profile of their packaging solutions. Regulatory developments, corporate sustainability commitments and increasing stakeholder expectations are driving interest in packaging systems that minimise environmental impact while maintaining product integrity and patient safety. For child-resistant packaging, sustainability can present particular challenges. Safety mechanisms often require additional components, specialised materials or more complex designs than conventional packaging formats. As a result, manufacturers must balance environmental objectives with the need to comply with established safety standards. Material selection has therefore become an important area of focus. Packaging developers are exploring opportunities to reduce material consumption, increase recyclability and optimise component design without compromising performance. At the same time, any design modifications must continue to meet functional requirements related to child resistance, usability and product protection. The industry is also examining broader lifecycle considerations, including manufacturing efficiency, transportation impacts and end-of-life management. While approaches vary between markets and product categories, the ability to integrate sustainability considerations into packaging development is becoming an increasingly important factor in long-term product strategies. Child-Resistant Nasal Drug Delivery Nasal drug products represent a particularly interesting area for child-resistant packaging development. Traditionally, many nasal delivery systems focused primarily on dose accuracy, reliability and patient usability. However, growing regulatory attention and a broader range of active pharmaceutical ingredients delivered through nasal routes are increasing interest in integrating childresistant features into these systems. www.international-pharma.com
Child-resistant features are designed to make access significantly more difficult for young children while remaining accessible and easy to use for adults, including older patients.
Unlike conventional tablet packaging, nasal delivery systems combine packaging and drug-delivery functions within a single device. Consequently, child-resistant features must be incorporated without adversely affecting spray performance, dose consistency or product reliability, as is the case for instance in Silgan Dispensing’s Child Resistant Nasal pump HiMark™ CR. This introduces additional technical considerations during device development, including mechanism design, component tolerances and long-term functional performance. Manufacturers must also ensure that child-resistant mechanisms remain effective throughout the product lifecycle. Nasal products are frequently used multiple times over extended periods, making durability and consistent functionality important design objectives. Integrating safety features while preserving the delivery characteristics of the device requires careful engineering and extensive testing under representative use conditions. As a result, device developers continue to explore designs that combine integrated safety mechanisms with reliable drug-delivery performance throughout the product lifecycle. Balancing Child Safety and Adult Usability One of the most significant challenges in child-resistant packaging design is achieving an appropriate balance between safety and
accessibility. A package that is difficult for a child to open may also present challenges for elderly patients, caregivers or individuals with limited dexterity. This consideration is particularly important as populations age and healthcare systems increasingly support treatment at home. Many pharmaceutical products are intended for regular or long-term use, meaning packaging must remain functional and intuitive throughout repeated interactions. For this reason, modern development processes often incorporate usability assessments alongside child-resistance testing. Designers and engineers seek to understand how users interact with packaging systems in real-world situations, identifying potential barriers to access while preserving the intended safety features. The objective is not simply to prevent access by children, but to do so without creating unnecessary complexity for legitimate users. Achieving this balance requires careful attention to ergonomics, user feedback mechanisms and the overall patient experience. Technical Considerations in Development The development of child-resistant delivery systems requires expertise across multiple disciplines, including human factors engine-ering, materials science, regulatory affairs and pharmaceutical manufacturing. INTERNATIONAL PHARMACEUTICAL INDUSTRY 41
Packaging
Silgan's HiMarkTM Child Resistant Nasal pump
Successful implementation depends on understanding not only packaging requirements but also patient behaviour, product compatibility and regional regulatory expectations. Regulatory requirements continue to evolve across different markets, making early planning essential. Manufacturers must ensure that testing protocols, documentation packages and product performance data align with applicable standards and expectations in target regions. At the same time, quality management systems and manufacturing controls remain fundamental considerations. As pharmaceutical companies evaluate long-term supply strategies, emphasis is increasingly placed on reliability, consistency and the ability to scale production while maintaining compliance with industry requirements. Human Factors and Patient-Centric Design Increasingly, pharmaceutical packaging is being viewed through the broader lens of patient-centered design. Beyond meeting regulatory requirements, packaging can influence how patients perceive, handle and use their medication. Human factors engineering has therefore become an important consideration in the development of delivery systems and packaging components. Design teams evaluate how users interact with products 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY
under different conditions, including varying ages, physical abilities and levels of familiarity with the product. Clear instructions, intuitive operating mechanisms and consistent performance all contribute to safe and effective product use. These elements may seem secondary to the drug itself, yet they can play a meaningful role in supporting proper administration and reducing the risk of user error. As healthcare delivery continues to evolve toward home-based treatment, selfadministration and digital health integration, the importance of patient-oriented packaging design is likely to increase further. Childresistant packaging will remain a critical safety feature, but its success will increasingly be measured by how effectively it combines protection, usability and overall patient experience. Conclusion As child-resistant packaging requirements continue to expand across the pharmaceutical industry, packaging is increasingly viewed as a strategic component of product development rather than solely a compliance requirement. Companies that integrate safety, usability, regulatory readiness and supply chain resilience into their packaging strategies may be better positioned to respond to evolving market expectations and regulatory requirements.
Expert perspective "Child-resistant packaging is increasingly being considered at the intersection of patient safety, regulatory compliance and user experience. As pharmaceutical products become more diverse and healthcare delivery continues to evolve, packaging systems must address a growing range of requirements. The challenge for the industry is to develop solutions that effectively protect children while remaining intuitive and accessible for adult users.” Aaron Small REFERENCES 1. 2.
Fortune Business Insights; Transparency Market Research CPSC; Fortune Business Insights
Aaron Small Aaron Small, Vice President Global Healthcare, Silgan Dispensing. With over a decade of leadership experience across the pharmaceutical and biopharmaceutical value chain, focused on commercial strategy, business development, and strategic partnerships.
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Leading the Leading the next generation next generation of nasal of nasal delivery. delivery. Patient-centric liquid and powder platforms designed to simplify administration, enhance patient experience and unlock new possibilities in intranasal drug delivery.
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Subsection: Injectables
The Elastomeric Stopper as Part of a System: Building Confidence Through Worst-Case Scenario Testing International Pharmaceutical Industry Journal speaks with Edouard Pagnoud, Product Line Manager – Vial Stoppers at Aptar Pharma, about the evolving expectations for elastomeric closures under USP <382>. The discussion explores the importance of evaluating closures as part of the complete Container Closure System (CCS), the value of worst-case scenario testing, and how system-level performance data can help pharmaceutical manufacturers build robust, risk-informed qualification strategies for sterile injectable products. With USP <382> establishing a performancebased evaluation framework for elastomeric closures in sterile injectable production, passing a specification test is no longer sufficient. The standard requires evaluation within the full Container Closure System (CCS) – vial, stopper, cap, drug formulation, and access devices, and demands that performance be demonstrated not only at release, but throughout the product's entire shelf life and point of use. Edouard Pagnoud, Product Line Manager for Vial Stoppers at Aptar Pharma, explains Aptar Pharma’s approach to providing pharmaceutical partners with confidence in how their products will perform when it matters most, including under worst-case scenarios.
tell you how the stopper's elastomeric structure actually responds under puncture stress. A drug manufacturer who reads those results that way can build a risk assessment on real mechanistic understanding rather than assumptions, and that changes every packaging decision they make downstream. Which stopper properties most directly drive functional performance, and how do formulation, sterilisation, and geometry each contribute? Edouard: Hardness and elasticity are the primary material drivers, determined by the rubber formulation and further influenced by sterilisation. Higher hardness increases penetration resistance, modifying piercing force, fragmentation behaviour, and selfsealing response. Gamma sterilisation amplifies these effects by hardening the elastomer. Within our portfolio, 6720GC (Bromobutyl) exhibits higher inherent hardness than 6422GS (Chlorobutyl). Geo-
metry adds a further dimension: increased piercing zone thickness raises piercing forces and increases sensitivity to needle gauge and repeated access. These effects are most significant under worst-case conditions; within intended use, all configurations remain fully compliant. These parameters do not act in isolation. How does Aptar Pharma's worst-case programme characterise their combined effects on stopper performance? Edouard: Under intended-use conditions, these interactions do not compromise stopper functionality; each configuration meets performance requirements as a system. Under worst-case conditions, however, combined effects become significant: material hardness, stopper geometry, and access conditions interact to amplify impacts on piercing force, fragmentation, and self-sealing. Mapping these combined effects, not just individual parameters in isolation, is precisely the value of a system-level evaluation approach.
Under USP <382>, primary responsibility for CCS qualification rests with the drug product manufacturer. What drives Aptar Pharma's decision to evaluate closures under worstcase conditions, beyond what is required of a primary packaging supplier? Edouard: It comes down to a deliberate choice about the scope of our role. As an elastomeric closure solutions provider, our obligation is to deliver closures that meet performance requirements under recommended conditions. We have chosen to go further. Aptar Pharma evaluates its stoppers under worst-case scenarios, larger needle gauges, repeated multi-piercing, and aggressive sterilisation, to map precisely where performance begins to change. Fragmentation and self-sealing results are not just compliance markers; they 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Figure 1: Functional Testing of Rubber Stopper Components Autumn 2026 Volume 18 Issue 3
Subsection: Injectables How should development teams integrate these findings into their USP <382> qualification strategy, from early-stage selection through to commercial supply? Edouard: Treat this data as a development input, not a late-stage compliance output. Understanding how your CCS responds to different sterilisation modes, needle types, and access conditions enables informed packaging decisions before they become costly to change. USP <382> creates the obligation to think systemically. Aptar Pharma provides the data and the technical partnership to make that thinking actionable from day one. General Overview Aptar Pharma’s closure solutions for injectable drug vials is supported by a comprehensive in-house testing strategy designed to exceed regulatory requirements. By characterising stopper performance across a comprehensive matrix of conditions, formulations, sterilisation modes, needle gauges, stopper geometries, and multipiercing sequences, Aptar Pharma provides pharmaceutical manufacturers with the evidence base needed to implement USP <382> with confidence and to build robust, risk-informed qualification strategies. We will gladly provide you with further information on request. https://aptar.com/ en-us/contact-us?utm_campaign=52778154USP382-IPI-0%2F2026&utm_source= tradejournal&utm_medium=IPI
Edouard Pagnoud
Container Closure Integrity (CCI) must be maintained from sterilisation through to point of use, not simply confirmed at release. What does a lifecycle-based evaluation change about how manufacturers approach closure qualification? Edouard: Release testing provides a snapshot; lifecycle evaluation tracks how the system performs under conditions it will actually encounter. A closure must protect the drug product against both microbial www.international-pharma.com
contamination and environmental factors – oxygen, humidity, and light – throughout its entire shelf life. By considering the full system - vial, stopper, cap, and access tools – and how functional properties evolve across sterilisation processes, storage conditions, and access scenarios, a lifecycle approach ensures consistent performance from delivery through to point of use. This is the kind of evidence-based qualification that USP <382> now makes obligatory for the industry.
Edouard Pagnoud is Product Line Manager for Vials Solutions at Aptar Pharma's Injectables Division. A graduate in Chemical Engineering from Université Technologique de Compiègne, he brings over ten years of experience across the cosmetic and pharmaceutical industries. Before joining Aptar Pharma in 2021, he held technical and industrial roles focused on product development and lifecycle management. In his current position, Edouard oversees the vials solutions platform and supports customer development projects across the injectable packaging value chain.
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Subsection: Injectables
The Global Harmonisation of Contamination Control Strategy Regulations and Enforcement Holistic, risk-based contamination control and risk management expectations have evolved from a regional regulatory expectation to a globally recognised cornerstone of sterile pharmaceutical manufacturing. Regulatory authorities and standards organisations are increasingly converging on a risk-based, lifecycle approach to proactive contamination prevention, driven by the need to ensure product quality, patient safety, and supply continuity. Recent updates to key frameworks including ICH Q9(R1), EU GMP Annex 1, PIC/S PE 009, and WHO Technical Report Series (TRS) 1044 reflect a shared emphasis on end-to-end contamination control strategies that extend across facility design, manufacturing operations, supplier management, environmental monitoring, and ongoing process oversight. This global harmonisation signals a shift away from traditional, compliance-focused assessments toward evaluations of how effectively manufacturers identify, mitigate, and continuously manage contamination risks throughout the product lifecycle. Regulatory inspections increasingly scrutinise the robustness of risk management practices, the effectiveness of supplier oversight programmes, the investigation of recurring deviations, and the scientific justification underpinning contamination control decisions. Concurrently, international standards and compendia bodies, including ISO and USP, are embedding lifecycle contamination control principles into evolving industry guidance, further reinforcing expectations for proactive, integrated quality systems. As authorities worldwide adopt or align their good manufacturing practice (GMP) requirements with these emerging standards, the principles embodied in EU GMP Annex 1 are becoming a de facto global benchmark rather than a solely European regulation. In recent years, global regulatory authorities have renewed their focus on patient safety by requiring enhanced risk mitigation from manufacturers. This focus has expanded beyond the finished product to both upstream (supplier 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY
management, manufacturing, sterilisation, etc.) and downstream (distribution, lifecycle management, etc.) processes. International regulatory and standard updates worldwide are increasingly aligned around common principles, raising expectations for comprehensive, lifecycle based risk management and contamination control that apply broadly across markets. Specifically, the convergence of key initiatives including implementation of International Council for Harmonization (ICH) Q9, Quality Risk Management (R1), and the harmonised adoption of EU GMP Annex 1; the Pharmaceutical Co-Operation Scheme (PIC/S) Guide to GMP for Medicinal Products (PE 009 17); and the World Health Organization(WHO) Technical Report Series 1044 Annex 2: WHO good manufacturing practices for sterile pharmaceutical products, have established a new global benchmark for sterile injectable drug manufacturing.1,2,3,4 These developments have substantially redefined best practices and generated industry wide ripple effects. Since their introduction, regulators have intensified scrutiny of supplier qualification, cGMP compliance, and the adequacy of investigations and effectiveness of corrective actions related to recurring contamination issues, with greater enforcement actions where deficiencies are observed. EU GMP Annex 1 originated within specific European Union frameworks; however, it is now widely recognised as the new global standard for contamination control. While compliance to EU GMPs is already applicable to any global territory exporting to the EU, due to the harmonisation with the PIC/S and WHO, regulators internationally are increasingly expecting manufacturers to demonstrate alignment with these principles regardless of whether products are intended for the EU market. This alignment between the WHO, PIC/S and EU reflect a broader regulatory consensus that the contamination control and risk management principles articulated in EU GMP Annex 1 represent appropriate, modern expectations for sterile manufacturing globally. As a result, individual countries are increasingly codifying these requirements into national law or integrate them into local GMP regulations to make them enforceable. In terms of risk management, this was already an international inspection focus however,
the updated ICH Q9 has significantly shifted from an individual process/product driven checkbox toward driving organisations to identify, assess, justify, and continuously manage risks across the full product and global supply lifecycle regardless of jurisdictional origin of the product. Since 2023, many countries/territories have already moved to strengthen their GMP frameworks by aligning national requirements with the contamination control and risk management principles established in ICH Q9(R1) and EU GMP Annex 1, either through direct adoption or through functionally equivalent national requirements. The current adoption status internationally includes the following: • •
•
•
•
EU Member States – All EU member states are required to comply with EU GMP Annex 1. Non EU Countries Recognising EU GMP – Countries such as Canada, Iceland, Israel, Liechtenstein, New Zealand, Norway, Switzerland, Ukraine, and the United Kingdom formally recognise EU GMP compliance and therefore expect adherence to Annex 1 to utilise the international recognition schemes. PIC/S Adoption – Countries including Australia, Canada, Egypt, Indonesia, Hong Kong, Japan, Jordan, Saudi Arabia, Malaysia, Pakistan, Singapore, Taiwan, and Türkiye have issued national guidance adopting PIC/S PE 009 17. WHO Alignment – Countries such as Paraguay, Venezuela and others generally align GMP expectations with WHO guidelines. Equivalent Contamination Control Requirements – The United States, India, Eurasian Economic Union (EAEU) and China have not formally adopted EU or PIC/S guidance but have implemented or proposed comparable contamination control requirements within their national GMP frameworks.
In the United States, although not directly harmonised with EU GMP Annex 1, existing regulations, along with recently released guidance, stress the importance of contamination control principles such as robust risk management, the clinical impact Autumn 2026 Volume 18 Issue 3
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Subsection: Injectables of particulate, and holistic mitigation plans.5,6,7 Specific to end-to-end risk management, the Food and Drug Administration (FDA) agency’s view is clear with the adoption of ICH Q9 (R1), but risk is also woven into almost all recent guidance related to quality. For example, The FDA guidance Risk Management Plans to Mitigate the Potential for Drug Shortages (May 2022) notes, “Effective quality risk management can facilitate better, more informed decisions; can provide FDA with greater assurance that stakeholders understand and can manage the associated risks; and can potentially affect the extent and level of direct regulatory oversight.”7 In practice, recent FDA Inspections and Warning Letters indicate expectations in line with this statement. Approximately 39% of all drug recalls from the FDA are related to visible foreign particulate.8,9 Heightened supplier qualification scrutiny is also evident since 2023, with emphasis on data reliability, cGMP compliance, and adequacy of qualification procedures.10 When FDA inspection data are isolated to regulations associated with sterility assurance, contamination control, investigations, laboratory controls, and container closure systems, a pronounced post-2023 increase is observed.11 Following implementation of EU GMP Annex 1 in August 2023, Voluntary Action Indicated (VAI) findings increased from 104 in FY2023 to 172 in FY2025 (+65%), while Official Action Indicated (OAI) findings increased from 61 to 103 (+69%) over the same period. FY2026 year to date remains directionally consistent, with 66 VAI and 42 OAI findings already identified, although FY2026 should be interpreted cautiously because it represents partial-year data. The trend suggests heightened regulatory scrutiny of contamination control and sterility assurance systems, with deficiencies increasingly identified in inspection outcomes requiring regulatory action. The pattern is consistent with industry-wide challenges in meeting evolving Annex 1 expectations, particularly around investigations, microbiological control, and container-closure assurance. Communication from the FDA emphasises not only the importance of contamination control but the real-life consequences of a manufacturer’s inaction. The data suggest that FDA observations tied to Annex 1-adjacent topics are not merely routine inspection findings. Of the 220 target-regulation FDA Form 483s identified from FY2020 through FY2026, approximately one in five was followed by a Warning Letter.11 This reinforces the regulatory importance of contamination control, sterility 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY
assurance, laboratory controls, investigations, and container closure integrity as areas where inspectional findings may escalate beyond observation into formal enforcement action. Expectations are clear from the FDA that manufacturers have a deep understanding of their end-to-end products, processes, and suppliers. Specifically, to particulate contamination, the agency expects manufacturers to conduct studies on particulate levels and understand the impact of every individual process step (e.g. handling, incoming materials, processing including sterilisation, etc.) that could lead to particulate generation.6 Overall, the main objective of US applicants is to gain agreement from the FDA that the evidence provided in their submission and/or pre-approval inspection substantiates that the target product is safe and effective. It is clear from all available communication and enforcement trends that the FDA views contamination control as a key part of that evidence. In China, the National Medical Products Administration (NMPA) issued a revised draft of the Sterile Drug Annex to the GMP for Drugs (2010 Revision) in March 2025.12 The draft largely aligns with EU GMP Annex 1 while incorporating regional and technical requirements, such as enhanced material transfer controls and references to national pharmacopoeia standards (e.g., steam sterilisation condensate meeting Chinese water for injection specifications). China has continued to update its GMP framework, including publication of the Pharmaceutical Packaging Materials Annex (No. 1, 2025),
reinforcing risk management expectations and regulatory enforcement.13 Finalisation of the Sterile Drug Annex is anticipated in the near term and underscores how Annex 1 principles are being globally embedded and adapted, reinforcing their relevance as international benchmarks rather than region specific requirements. Beyond China, several countries including Algeria, Brazil, Iran, Lebanon, Mexico, North Macedonia, Serbia, and South Africa are proposing or consulting on the implementation of enhanced contamination control measures, signalling further global alignment by tightening of requirements in the coming years. In parallel with regulatory changes, standard setting organisations are also undergoing revision. Recent updates include ISO 14644 5:2025, Cleanrooms and associated controlled environments, Part 5: Operations and proposed USP chapters addressing contamination control and particulate mitigation. These standards embed holistic risk management principles across the product lifecycle, from initial development and facility design to equipment selection, materials, manufacturing processes, packaging, labelling, and supplier management. Across both regulations and standards, expectations now reinforce integral aspects for effective contamination control strategies including robustness of risk governance, organisational accountability, data-driven decision making, improved supplier oversight, deviation recurrence handling, and continual improvement mechanisms Autumn 2026 Volume 18 Issue 3
HYPODERMIC NEEDLES Ideal to By-pack with Drug Products!
Each needle is sterile packed individually in a hard case unit pack
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Color-coded labels and barcode on label enable in-line product identification
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www.international-pharma.com pharmapackaging@nipro-group.com | www.nipro-group.com
Nipro Corporation www.nipro.co.jp INTERNATIONAL PHARMACEUTICAL INDUSTRY 49
Subsection: Injectables
Overall, in the relatively short period since these initiatives were introduced, enhanced lifecycle risk management and contamination control expectations are becoming firmly established as a global norm that extends beyond compliance with any single guideline or geographic region. For jurisdictions that already have these enhanced regulations in force, manufacturers must quickly adapt processes, quality culture and documentation to remain in compliance. For jurisdictions with regulations not yet in force, manufacturers that implement comprehensive, riskbased contamination control strategies and demonstrate sustained effectiveness through continuous improvement will be better positioned to meet regulatory expectations, maintain inspection readiness, and support reliable supply of sterile products in an increasingly harmonised regulatory environment.
REFERENCES 1. 2.
3. 4.
5. 6. 7. 8. 9.
ICH Q9, Quality Risk Management, 18 January 2023 The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, 22 August 2022 Pharmaceutical Co-Operation Scheme (PIC/S) Guide to GMP for Medicinal Products (PE 009 17), 25 August 2023 World Health Organization (WHO) Technical Report Series 1044 Annex 2: WHO good manufacturing practices for sterile pharmaceutical products, 31 October 2022 FDA Guidance, Q9 (R1) Quality Risk Management, May 2023 FDA Guidance, Inspection of Injectable Products for Visible Particulates, Dec 2021 FDA Guidance, Risk Management to Mitigate the Potential for Drug Shortages, May 2022 U.S. Food and Drug Administration. Drug Recalls. Accessed February 2026. U.S. Food and Drug Administration. Recalls for
10. 11. 12.
13.
Biologics. Accessed February 2026. U.S. Food and Drug Administration. Warning Letters. Accessed July 2026. U.S. Food and Drug Administration. Inspections Database. Accessed July 2026. Public Opinions Solicitation of Department of Comprehensive Affairs, Planning, and Finance Affairs of the National Medical Products Administration for the Sterile Drug Annex of the Good Manufacturing Practice for Drugs (2010 Revision) (Exposure Draft), March 17, 2025 Announcement of the National Medical Products Administration on Issuing the Appendices for Pharmaceutical Excipients and Drug Packaging Materials and Containers of the Good Manufacturing Practice for Drugs (2010 Revision) (No.1, 2025), January 2, 2025
Lauren Orme Lauren Orme has more than 24 years of experience in pharmaceutical packaging, medical devices, and analytical services. She leads Regulatory Affairs Intelligence and Policy at West Pharmaceutical Services, overseeing global regulatory monitoring and compliance activities. Previously, she held technical and commercial roles supporting customer adoption of West’s products and services. Lauren holds a B.S. in Biology from West Chester University and is a PMP-certified professional.
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Autumn 2026 Volume 18 Issue 3
Make the next transition feel seamless The transition to next-generation propellants raises the bar for sustainability, while demanding proven performance and dependable commercial supply. Kindeva supports the seamless transition to next-generation propellants, helping ensure tomorrow’s MDIs match the performance of today’s inhalers.
See how Kindeva supports your MDI www.international-pharma.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 51
Subsection: Injectables
Redrawing the Delivery Map: The Next Dosage Form Is One That Patients Barely Notice In recent years, drug discovery has advanced rapidly to yield increasingly sophisticated medicines, yet our primary method of administering these drugs remains remarkably unchanged. Many of these new and advanced macromolecules still rely on standard liquid injections, a dependence that imposes a significant physical and financial burden on patients and healthcare systems alike. Liquid injections frequently require cold-chain transport, clinic visits, administration by trained professionals and the physical discomfort of a needle. Translating complex molecular science into patient-centric healthcare requires drug developers to pair therapeutic innovation with equally advanced, patient-directed dosage forms. Dermal drug delivery through microneedle array patches (MAPs) offers a viable solution to these translational challenges. This approach restricts penetration to the non-vascular outer layer of the skin to avoid the pain and anxiety associated with injections and remove the safety risks that require professional clinical administration. This transition away from legacy drug delivery methods can directly improve patient compliance, clinical outcomes and global accessibility. The Legacy of Liquid Injection Biologics now represent approximately 40% of the global drug development pipeline and account for nearly half of all new drug approvals.1 These complex macromolecular therapies are transforming treatment across chronic therapeutic areas, including autoimmune diseases, cancers, endocrine disorders and genetic conditions. Despite their therapeutic promise, these complex structures cannot survive oral administration, as gastric enzymes and the acidic environment of the stomach degrade the molecules before they can enter the bloodstream.2 While bypassing this gastric barrier has long made liquid subcutaneous or intramuscular injections the default pathway for systemic biologic delivery, this approach carries physical and logistical challenges: 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY
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Clinic visits require travel, consume patient time and increase the overall cost of care. Self-injection demands a high degree of manual dexterity and patient training.
Beyond these administration challenges, liquid formulations often present significant shelf-life limitations due to their molecular instability at room temperature. These formulations remain highly vulnerable to thermal fluctuations, light and mechanical stress. This sensitivity necessitates a continuous cold chain from manufacture to administration, which limits medicine distribution in developing regions, increases carbon footprints and generates substantial waste when temperatures slip outside of safe limits. How Direct Dermal Penetration Unlocks Large Molecule Therapies Traditional transdermal patches rely exclusively on passive diffusion to slowly seep small-molecule drugs through the stratum corneum, the highly resilient outermost layer of the skin. Because the stratum corneum is designed to keep foreign substances out, only a very narrow class of lipophilic, lowmolecular-weight drugs can use this route, making transdermal delivery unsuitable for large macromolecules, proteins and vaccines.3 MAPs operate on a fundamentally different delivery principle. A MAP uses an array of microneedles to create precise, microscopic gateways directly into the underlying epidermal and dermal layers of the skin, physically bypassing the stratum corneum. These needles do not reach the deeper pain receptors or blood vessels located in the lower dermis, allowing for a painless delivery experience. The dermal layer itself is a valuable target for drug delivery. It is highly vascularised and rich in antigen-presenting cells, such as Langerhans cells and dermal dendritic cells, making it the ideal site for vaccine delivery.4 When an antigen is delivered directly to this immunologically active environment, the response is often far more robust than when the same antigen is injected into muscle tissue. Clinical studies also suggest that dermal vaccine delivery can support dose sparing, which allows developers to use less active
ingredient to achieve the same protective effect.4 It may also reduce or eliminate the need for adjuvants, which can be the cause of local injection-site reactions. Beyond vaccines, the rich vascular network of the dermis enables rapid systemic absorption of therapeutic peptides and proteins, making it an excellent path for daily or weekly biologic regimens. At-Home Autonomy: Overcoming Needle Anxiety Needle phobia is a highly prevalent condition that affects a significant portion of the global population.5 This anxiety often leads to treatment avoidance, missed doses and eventually complete non-adherence. In chronic diseases such as severe osteoporosis or diabetes, inconsistent dosing can accelerate disease progression and increase hospitalisations. By removing the needle from view and eliminating associated pain, microneedle patches redefine the patient experience through a simple and intuitive application process. Patients apply the patch to the skin using a customised applicator device that automatically ensures the correct force and velocity of insertion, resulting in only a sensation of slight pressure. This straightforward ease of use supports patient autonomy and allows individuals to manage chronic conditions in the comfort of their home. This opportunity for self-management is particularly advantageous for therapeutic classes that traditionally demand highly frequent, invasive dosing regimens to achieve therapeutic efficacy. In the rapidly expanding field of glucagon-like peptide-1 (GLP-1) receptor agonists, patient adherence remains highly dependent on overcoming the physical discomfort and anxiety of needles. Introducing a daily or weekly microneedle patch for GLP-1 delivery eliminates the need for regular subcutaneous injections, converting a potentially painful medical task into a routine wellness habit. Similar clinical benefits apply to daily therapies for osteoporosis, where elderly patients often struggle with the physical demands of preparing and administering liquid injections. By simplifying the administration process across these diverse indications, MAPs Autumn 2026 Volume 18 Issue 3
Subsection: Injectables empower patients to take control of their health, which directly leads to higher adherence and better long-term clinical outcomes. The Potential for Solid-State Stability One of the most profound advantages of solid-coated microneedle technology is the transition from liquid to solid-state chemistry. To create a solid-coated MAP, formulation scientists transfer a biologic from a liquid format to a specialised coating solution that can then be deposited as droplets on the tips of the microneedles. Once dried, the active biologic molecule is held in a stable, solidstate matrix. Liquid formulations are highly dynamic environments where molecules are free to move, aggregate and degrade. The solid-state matrix of a coated microneedle immobilises the biologic, which restricts molecular movement and drastically reduces the rate of chemical degradation. Through this immobilisation, biologics that would normally denature within hours at room temperature can remain stable on a patch for months or even years without refrigeration.6 The commercial and humanitarian implications of this stability are vast. From a logistics perspective, eliminating the cold chain simplifies the distribution network. Pharmaceutical companies can ship vaccines and biologics through standard postal services directly to patients, bypassing the expensive infrastructure of refrigerated shipping and specialised clinic storage. In developing nations or disaster zones where refrigeration is unavailable, room-temperature stable patches can be distributed safely to remote populations. This stability also reduces the risk of medicine waste, ensuring that stockpiles of critical therapies remain viable for extended periods without ongoing energy costs. Designing for the Patient Experience Creating a successful patient-centric MAP requires a deep understanding of both formulation chemistry and mechanical design. The physical design of the microneedle array must be optimised for both skin penetration and drug release. At Kindeva, this microarchitecture is engineered using a proprietary liquid crystalline polymer (LCP) platform. LCP is an exceptionally strong, biocompatible material that maintains its structural integrity during skin insertion, ensuring that the needles do not bend or break during use. Every aspect of the array architecture can be customised to suit the specific therapeutic target: www.international-pharma.com
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Needle length: Determining the precise length ensures the needles target either the shallow epidermis for local therapies or the deeper dermis for rapid systemic absorption. Needle spacing and density: Optimising the distance between needles ensures the application force is concentrated effectively to penetrate the skin barrier without causing unnecessary tissue displacement. Formulation concentration: Maximising API concentration in the coating droplet allows us to deliver the target dose within a very limited physical surface area.
the promise of microneedle technology into a commercial reality.
While customising this micro-architecture optimises the patch, clinical success ultimately relies on pairing the array with an applicator device that overcomes natural variations in skin physiology. Because skin elasticity varies significantly across age groups and body types, a reusable or single-use applicator is essential to ensure consistent drug delivery. By applying the patch at a standardised velocity and force, this integrated mechanism guarantees that the microneedles penetrate the skin to the exact target depth every single time, regardless of whether the user is an elderly patient or a young caregiver.
For biopharma innovators looking to differentiate their products, serve patients more effectively and secure their pipelines, MAPs represent the path to progress. The dermal revolution is here, and the future of medicine is ready to be applied.
•
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The Industrial Horizon Scaling microneedle arrays beyond laboratory benchtop environments represents a sizable industrial challenge, as many early architectures performed reliably in controlled R&D settings but proved impossible to reproduce consistently at high volumes. To overcome this industrialisation bottleneck, developers must design with manufacturability in mind from the very beginning of a programme. This means understanding the constraints of commercial assembly lines and engineering backward to the early design phase. Translating this early design philosophy into a scalable reality requires specialised, highly automated production lines that integrate advanced robotics, isolated cleanroom environments and machine vision systems to guarantee that every patch meets strict regulatory and quality standards. By establishing this end-to-end manufacturing pathway, developers can significantly de-risk the scale-up process. Biopharma companies can initiate feasibility studies with the confidence that the same formulation and process can be scaled seamlessly to commercial production. This industrial maturity is the final, essential step in turning
Embracing the Future of Patient-Centric Medicine Prioritising the patient's daily experience is becoming the defining requirement for modern drug delivery. By combining the clinical efficacy of injections with the ease and stability of a dry patch, MAPs offer an unparalleled opportunity to modernise healthcare. This technology eliminates needle pain, enables at-home self-administration, can remove cold-chain restrictions and ensures precise, automated dosing.
REFERENCES 1.
2.
3.
4.
5.
6.
“The Future of Biologics and Bio-betters: A Strategic Deep Dive into Next-Generation Therapies.” Drug Patent Watch, 2026. https:// www.drugpatentwatch.com/blog/the-future-ofbiologics-bio-betters-and-the-dawn-of-nextgeneration-therapies/ Zhu, Quangang, Zhongjian Chen et al. “Oral delivery of proteins and peptides: Challenges, status quo and future perspectives.” Acta Pharmaceutica Sinica B. 11.8 (2021): 2416-2448. Print. https:// pubmed.ncbi.nlm.nih.gov/34522593/ Bos, Jan and Marcus Meinardi. “The 500 Dalton rule for the skin penetration of chemical compounds and drugs.” Experimental Dermatology. 9.3 (2000): 165-169. Print. https:// pubmed.ncbi.nlm.nih.gov/10839713/ Menon, Ipshita, Priyal Bagwe, et al. "Microneedles: A new generation vaccine delivery system." Micromachines. 12.4 (2021) Web. https://pmc. ncbi.nlm.nih.gov/articles/PMC8070939/ McLenon, Jennifer and Mary Rogers. “The fear of needles: A systematic review and meta-analysis.” Journal of Advanced Nursing. 75.1 (2019): 30-42. Print. https://pubmed.ncbi.nlm.nih.gov/30109720/ Nguyen, Thuy Trang, Yujeong Oh, et al. "Progress in microneedle array patch (MAP) for vaccine delivery." Human Vaccines & Immunotherapeutics. 17.1 (2020): 316-327. Print. https://www.tandfonline.com/doi/full/10.1080 /21645515.2020.1767997
Andrew Riso Andrew Riso, Vice President, Dermal Delivery and Licensing at Kindeva.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 53
Subsection: Neurodegenerative Diseases
Mass Spectrometry Imaging Drives Research into Parkinson’s Disease Parkinson's disease is a progressive neurological disorder that affects movement in the body. With a study published in Nature Medicine indicating that more than 57 million people across the globe suffer from neurodegenerative disease, a figure expected to double every 20 years as the population ages, it is imperative to further our understanding of the causes of Parkinson’s disease, as well as the conflicting side effects of a therapeutic drug used to alleviate its symptoms.1 The capability of mass spectrometry imaging (MSI) to detect a range of neuroactive compounds and metabolites in a single tissue section has firmly established its potential in neuroscientific research. This article will explore the ground-breaking research by the Spatial Mass Spectrometry group at Uppsala University in Sweden, one of the largest centres for life sciences in Europe, into Parkinson’s disease, specifically a specific stage of the disease, called levodopa (L-DOPA)induced dyskinesia (LID), which develops in approximately 50 percent of patients after five to six years of L-DOPA treatment. A Deeper Understanding of Parkinson’s Disease Parkinson’s disease is an incurable neurodegenerative disease caused by the loss of dopamine-producing nerve cells in the brain. It is characterised by motor dysfunction, tremors, bradykinesia (or slowed movement), muscle rigidity, and postural instability including involuntary and unpredictable body movements. L-3,4-dihydroxyphenylalanine (levodopa, or L-DOPA) administration is the primary treatment for Parkinson’s. L-DOPA is a precursor to dopamine that crosses the blood-brain barrier where it is converted into dopamine, replenishing the brain’s depleted supply of dopaminergic neurons in the substantia nigra pars compacta region that leads to reduced dopamine in the striatum, an area of the brain responsible for movement control in the body. L-DOPA is highly effective in the early stages, but its long-term use is often accompanied 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY
by the side-effect LID, a treatment-limiting complication which exhibits as involuntary, erratic, and uncontrollable tremors and whose pathophysiology is poorly understood. LID has a significant negative impact on quality of life. What is not yet known is why only certain people are affected. Working with animal models, as well as human blood– cerebrospinal fluid (CSF) biobank samples supplied by collaborators at the Karolinska Institute, Stockholm, Bordeaux University, and Kings College London, researchers in the Department of Pharmaceutical Biosciences at Uppsala University are using MSI to investigate the elevated L-DOPA levels in the brain that are linked with LID. The MSI Advantage MSI is an advanced, label-free mass spectrometry tool that can be used to map the spatial distribution of molecules such as lipids, proteins and metabolites directly within thin tissue sections. MSI can be integrated with microscopy or histology, and provides an additional parameter for identification over traditional MS by enabling the accurate simultaneous determination of multiple tissue distributions. This allows quantitative regional mapping, and high resolution visualisation of molecular change to support neurodegenerative disease research. The research at Uppsala is focused on imaging the spatial distribution of neurotransmitters, or the signalling molecules in the brain, that are known to be affected in Parkinson’s disease. The group has developed a method to image neurotransmitters in a specific brain region, at the same time providing a new view of the brain and the transmitters involved in current Parkinson’s disease models. This method, using MALDI MSI, has enabled researchers to measure and quantify different neurotransmitters, and their metabolites and precursors, simultaneously. MSI Supports Identification of Elevated Brain L-DOPA Levels A study used ultrahigh mass resolution Fourier transform ion cyclotron resonance (FTICR) matrix-assisted laser desorption/
ionisation (MALDI) MSI (7T solariX XR) to map the distribution of L-DOPA and monoaminergic pathways in the brains of dyskinetic and nondyskinetic animal models.2 Fourteen neurotransmitters and metabolites were simultaneously imaged and identified with accurate mass. Elevated levels of L-DOPA and its metabolite 3-O-methyldopa were found in all measured brain regions of dyskinetic animals, and increases in dopamine and metabolites were noted in all regions analysed, except the striatum. It was found that LID is linked to a dysregulation of L-DOPA metabolism throughout the brain: the inability of extrastriatal brain regions to regulate the formation of dopamine during L-DOPA treatment introduces the potential of dopamine, or L-DOPA itself, to modulate neuronal signalling widely across the brain, causing unwanted side effects. Neuropeptides Demonstrate Link With LID Parkinson's disease and LID have both been linked with altered expression of neuropeptide precursor messenger ribonucleic acids (mRNA). An investigation into the basal ganglia neuropeptides that have been associated with LID development found that dyskinesia severity correlated with elevated levels of some abnormally processed peptides in multiple brain regions.3 Dynorphin, enkephalin and tachykinin neuropeptides of the basal ganglia have many effects, including regulation of neurotransmitter release, modulation of blood-brain barrier permeability and stimulation of neuro-inflammatory responses. MALDI-MSI was used to characterise neuropeptide alterations in the same preexisting cohort of samples from an animal model of Parkinson’s disease during the peak LID behaviour period, targeting the depletion of catecholaminergic neurons to closely mimic symptoms of Parkinson’s and LID. In the study, MALDI-MSI was used to image and identify 23 neuropeptides, as Autumn 2026 Volume 18 Issue 3
Subsection: Neurodegenerative Diseases
3.
4.
well as image and analyse the effect of LID on these neuropeptides in the brain. It was found that LID was associated with an increase in the multiple neuropeptide levels across the basal ganglia structures, while non-LID animals had low levels of these neuropeptides. The severity of LID correlated with the abundance of processed derivatives of the active neuropeptides in certain basal ganglia regions, and putaminal levels of L-DOPA correlated with the abundance of the active neuropeptides, but did not correlate with the levels of processed derivatives, suggesting that striatal L-DOPA itself may induce neuropeptide signalling, without first being converted to dopamine. Lipid Dysregulation As lipids are increasingly considered a prominent class of metabolites in neurodegenerative disease research, lipidomics has become an important metabolomics research pathway. Lipids are strongly linked to many aspects of Parkinson’s disease, but there are few studies on their impact on LID-specific changes. High resolution MSI was used in a study to map brain region-specific alterations of glycerophospholipids and sphingolipids in the same animal model of Parkinson’s with and without LID following long term L-DOPA treatment.4 Spatial lipidomic analysis identified region-specific lipid dysregulation as a novel aspect of LID pathology, highlighting lipid pathways as potential targets for future research. LID was associated with depletion of antioxidant ether phosphatidylcholines and www.international-pharma.com
altered PUFA-containing glycerophospholipids in regions critical for motor function, which differed from similarly treated non-dyskinetic animals, suggesting lipid composition mediates differential susceptibility to LID. Lipid alterations correlated strongly with dyskinesia severity, dopamine and L-DOPA concentrations, supporting a mechanistic link between lipid metabolism, neurotransmitter dysregulation and LID. Building a Better Understanding of LID The new workflows for imaging neurotransmitters will continue to support neuroscience research using MSI. Adopting an integrated spatial omics approach that combines MSI with spatial transcriptomics and spatial proteomics facilitates precise measurements of metabolites across brain tissue regions. These advances will continue to support fundamental research into the mechanisms underlying Parkinson’s disease and treatment response. REFERENCES 1.
2.
Imam F, Saloner R, Vogel JW, et al. The Global Neurodegeneration Proteomics Consortium: biomarker and drug target discovery for common neurodegenerative diseases and aging. Nat Med. 2025 Aug;31(8):2556-2566. doi: 10.1038/s41591-025-03834-0. Epub 2025 Jul 15. PMID: 40665048; PMCID: PMC12353841. Fridjonsdottir E, Shariatgorji R, Nilsson A, Vallianatou T, Odell LR, Schembri LS, Svenningsson P, Fernagut PO, Crossman AR, Bezard E, Andrén PE. Mass spectrometry imaging identifies abnormally elevated brain l-DOPA levels and extrastriatal monoaminergic
dysregulation in l-DOPA-induced dyskinesia. Sci Adv. 2021 Jan 6;7(2):eabe5948. doi: 10.1126/ sciadv.abe5948. PMID: 33523980; PMCID: PMC7787486. Hulme H, Fridjonsdottir E, Vallianatou T, Shariatgorji R, Nilsson A, Li Q, Bezard E, Andrén PE. Basal ganglia neuropeptides show abnormal processing associated with L-DOPAinduced dyskinesia. NPJ Parkinsons Dis. 2022 Apr 13;8(1):41. doi: 10.1038/s41531-022-00299-7. PMID: 35418178; PMCID: PMC9007979. Kaya I, Vallianatou T, Nilsson A, Bjärterot P, Shariatgorji R, Svenningsson P, Bezard E, Andrén PE. Brain-region-specific lipid dysregulation in L-DOPA-induced dyskinesia in a model of Parkinson's disease. NPJ Parkinsons Dis. 2025 Aug 23;11(1):258. doi: 10.1038/s41531-025-011096. PMID: 40849420; PMCID: PMC12374971.
Dr. Per Andrén Mass spectrometry veteran Dr. Per Andrén was a postdoc in the group of Professor Richard Caprioli, in the early days of electrospray ionisation, and became the world’s first Professor of Mass Spectrometry Imaging, at the Department of Pharmaceutical Biosciences, Uppsala University, Sweden, having originally gained his MSc in Pharmacy and PhD in Medical Sciences (Psychiatry) at Uppsala University. Today, Dr. Andrén is interested in the use of MSI for the analysis of biological systems and focuses on MSI method development in applications for the brain and neurodegenerative diseases, with a particular emphasis on Parkinson’s disease.
Dr. Michael Easterling Dr. Michael Easterling is Vice President of MALDI Imaging at Bruker Daltonics. Following his PhD in Chemistry from The University of Georgia, Dr. Easterling has worked at Bruker Daltonics for almost 25 years, specialising in MALDI mass spectrometry. Dr. Easterling focuses on multimodal spatial analysis, more recently integrating mass spectrometry imaging with transcriptomics and proteomics to advance understanding of complex biological systems, including neurodegenerative disease.
INTERNATIONAL PHARMACEUTICAL INDUSTRY 55
Subsection: Neurodegenerative Diseases
Rethinking CNS Drug Development: From Symptom Control to Durable Brain Health Central nervous system disorders present one of the greatest challenges in life sciences today. They are the Everest of medicine – stubborn, unyielding, awkward; still unconquered many decades after other seemingly impenetrable horizons have been comprehensively mapped, even if they haven’t been entirely tamed. Like that giant looming above us, CNS disorders present a series of particular challenges that require huge amounts of highly technical know-how, teamwork, the sharing of ideas, a great deal of trial and error – and persistence. In fact, so unique is each disorder that each is like its own vast mountain, its own world of problems to be learned and hopefully mastered – and the CNS field more like the whole Himalayan range stretching on and on. Nonetheless, they share common problems for drug developers: their biology is often complex; diagnosing them can be difficult – especially early in the course of disease; so too can be measuring their severity and how they are progressing. While oncology, immunology and rare disease medicine have been reshaped by molecular stratification, biomarkers and targeted therapies, progress in most CNS indications has been slower and less predictable. In disorders of the brain, the target is rarely a single impaired component. More often, disease emerges from disrupted networks: genetic vulnerability, altered synaptic signalling, neuroinflammation, neuroplasticity imbalance, vascular dysfunction, environmental effects and ageing biology may all contribute to different combinations. That makes CNS drug development less like replacing a faulty part and more like trying to retune a highly adaptive system. The Problem of Translation As mentioned above, the first major challenge is biological complexity. Many CNS diseases 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY
are not driven by one pathway in the way that some monogenic or oncology indications can be. Even where a clear genetic driver exists, as in fragile X syndrome – the most common inherited cause of intellectual disability – the downstream effects can extend across synaptic function, RNA translation, mitochondrial biology, dendritic spine development and broader neural network pattern. Recent proteomics work in fragile X syndrome, for example, has discovered that individuals exhibit a wide range of dysregulated proteins which are thought to negatively affect synaptic plasticity and cellular function. This reinforces that CNS diseases need to be understood at the systems level rather than through a single target alone. This creates a second challenge: modelling. Quite simply, modelling how the brain works, what happens when compromised by a disease, and how a drug might affect it, is extremely difficult. Traditional cell systems can be useful for testing defined molecular hypotheses, but they cannot reproduce the three-dimensional organisation, cellular diversity and dynamic signalling of the human brain. Animal models remain essential, particularly for understanding circuitry and behaviour, but species differences in brain development, cognition and disease progression limit their translatability value. As a result, encouraging preclinical findings often fail to translate into meaningful clinical benefit. We are getting better at this. Sophisticated new tools such as human induced pluripotent stem cell models, brain organoids, assembloids, organ-on-chip systems and multi-omics profiling are helping us bridge this gap. Yet these platforms are not fully mature, nor are they ever likely to be replacements for clinical evidence, however good they get. They might, however, help developers identify more human-relevant mechanisms, test therapeutic hypotheses earlier and better understand why particular subgroups of patients respond differently. Biomarker Breakthroughs? Measuring What Matters A third and closely related obstacle is measurement. In many CNS disorders,
diagnosis still depends heavily on clinical observation, symptom scales and patient or caregiver reporting. These tools are important, but they are often subjective, variable and fail to spot early biological change. For progressive neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, to name just two, the underlying pathology often begins years before symptoms emerge. Once symptoms are obvious, the underlying neurodegeneration has usually progressed substantially. Neurodevelopmental and psychiatric disorders are different, and while they might not be characterised by a ‘silent sleeper’ problem they come with their own diagnostic and measurement challenges. Meaningful clinical change may involve altered cognition, social interaction, behaviour, daily functioning, sleep, anxiety, learning or caregiver burden. Such variables are not always captured cleanly by conventional endpoints and can be extremely subjective too. This is one reason why biomarkers are becoming central to development of CNS therapeutics. In Alzheimer’s disease, the field has moved furthest, with imaging and cerebrospinal fluid markers now complemented by increasingly accurate blood-based biomarkers such as plasma phosphorylated tau. The broader lesson extends beyond Alzheimer’s. Reliable biomarkers will help us identify patients earlier, stratify heterogeneous populations into more homogenous sub-groups, confirm target engagement, monitor disease progression and provide supportive evidence of therapeutic response. Without them, trials risk enrolling biologically mixed populations – diluting treatment effects, extending timelines and leading to costly and dispiriting failures. Digital biomarkers could also become increasingly important too. Wearables, smartphones and remote monitoring tools can collect high-frequency data on movement, sleep, activity, cognition and behaviour in real-world settings – helping monitor chronic neurological conditions in real time, where clinic visits provide only Autumn 2026 Volume 18 Issue 3
Subsection: Neurodegenerative Diseases
snapshots. However, digital measures must be standardised, clinically meaningful and accepted by regulators before they can really change drug development. The Blood-Brain Barrier Even when the biology is understood and the right patient population can be identified, CNS drug delivery remains a major hurdle. That’s due to the blood–brain barrier, which protects the brain from toxins and pathogens, but it also limits the entry of many therapeutic agents, particularly biologics and larger molecules. It’s tempting to call this hurdle the Hillary Step of CNS disorders, but that would be misleading. Overcoming the blood-brain barrier is more like just getting to base camp with all the kit you need for the ascent intact. The blood-brain barrier has shaped the CNS pipeline for decades, and chances are, it will do so for decades to come. Small molecules with favourable brain penetration remain attractive, but not every biological target is readily druggable by a conventional small molecule. The barrier means that other modalities such as gene therapies, antisense oligonucleotides, antibodies and RNAbased approaches usually require invasive administration or specialised delivery www.international-pharma.com
technologies. New approaches – including receptor-mediated transport, nanoparticles, intrathecal delivery, intranasal delivery and focused ultrasound – are being explored, but each brings its own safety, scalability and regulatory considerations. They are in the foothills of development. The delivery question is therefore not merely technical. It influences target selection, modality choice, dosing, patient burden and commercial feasibility. A therapy that is biologically elegant but difficult to administer repeatedly may face challenges in chronic diseases requiring long-term treatment. From Symptoms to Systems Despite this challenging backdrop, progress is being made. We are higher up the mountain than we were. The aim of many drugs in development today is not merely symptom suppression – important as that is – but restoration of underlying brain function. This is particularly evident in the growing interest around neuroplasticity. Neuroplasticity is the brain’s capacity to change its structure, function and connectivity in response to internal and external stimuli. It underpins learning, memory, adaptation and recovery. In disease, however, plasticity can be impaired, excessive or misdirected. In neurodevelopmental disorders, abnormal synaptic development and altered network
maturation may affect cognition and behaviour. In neurodegeneration, loss of synaptic resilience may contribute to functional decline. In mental health disorders, maladaptive circuit activity may reinforce persistent symptoms. The therapeutic opportunity is not simply to “boost” plasticity. The brain’s adaptability is powerful precisely because it is regulated. Impaired plasticity may limit learning and recovery; too much or poorly directed plasticity modulation may destabilise circuits – causing undesired adverse events. A more promising concept is restoration of plasticity balance, thus supporting healthier synaptic and network function in a way that translates into durable benefit. In fragile X syndrome, this systemslevel thinking is particularly relevant. The condition arises from loss or deficiency of FMRP, an essential RNA-binding protein that regulates protein synthesis in the brain. FMRP deficiency might be the trigger, but the clinical effects reflect broad downstream disruption in synaptic signalling, dendritic spine maturation and network function. This helps explain why highly selective approaches aimed at individual pathways have so far struggled to deliver consistent disease-modifying benefit. It also supports growing interest in approaches that address circuit-level dysfunction and adaptive brain function more broadly. INTERNATIONAL PHARMACEUTICAL INDUSTRY 57
Subsection: Neurodegenerative Diseases indications where no single organisation can solve the problem alone. Towards Durable Outcomes Ultimately, progress in CNS medicine should be judged not only by whether symptoms improve over weeks or months, but by whether treatments change the trajectory of disease and daily life. In neurodegeneration, which could mean slowing decline, preserving independence or delaying the need for care. In neurodevelopmental disorders, it might mean sustained gains in learning, communication, behaviour, social participation and family functioning. In mental health, it may mean longer-lasting recovery, reduced relapse and improved ability to work, study and maintain relationships. This is where neuroplasticity, biomarkers and precision medicine converge. The goal is not simply to produce more CNS drugs, but to produce treatments developed with stronger models, tested in better-defined patients, measured with more meaningful tools and aimed at outcomes that last. Precision Medicine Precision medicine is revolutionising other medical fields, such as oncology, where the type of genetic mutation a tumour carries might now dictate the treatment strategy. In CNS medicine genetics won’t always be the way we subdivide patients into groups, but the same principle is being applied: better matching so the right patients get the right treatment at the right time. This approach will require integration of multiple data types. Genetics might identify causal mechanisms in rare neurodevelopmental disorders. Imaging might reveal network or structural changes. Fluid biomarkers might indicate underlying pathology. Digital measures might capture real-world function. Clinical and behavioural data might define meaningful outcomes for patients and families. Artificial intelligence and machine learning could help interpret these multimodal datasets, although their use must be transparent, validated and clinically interpretable. Early Diagnosis and Intervention In many neurodegenerative diseases, by the time symptoms are clear, substantial damage has already occurred. Meanwhile, in neurodevelopmental conditions, intervening earlier is likely to influence developmental trajectories more. Diagnosing disease early is therefore of paramount importance – 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY
although not straightforward. The technical, economic and ethical challenges are considerable. Is a test accurate? Is it cheap enough to be rolled out at scale? Even if it meets these criteria, can anything be done for those we identify with the disease? Regulation and Collaboration Nonetheless, the direction of travel is clear. We are beginning to make strides towards identifying CNS disorders earlier, more precisely, and beginning to develop therapies for them that have disease-modifying potential. All this is good. To go further – to climb higher – the regulatory environment will be critical. Developers need clarity on how biomarkers, digital tools, adaptive trial designs and novel preclinical models can support decisionmaking. Regulators, in turn, need robust evidence that these tools are reliable, reproducible and linked to outcomes that matter. Adaptive and platform trials may help in heterogeneous diseases by testing multiple interventions or patient subgroups more efficiently. Decentralised trials could help boost recruitment, speed up trials and reduce the burden on patients and caregivers. Collaborations will also play an important role by enabling greater data sharing and reducing duplication of effort. This will be particularly important in rare or high-risk
The brain is not a static organ. It changes throughout life, for better and worse. The next phase of CNS drug development will depend on learning how to measure, guide and restore that change with far greater precision. The next phase might not take us to the peak, but it will raise us higher up, and from there we will have a clearer view of the challenges ahead.
Dr. Josep Prous, Jr Co-founder and CSO of CONNECTA, codiscoverer of CTH120 and CONNECTA’s Principal Investigator, leads the company’s scientific strategy. His experience encompasses management roles as Executive Director-Science of Prous Institute for Biomedical Research and strategic advisor in several biomedical companies. He has previously founded other companies that were subsequently acquired by major players in the industry. Josep has a long experience in establishing collaborations with academic institutions and regulatory authorities, as well as with KOLs in science and medicines.
Autumn 2026 Volume 18 Issue 3
Transforming your bright ideas into brilliant opportunities for decades
Aptar Pharma – your go-to drug delivery partner, from formulation to patient When pharmaceutical companies around the world want to develop safe, efficient and compliant medicines, they turn to Aptar Pharma for proven drug delivery solutions. Leveraging our therapeutic insights, over 30 years of regulatory expertise and the widest portfolio of solutions and services in the industry, we accelerate and derisk our customers’ drug development process, helping them transform bright ideas into new market opportunities to improve and save patient lives. Let’s partner together on your next bright idea. Visit www.aptar.com/pharmaceutical to get started.
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59
Subsection: Neurodegenerative Diseases
Translating Clinical Evidence to Advance N2B Drug Development For decades, nose-to-brain (N2B) drug delivery has offered an attractive proposition as a non-invasive means of reaching the central nervous system (CNS) while reducing reliance on transport across the blood–brain barrier.1,2 The scientific rationale has been supported by extensive preclinical research yet one fundamental question has continued to limit clinical confidence: can a molecule administered through the nose be shown to reach relevant regions of the human brain?2,3 Nasal administration is already established in several CNS-related conditions, including epilepsy, migraine, depression and opioid overdose.4 These products demonstrate many of the advantages that continue to drive interest in the nasal route, offering a noninvasive, easy-to-use alternative to injectable administration while providing a similarly rapid onset of action.4,5 Most, however, primarily depend on absorption through the nasal mucosa into the systemic circulation, with CNS exposure achieved after the active molecule crosses the blood–brain barrier. 5–7 Direct N2B delivery has a different objective. It seeks to use the anatomical connections of the olfactory and trigeminal pathways to transport therapeutics from the nasal cavity to the CNS.8 Interest in this approach is increasing as the development pipelines expand to include peptides, proteins and other molecules with limited blood–brain barrier permeability.1,5 It is also being driven by demand for patient-friendly treatments capable of achieving rapid and meaningful CNS targeting while reducing systemic exposure and the associated risk of peripheral effects.1,2 Recent human imaging studies have now provided direct evidence of N2B transport in humans. As a result, the development question is no longer limited to whether this pathway exists.9 Attention is increasingly turning to how reliably it can be achieved, which factors influence delivery in different individuals and how the formulation and delivery system can be configured to improve performance. 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The Challenge of Human Validation Before this direct human imaging data became available, N2B delivery had long generated scientific interest but translation into clinical development was constrained by two related challenges: 1) demonstrating that a molecule reached the human brain and 2) achieving sufficiently consistent administration to interpret therapeutic outcomes.2,10 Preclinical studies have provided substantial evidence that compounds can move from the nasal cavity into the CNS along pathways associated with the olfactory and trigeminal nerves.2 However, evidence of transport in an animal model does not necessarily establish how a formulation and delivery system will perform in humans.10 Differences in nasal anatomy, administration technique, formulation behaviour and disease-related physiology may all affect the amount, location and timing of brain exposure.2,10,11 This uncertainty has made it difficult to separate the performance of a therapeutic molecule from the performance of its delivery method. If a clinical study does not produce the expected therapeutic response, it may be unclear whether the underlying biological hypothesis was incorrect or whether the administered dose failed to reach the intended CNS regions consistently.2 Early clinical experience illustrates this challenge: in the SNIFF trial with intranasal insulin, a change in delivery system during the study was associated with different clinical outcomes, highlighting how administration can complicate interpretation of therapeutic efficacy.12
This field is consequently moving towards system-level approaches supported by direct human evidence. Rather than treating the nasal spray system as a passive container, developers are increasingly considering formulation properties, spray performance, deposition location and user interaction as interdependent elements of the therapeutic strategy. By leveraging human imaging, researchers can evaluate the in vivo performance of the device–formulation platform, providing a deeper understanding of the nasal delivery system and creating new opportunities for optimisation. A Step Towards Evidence-Driven N2B Development A first-in-human PET study by researchers at Wake Forest University demonstrates how human imaging can be applied to evaluate N2B delivery in vivo.9 The investigation evaluated the safety, kinetics and regional distribution of intranasally administered radiolabelled insulin in 16 older adults (mean age 72 years) who were either cognitively normal or had mild cognitive impairment (MCI). Researchers administered the novel PET radiotracer using Aptar Pharma’s Cartridge Pump System (CPS), followed by a 40-minute dynamic PET scan to quantify regional brain uptake over time. A positioning guide was used to align the system with the nasal septum and increase the likelihood of deposition towards the superior turbinate and olfactory-regions. The importance of the study lies beyond insulin itself. PET enabled researchers to visualise and quantify brain uptake over time rather than inferring delivery solely from Autumn 2026 Volume 18 Issue 3
Subsection: Neurodegenerative Diseases clinical outcomes or peripheral measurements. It therefore provided information about the performance of an established nasal delivery system in a human N2B application and created a basis for further investigation and optimisation. What the Study Reveals About Human N2B Delivery Brain delivery is achievable. Following administration, radiolabelled insulin was detected in multiple regions associated with cognition and Alzheimer’s disease pathology, including the hippocampus, amygdala and temporal cortex. These findings provide direct human evidence that biologically active molecules can be delivered from the nasal cavity to anatomically distinct regions of the brain, supporting the translational relevance of the olfactory and trigeminal pathways previously identified in preclinical studies.9 Delivery is rapid and measurable. PET imaging showed that radiolabelled insulin reached the brain shortly after administration, with most uptake and clearance occurring within the 40-min imaging period.9 This temporal PET signal reflects the kinetics of brain delivery and radiotracer clearance rather than the duration of insulin’s biological activity, which may continue through receptor binding and downstream signalling.13,14 These findings provide direct insight into CNS delivery kinetics following intranasal administration, representing an important step towards defining CNS pharmacokinetics and informing rational dosing strategies. Delivery varies across individuals. Significant brain uptake was observed across the cohort, but the timing and extent of uptake were associated with physiological and clinical characteristics. Importantly, uptake in the MCI group generally peaked earlier, declined more rapidly and was lower across the evaluated brain regions. These findings suggest that N2B delivery is influenced not only by the administered therapeutic and delivery system, but also by individual biology and the integrity of the underlying transport pathways.9 Delivery can limit systemic insulin exposure. No major safety concerns were identified. Plasma insulin levels did not change significantly following administration, blood pressure remained stable and glucose levels remained above the threshold for hypoglycemia.9 Although the study was not designed to evaluate long-term safety or repeated administration, the findings provide www.international-pharma.com
initial human evidence that CNS delivery can be achieved without substantial systemic exposure.
and spray characteristics, particularly when precise targeting of the upper-nasal cavity is required.2,5
Taken together, the results demonstrate both the feasibility of human N2B delivery and the complexity of achieving consistent exposure across populations. By providing direct evidence of CNS transport in humans, imaging studies such as this one may also help distinguish whether an apparent lack of observable effect reflects the underlying therapeutic hypothesis, insufficient or inconsistent delivery to the intended CNS regions or a combination of both. This distinction could support more informed development decisions by reducing uncertainty around whether the drug or the delivery approach is limiting clinical performance. The study also provides an early indication of how delivery-related variability may be addressed: its use of a positioning guide to target the upper-nasal cavity illustrates the importance of administration strategy alongside formulation as the field moves beyond proof of concept towards optimising performance. Future progress will therefore depend not only on improving the consistency and targeting of delivery, but also on understanding how molecular characteristics influence transport and CNS exposure.
Conventional nasal spray pumps, including the CPS used in the PET study, were primarily developed for local or systemic applications, where broad deposition within the nasal cavity is often sufficient. N2B delivery presents a different engineering objective because effective engagement of the relevant neural pathways depends on reaching the olfactory and upper turbinate regions more reliably.2,11
The Challenge of Consistent and Targeted Delivery The nasal cavity presents a demanding environment for targeted drug delivery. Its internal geometry is complex, and the olfactory-region occupies only a small area high within the nasal cavity.5 Successful deposition depends on both device performance and user technique, including factors such as spray angle, insertion depth
The PET findings demonstrate that the CPS could support measurable N2B delivery, but they also highlight why delivery performance must be interpreted in context. The use of a positioning guide to improve targeting of the upper-nasal cavity reflects efforts to standardise administration and minimise user-related variability during delivery.9 There is therefore growing interest in configurations that can build on these established nasal technologies while further improving uppernasal deposition and reducing dependence on highly precise user technique. Treating N2B Delivery as an Integrated System Traditional pharmaceutical development often begins with the therapeutic molecule, with the delivery device selected later in the process. For N2B programmes, however, this sequence may create avoidable risk. Formulation properties, spray performance and user handling can all influence the effectiveness and reproducibility of drug delivery. This creates a need for delivery solutions designed to address the unique physiological and technical demands of N2B administration, while supporting more INTERNATIONAL PHARMACEUTICAL INDUSTRY 61
Subsection: Neurodegenerative Diseases precise, reproducible and clinically relevant CNS delivery.15 As N2B drug development matures, administration strategy is becoming increasingly important to improve confidence in development decisions, strengthen clinical interpretation and reduce programme risk. As a result, N2B delivery should be treated as an integrated system involving the formulation, pump, actuator and administration procedure. Consideration of human factors is particularly important because relatively small changes in insertion depth or orientation may alter the location of deposition. Accordingly, device– formulation co-development, informed by administration strategy and human factors, is increasingly being recognised as critical to optimising therapeutic performance and advancing development-ready N2B strategies. Evolving N2B Platforms: Validated Foundations and Purpose-Configured Targeting To support this integrated development approach, Aptar Pharma has introduced NeuroSpray™, a purpose-configured multidose platform specifically engineered for CNS applications. Building on clinically established platforms, including the CPS used in the landmark first-in-human PET study, NeuroSpray™ combines validated delivery technology with design features intended to support more consistent upper-nasal targeting without the need for external positioning accessories. Compared with conventional nasal spray configurations, NeuroSpray™ incorporates a narrower, more concentrated spray plume to better align with the targeting requirements
of upper-nasal delivery. Pre-compression actuation supports more controlled and reproducible spray generation while reducing run-off, thereby increasing contact time within the intended deposition region. NeuroSpray™ was also developed with human factors considerations integrated directly into the system design. Ergonomic controls and nostril-positioning features were incorporated to reduce sources of realworld variability, such as nasal alignment, insertion depth, orientation errors and the risk of misuse. Together, these elements aim to reduce reliance on perfect technique while supporting patient comfort and usability across diverse patient populations. The platform has been evaluated through a combination of preclinical, performance and human factors studies to characterise its delivery performance under clinically relevant conditions. These internal studies
have demonstrated targeted upper-nasal deposition, reproducible administration and usability under real-life conditions. For example, in vitro testing using a low-viscosity placebo formulation has shown olfactoryregion deposition of up to 50% under varied spray angles with NeuroSpray™, compared with approximately 1–5% for the standard pump configuration.2 Collectively, these capabilities demonstrate how an integrated device–formulation approach can support more consistent CNS-focused administration across diverse formulations and clinical programmes, helping to advance the development of noninvasive CNS therapies. Implications for Future Drug Development Purpose-configured delivery platforms such as NeuroSpray™ represent one example of how advances in administration technology can complement emerging human evidence. More broadly, they illustrate the direction in which N2B development is evolving, from demonstrating biological feasibility toward systematically optimising delivery performance. To address this growing need to validate delivery performance alongside therapeutic efficacy, NeuroSpray™ helps developers incorporate delivery configuration into the N2B development strategy. Device– formulation co-development, supported by deposition modelling, in vitro testing, imaging and human factors evaluation, can help characterise CNS exposure and guide development to help reduce uncertainty earlier in development. Conclusion N2B delivery is becoming a more structured and evidence-driven development field.
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Autumn 2026 Volume 18 Issue 3
Subsection: Neurodegenerative Diseases Human PET imaging has now demonstrated that intranasally administered insulin can reach multiple cognition-related regions of the brain, while also revealing differences in uptake associated with cognitive status and other biological variables. These findings validate the feasibility of the route but reinforce the need for larger studies, deeper investigation of patient variability and stronger control of upper-nasal deposition. Progress will depend on integrating molecular science with formulation development, device engineering, imaging and human factors. As N2B drug development evolves, device–formulation co-development offers a framework for integrating these elements into a single therapeutic strategy. Platforms such as NeuroSpray™, which combine purposeengineered delivery technology with human factors and performance validation, illustrate how this approach may help improve delivery consistency while supporting the development of non-invasive, patient-friendly CNS therapies.
3.
4.
5.
6.
7.
8. 9.
REFERENCES 1. 2.
Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012;64:614–28. Drath I, Richter F, Feja M. Nose-to-brain drug delivery: from bench to bedside. Transl Neurodegener 2025;14.
10.
Solingapuram Sai KK, Erichsen JM, Gollapelli KK, Krizan I, Miller M, Bansode A, et al. First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys. Journal of Alzheimer’s Disease 2024;101:309–20. Chung S, Peters JM, Detyniecki K, Tatum W, Rabinowicz AL, Carrazana E. The nose has it: Opportunities and challenges for intranasal drug administration for neurologic conditions including seizure clusters. Epilepsy Behav Rep 2023;21:100581. Djupesland PG, Messina JC, Mahmoud RA. The Nasal Approach to Delivering Treatment for Brain Diseases: An Anatomic, Physiologic, and Delivery Technology Overview. Ther Deliv 2014;5:709–33. Martin V, Hoekman J, Aurora SK, Shrewsbury SB. Clinical Medicine Nasal Delivery of Acute Medications for Migraine: The Upper Versus Lower Nasal Space. J Clin Med 2021:10. Raza AA, Ahmed GU, Zafar H, Owais Akhtar S, Bin Mobin M, Samadi A. Spravato for TreatmentResistant Depression: Efficacy and Sexual Side Effect Profile 2025;21:2125–140. Nguyen LTT, Duong VA. Nose-to-Brain Drug Delivery. Encyclopedia 2025, Vol 5, Page 91 2025;5:91. Sai KKS, Erichsen JM, Gollapelli KK, Krizan I, Miller M, Damuka N, et al. First-in-human positron emission tomography study of intranasal insulin in aging and MCI. Alzheimers Dement (N Y) 2025;11:e70123. Patharapankal EJ, Ajiboye AL, Mattern C, Trivedi V. Nose-to-Brain (N2B) Delivery: An Alternative Route for the Delivery of Biologics in the Management and Treatment of Central Nervous System Disorders. Pharmaceutics 2023;16:66.
11.
12.
13.
14.
15.
Alwali B, Parumasivam T, Al-Tabakha MM. Intranasal drug delivery: Unlocking the nose-tobrain route for central nervous system therapies. Int J Pharm X 2026;11:100521. Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol 2020;77:1. Shaw RC, Tamagnan GD, Tavares AAS. Rapidly (and Successfully) Translating Novel Brain Radiotracers From Animal Research Into Clinical Use. Front Neurosci 2020;14:871. https://doi.org/10.3389/ FNINS.2020.00871. Meng X, Kong X, Xia L, Wu R, Zhu H, Yang Z. The Role of Total-Body PET in Drug Development and Evaluation: Status and Outlook. J Nucl Med 2024;65:46–53. https://doi.org/10.2967/ jnumed.123.266978. Deruyver L, Rigaut C, Lambert P, Haut B, Goole J. The importance of pre-formulation studies and of 3D-printed nasal casts in the success of a pharmaceutical product intended for noseto-brain delivery. Adv Drug Deliv Rev 2021;175. https://doi.org/10.1016/j.addr.2021.113826.
Julie D. Suman Julie Suman, PhD, is the Vice-President of Scientific Affairs for Aptar Pharma. Dr Suman holds a BSc in Pharmacy and a PhD in Pharmaceutical Sciences. She is co-editor for Respiratory Drug Delivery Proceedings, and an Affiliate Assistant Professor in the Department of Pharmaceutics at Virginia Commonwealth University (VA, US). She also co-founded Next Breath, an analytical services company. Dr. Suman has published in several peer-reviewed journals and presented at numerous international meetings.
Reenal Gandhi Reenal Gandhi is Global Business Development Director at Aptar Pharma’s Prescription division, focused on assessing new technologies. With over 15 years in drug delivery and pharma, she is passionate about developing combination products that balance formulation, device technology, and commercial potential. Prior to joining Aptar in 2020, she held roles in licensing and acquisitions at global pharma and device companies.
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Subsection: Nasal & Pulmonary
Keeping Pace with Increasing Complexity in Pharmaceutical Analytics Founded in 1995 in response to a growing need for outsourced pharmaceutical stability testing, A&M STABTEST has developed into a broad analytical service provider. In this interview with The International Pharmaceutical Industry Journal, the company looks back at its origins and discusses how increasingly complex drug products, inhalation therapies, new analytical technologies and digitalisation are changing the requirements for pharmaceutical analytics. Please introduce A&M STABTEST. How was the company founded, and which analytical testing services does the company provide to the pharmaceutical industry today? The story of A&M STABTEST began with four analytical scientists who studied together at the University of Cologne and later worked in the pharmaceutical industry, gaining first-hand experience of its analytical and regulatory requirements. In the early 1990s, new ICH guidelines and increasing post-authorisation requirements created a growing need for stability testing, while external capacity remained limited. The four scientists recognised this gap and, in 1995, founded A&M STABTEST as one of the first German GMP-certified provider to offer pharmaceutical analytics and stability testing as a strategic outsourcing solution. GMP has been at the core of the company from the beginning. A&M STABTEST has been GMP-certified since its foundation and is operating in an international regulatory environment since many years, including regular inspections by the EMA, the FDA and other regulatory authorities. From these beginnings, the company has developed considerably. Today, A&M STABTEST employs nearly 400 people across two sites in Bergheim and Mainz and provides analytical services along the pharmaceutical product lifecycle. Our work ranges from API and excipients testing through process performance qualification (PPQ) to finished pharmaceutical products and combination products. It also includes packaging and drug-device testing, including extractables 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY
and leachables, material characterisation, container closure integrity and functional testing. Our scientific scope has expanded accordingly. In addition to classical pharmaceutical analytics and stability testing, we provide analytical method development, transfer and validation, quality control and release testing, mass spectrometry, bioassays, biopharmaceutical characterisation and specialised inhalation analytics. We work with classical small molecules as well as biological molecules, complex formulations and new therapeutic approaches. For us, development is therefore not simply about adding laboratory space or new instruments. It is about continuously building the analytical capabilities and specialist expertise required as pharmaceutical products and regulatory requirements become more complex. What sets A&M STABTEST apart? How does the company differ from other analytical service providers? A characteristic of A&M STABTEST is the combination of scientific expertise, flexibility and personal communication. We are large enough to offer a broad analytical portfolio and support complex projects in a regulated pharmaceutical environment. At the same time, we have maintained direct communication structures. For our customers, this means that they are not simply sending samples to a laboratory and receiving results some weeks later. They communicate directly with the scientists involved in their projects. This becomes particularly important when something does not work as expected – and in pharmaceutical development, this can always happen. In such situations, you need more than an analytical result. You need people who understand the method and the product and who can discuss possible solutions with you. Another important aspect is specialist knowledge. Particularly when dealing with unexpected results or working under
time pressure, a good understanding of the customer's regulatory requirements is essential. Many of our employees have been with A&M STABTEST for many years, building extensive knowledge of specific products, analytical methods and their history. This experience allows us to assess unexpected results in the appropriate context and provide the analytical support required. For us, good service therefore means more than generating GMP-compliant data. We also want to understand why an analysis is needed, which question has to be answered and how the results will be used. What are the key analytical challenges associated with testing dry powder and metered-dose inhalers, and how do you help customers address them? Inhalation products are particularly interesting from an analytical point of view because you are not only analysing the formulation, but also the performance of the complete drug-device combination. For both dry powder inhalers and metered-dose inhalers, parameters such as Aerodynamic Particle Size Distribution (APSD), and Delivered Dose (DD) are essential. It is not sufficient to determine how much active pharmaceutical ingredient is present in the product. You also need to understand how the dose is delivered, which particle sizes are generated and whether this performance is reproducible. With DPIs, for example, airflow plays an important role because the patient’s inspiratory effort contributes to the dispersion of the powder. MDIs have different challenges, particularly regarding consistent aerosol generation and dose delivery. Each inhalation system therefore has to be understood and tested according to its specific characteristics. The analytical procedures themselves are also demanding. Cascade impaction requires specialised equipment, several analytical steps, controlled environmental conditions and, most importantly, experienced analysts. For this reason, we have invested in the necessary instrumentation as well as Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary dedicated inhalation laboratories with controlled temperature and humidity conditions. However, having the right equipment is only one part of it. You also need people who perform these analyses regularly and understand the critical parameters of the method and the product. You can buy an instrument quite quickly. Building the necessary experience takes years. What trends are currently shaping the development of inhalation therapies, and how are they influencing analytical testing requirements? One interesting development is that inhalation is no longer only associated with classical respiratory indications such as asthma or COPD. The lung is increasingly being considered as a route for more complex therapeutic molecules. We see growing interest in nanoparticle-based formulations, biological molecules and nucleic-acid-based approaches, for example LNP-formulated mRNA and DNA. From an analytical perspective, this makes the situation much more complex. Classical inhaler performance testing remains essential. We still need to understand Delivered Dose and aerodynamic particle behaviour, but these tests increasingly have to
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be combined with advanced characterisation of the formulation and the active substance. As a result, different analytical areas are coming closer together. Aerosol science may need to be combined with mass spectrometry, particle characterisation, biological assays or other specialised technologies. At the same time, there is greater focus on the device and packaging components that are in contact with the pharmaceutical formulation. This means that extractables and leachables are becoming increasingly relevant, together with other aspects of packaging and device testing such as material identification and characterisation, container closure integrity and functional testing. This shows that inhalation analytics is becoming increasingly multidisciplinary. It is no longer only about testing aerosol performance, but about understanding the formulation, the device and their interaction as a complete system. How does A&M STABTEST ensure it consistently meets the quality expectations of customers and the requirements of global regulatory authorities? For a pharmaceutical analytical service provider, quality as well as trust and confidence are fundamental. Our customers
rely on our data for regulatory submissions, batch release and other important decisions. They therefore need confidence not only in the results, but also in the processes and people behind them. Our laboratories operate according to current GMP requirements, applicable regulatory guidelines and customer-specific requirements. We also have many years of experience with regulatory inspections and customer audits, including repeated FDA inspections. However, compliance alone does not create trust. Customers also expect reliable timelines, transparent communication and scientifically sound investigations when unexpected results occur. This requires experienced scientists who understand the method, the product and its regulatory context. Many of our employees have worked with certain methods and customer products for many years, building specialised knowledge that can be particularly valuable when assessing unusual results. For us, quality therefore combines regulatory compliance, scientific expertise and reliable processes. Together with open communication, these elements create confidence in our work and the long-term trust required between a pharmaceutical company and its analytical service provider.
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Subsection: Nasal & Pulmonary How is A&M STABTEST continuing to develop its analytical capabilities? We grow with our customers. We listen closely to their needs and follow how their products and pipelines are developing.
and analytical requirements become more complex. Quality control and stability testing will remain important parts of our business, while we continue to evolve with the market and develop areas that require specialised infrastructure and scientific expertise.
For us, the question is not just, “Which new instrument should we buy?” The more important question is, “Which analytical problems will our customers have to solve in the coming years?” This is what drives the development of our capabilities.
Inhalation is one example. As more complex therapeutic modalities are developed for pulmonary and nasal delivery, we can combine established OINDP testing with advanced analytical technologies to address the resulting analytical challenges.
We are currently strengthening areas such as inhalation analytics, extractables and leachables – including new requirements such as USP <665> – and force measurement, while continuing to expand our capabilities for complex pharmaceutical and biopharmaceutical products.
Digitalisation is another important topic. We have started a long-term project that will gradually bring our complete operations into one integrated system. It is not simply about replacing paper with electronic documents, but about connecting processes and data across the company. In a GMP-regulated environment, this transformation has to be carefully planned, validated and implemented step by step.
Scientific exchange is also important for us. We organise technical workshops at our sites, bringing together customers, specialists and industry partners for presentations, demonstrations and informal exchange. This October, our Mainz workshop will focus on OINDP testing and inhalation analytics, cohosted by Copley, while the Bergheim workshop will cover advanced protein characterisation, co-hosted by Bio-Techne/R&D Systems. These are not intended as sales events. They provide an opportunity to discuss technologies, practical applications and real analytical challenges. At the same time, the exchange helps us understand which capabilities our customers may need from us in the future.
We are therefore developing A&M STABTEST on several levels at the same time – scientifically, technologically and operationally. Finally, you came to A&M STABTEST from a different professional background. How does this influence your role in Business Development?
What does the future of the company look like?
That’s right. I’m a trained molecular biologist, and before joining A&M STABTEST I spent 15 years in product sales and the management of service projects in life science research. Moving into pharmaceutical analytics meant entering a new and highly regulated field, but my scientific background and commercial experience provide a useful perspective for my responsibilities at A&M STABTEST.
We want to remain a reliable analytical partner for our customers as their products
Business Development at A&M STABTEST is mainly strategic. We analyse developments
in the pharmaceutical market, follow new technologies and therapeutic trends, monitor the competitive environment and identify areas where A&M STABTEST should further develop its analytical portfolio. Another important part of our role is positioning the company in the market and representing A&M STABTEST within regional and wider life science and pharmaceutical networks. For me, this combination makes pharmaceutical analytics an exciting market to work in. I enjoy the exchange and collaboration with our customers and industry partners, and I look forward to the new challenges and opportunities the coming years will bring. UPCOMING WORKSHOPS A&M STABTEST Technical Workshops 2026 07+08 October, Mainz: OINDP Testing & Inhalation Analytics – co-hosted by Copley Further information and registration: https://events.am-labor.de/mz/ workshop/07-08.10.26 15 October, Bergheim: Advanced Protein Characterisation – co-hosted by Bio-Techne/R&D Systems Further information and registration: https://engage.bio-techne.com/ amstabtest
Dr. Regina Ohmer Dr. Regina Ohmer joined A&M STABTEST’s Business Development team in 2025, following 15 years in the life science industry, including positions at Tebubio and Singleron. Her experience covers customer-focused business development, project management and marketing, and she represents A&M STABTEST in regional and international industry networks. A trained Biological Technical Assistant, she holds a PhD in Molecular Genetics from the University of Cologne.
66 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Autumn 2026 Volume 18 Issue 3
LABORATORY FOR ANALYSIS AND STABILITY TESTING
Precision in Inhalation Confidence in Every Dose ADVANCED ANALYTICAL TESTING FOR INHALED DRUG PRODUCTS Fully compliant with cGMP and ICH guidelines; 30 years experience as GMP-certified lab From development studies to market release Extended Storage at ICH-conditions
OUR INHALATION TESTING CAPABILITIES INCLUDE: MDI • DPI • Nebulizers • Nasal Including advanced modalities (e.g. mRNA, viral vectors) Method development • Validation service Routine testing • Release testing
ical Techn r u o t sa p Meet u rksho o W n tio Inhala ientific ley Sc p o C z, with , Main r e b o t c 7-8O ny Germa
w w w. a m - l a b o r. d e www.international-pharma.com
r e q u eINTERNATIONAL s t . m z @ aPHARMACEUTICAL m - l a b o r. dINDUSTRY e 67
Subsection: Nasal & Pulmonary
Why Is the Nasal Route Redefining Systemic and CNS Drug Delivery? Converging Trends Driving Changes in Nasal Route Medicines Until about ten years ago nasal drug delivery was primarily associated with the treatment of local conditions such as allergic rhinitis, sinusitis, and nasal congestion. Since then, advances in pharmaceutical sciences, formulation technologies, device engineering, and patient-centric healthcare are redefining therapeutic opportunities in intranasal drug delivery. A growing number of prescription systemic-acting drugs originally administered in injectable forms have been successfully repurposed and achieved market approval in metered-dose nasal sprays. Innovative clinical stage pharmaceutical companies are focussing on nasal systemic drug delivery as an efficient route of administration for therapies requiring rapid absorption, ease of use, and improved patient experience. By targeting the highly vascularised nasal mucosa, drugs can enter systemic circulation quickly while bypassing gastrointestinal degradation and first-pass hepatic metabolism, offering a compelling alternative to systemic delivery via oral and injectable route. Further advances in nasal delivery are being driven by efforts to target drug delivery to the olfactory zone as the approach underpinning direct noseto-brain uptake via the olfactory nerve and epithelial pathways. These exploratory drug transportation pathways may enable the development of clinically effective, and more patient-friendly therapies compared with invasive injections. At Nemera, we see this evolution being driven by several converging trends: the need for non-invasive treatment options, increasing demand for self-administration, and the shift toward healthcare solutions that can be delivered outside traditional clinical settings. This momentum is reflected in market forecasts, with leading intranasal therapies expected to grow at a compound annual growth rate (CAGR) of 14.7% between 2025 and 2030.1 New Therapeutic Frontiers for Nasal Systemic Drug Delivery What was once a route dedicated to local 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY
treatments is expanding across multiple therapeutic areas where speed, convenience, and accessibility are critical. Emergency and Rescue Medicines Emergency care remains one of the most established applications for nasal systemic drug delivery. Systemic-acting compounds such as naloxone and nalmefene for opioid overdose reversal; epinephrine for acute epileptic seizures and zavegepant and sumatriptan for migraine rescue, have demonstrated the effectiveness of nasal administration in emergency and rescue situations. The evolution of the nasal naloxone market provides interesting insights into realistic future opportunities in intranasal systemic-acting drug development. The FDA's approval of Narcan® (naloxone hydrochloride) nasal spray for over-thecounter (OTC) use in March 2023 marked a significant public health milestone. Driven by the urgent need to address the escalating opioid overdose crisis in the United States, where more than 100,000 overdose deaths have been reported annually, largely linked to synthetic opioids such as fentanyl, the decision aimed to expand access to a lifesaving treatment capable of rapidly reversing opioid overdoses.2 A key factor supporting both the FDA's decision and the subsequent growth of the nasal naloxone market was the inherent usability of the drug-device combination product. The ready-to-use single dose nasal spray requires no pre-assembly, can be administered quickly without specialised training, and is suitable for use by family members, caregivers, first responders, and bystanders. Based on robust evidence demonstrating the safety of naloxone and the ease with which consumers can correctly use the nasal spray device without healthcare professional supervision, the FDA concluded that OTC availability was appropriate. This combination of clinical effectiveness, accessibility, and user-friendly device design has reinforced the nasal route as a compelling platform for emergency interventions. Beyond its immediate public health impact, the OTC switch has provided strong
regulatory validation for nasal drug delivery as a route capable of accommodating selfadministration in acute critical care situations. The approval has reinforced industry confidence in nasal technologies, encouraging further investment and development across a broader range of therapeutic areas where improved accessibility, emergency intervention, or patient self-management can deliver meaningful healthcare benefits. Metabolic and Cardiovascular Disorders For the treatment of severe hypoglycaemia, nasal glucagon was developed primarily to solve a practical problem: injectable glucagon is highly effective pharmacologically, but in a real-life emergency it is often difficult for caregivers to prepare and administer correctly. Clinical studies have shown that nasal glucagon provides comparable glucose recovery while being substantially easier to use. More recently, the approval of etripamil as an on-demand rescue treatment of Paroxysmal Supraventricular Tachycardia (PSVT) enables patients to self-administer at symptom onset to terminate an episode before requiring emergency intervention and intravenous therapy. These examples illustrate the potential of the nasal route to create therapeutic value in cardiovascular disease management, enabling patients to manage acute episodes independently and safely, reducing reliance on hospital interventions and supporting the broader trend toward decentralised care. Neurological and Mental Health Care The growing burden of mental health disorders, combined with the need for rapid therapeutic intervention, is driving interest in intranasal approaches for central nervous system (CNS)-acting therapies. Among the most notable examples is esketamine nasal spray, approved for treatment-resistant depression and major depressive disorder with acute suicidal ideation or behaviour. Intranasal, esketamine has been shown to provide rapid systemic absorption resulting in clinical benefits and is therefore a viable alternative to traditional oral antidepressant therapies, which may require several weeks to achieve full therapeutic effect. Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary Beyond depression, pharmaceutical companies are actively exploring intranasal approaches for anxiety disorders, posttraumatic stress disorder (PTSD), schizophrenia, and other neuropsychiatric conditions where rapid symptom control, improved patient adherence, or enhanced CNS exposure may offer clinical benefits. As innovation in formulation science and device technologies continues, mental health care is expected to remain a key area of growth for nasal systemic drug delivery. Central Nervous System and Brain Diseases Nose-to-brain delivery continues to attract interest as a non-invasive strategy for transporting therapeutics to the CNS and the brain while potentially circumventing the blood-brain barrier and avoiding undesirable systemic exposure. The therapeutic scope encompasses chronic neurodegenerative conditions, particularly Alzheimer’s and Parkinson’s diseases and brain tissue damage and primary or metastatic brain cancers. Therapeutic compounds under investigation range from conventional small molecules to peptides and proteins, including insulin, growth factors and neuropeptides, as well as antibodies, nucleic-acid-based therapeutics and extracellular vesicle-derived biological materials.
However, successful translation will depend not only on the intrinsic properties of the active substance, such as molecular weight, stability, lipophilicity and surface charge, but also on formulation characteristics, nasal anatomy, and delivery-device performance. This is driving research in advanced formulations designed to protect sensitive active ingredients, increase residence time at the nasal mucosa and facilitate transport towards or across the nosebrain interface. Examples include mucoadhesive and thermo-responsive gels, liposomes, polymeric nanoparticles, nanostructured lipid carriers and lipid nanoparticles. Exosomes and other extracellular vesicles are also emerging as biologically derived carriers with potential applications in CNS and brain delivery. As innovation in pharmaceutical sciences and device design advance in parallel, the N2B route may unlock new therapeutic possibilities for a significant number of high interest compounds that cannot cross the blood-brain barrier. An Attractive and Fast-Growing Market Several indicators highlight the growing commercial opportunity for nasal systemic drug delivery: •
Leading intranasal therapies are forecast to grow at a compound annual growth
Life-saving, emergency & crisis application. KEY POINTS Single metered dose of 100 μL One-handed activation & 360° handling Compliant with reliability criteria for emergency use applications Clear activation confirmation after use Proven bioequivalence versus key reference products Figure 1: UniSpray IPI2 www.international-pharma.com
rate (CAGR) of 14.7% between 2025 and 2030, reflecting sustained investment across both established and emerging therapeutic areas.1 •
The global epinephrine market is projected to exceed $6 billion by 2033, supported by growing interest in needle-free treatment options and the emergence of novel intranasal alternatives to traditional autoinjectors.3
•
The successful commercialisation of products such as Narcan® (naloxone), Baqsimi® (glucagon), Spravato® (esketamine) and Zavzpret® (zavegepant) confirms the ability of nasal delivery technologies to support diverse therapeutic applications, ranging from emergency interventions to chronic disease management.
Together, these trends indicate that nasal delivery is evolving from a niche administration route into a strategically important segment of the drug delivery market. Device Innovation: Enabling the Next Generation of Nasal Systemic Therapies As nasal delivery expands into new therapeutic frontiers, successful products increasingly rely on delivery systems that combine performance, ease of use, and development flexibility. Nemera's portfolio of nasal platforms, including UniSpray (Figure 1), DuoSpray (Figure 2) and Guided Stream Technology (Figure 3) have been developed to address the evolving needs of systemic, CNS, and nose-to-brain therapies, providing pharmaceutical companies with scalable, patient-centric solutions that support differentiated products across both established and emerging therapeutic areas. UniSpray: A Unit-Dose Platform for Emergency and Rescue Therapies UniSpray is a ready-to-use, primeless nasal device designed to deliver a single metered liquid dose of 100 µL through one-handed actuation and in 360° device orientations. After actuation, the plunger is secured in its final position, providing a visible indication that the device has been used, preventing inadvertent reuse and limiting post-use disassembly (Figure 1). It is compliant with the FDA’s strict reliability specifications for rescue and emergency medicines. UniSpray is strategically positioned as a robust platform for both generic and overthe-counter (OTC) naloxone nasal sprays. It has been evaluated against the reference INTERNATIONAL PHARMACEUTICAL INDUSTRY 69
Subsection: Nasal & Pulmonary by patients and caregivers across a range of care settings, from home-based treatment to healthcare environments.
KEY POINTS Two metered doses of 100 µL (200 µL total) Visual dose indicator One-handed activation & 360° handling Compatible with industrystandard filling processes Supports in vitro bioequivalence strategies
Figure 2: DuoSpray
product Narcan® through a comprehensive test programme including usability, threshold and interchangeability assessments. These studies demonstrated that users can operate the device safely, reliably and without training, supporting the demands of realworld overdose situations. Importantly, the FDA-reviewed threshold analysis concluded that the identified design differences between UniSpray and the reference product did not affect critical user interactions, dose delivery, activation or overall performance. Furthermore, the subsequent interchangeability assessment confirmed that individuals familiar with Narcan® could transition to UniSpray without additional training. Based on these findings, the FDA determined that no comparative human factors study was necessary, reinforcing UniSpray's suitability as a regulatory-ready platform that can help accelerate the development of affordable generic and OTC naloxone products. Leveraging Nemera's proven experience in emergency and rescue therapies, this is a regulatory-ready platform supported by bioequivalence data generated in generic development programmes for epinephrine, nalmefene and zavegepant, helping accelerate development timelines and reduce programme risk. 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY
DuoSpray: Precision for Acute and Rescue Therapies For therapies requiring accurate bidose administration, DuoSpray provides a readyto-use solution featuring: • • •
Two metered sprays of 100 µL each No priming required before use User-friendly administration in timecritical situations
These characteristics make DuoSpray particularly well suited for acute and rescue applications, including cardiovascular and neurological indications. Designed to deliver two sequential doses from a single device, DuoSpray supports treatment regimens that may require dose repetition while maintaining a simple and intuitive administration process. The compact, ready-to-use format eliminates preparation steps and enables rapid treatment initiation when speed and ease of use are essential. The platform combines patient convenience with dosing flexibility, offering pharmaceutical developers a solution adapted to therapies where a second administration may be required to achieve the desired clinical outcome. Its ergonomic design supports use
Compatible with established primary container formats and conventional filling processes, DuoSpray facilitates integration into existing pharmaceutical development and manufacturing pathways. This compatibility can help streamline product development while reducing technical complexity during scale-up and commercialisation. Guided Stream Technology: Designed for Nose-to-Brain Delivery Realising the clinical potential of CNS and brain-acting therapeutics requires a noninvasive device capable of depositing a defined liquid volume reproducibly in the olfactory region, a small and anatomically remote area located towards the back of the nasal cavity. Conventional atomised nasal sprays were developed primarily for local or systemic delivery and typically deposit most of the emitted dose in the anterior and inferior nasal passages, with reported olfactory deposition generally below 5%. Nemera is closing this performance gap with its Guided Stream Technology (GST), which combines an established nasal pump with a proprietary nozzle that generates a narrow, directionally stable liquid stream rather than a dispersed atomised plume. The stream is designed to travel up the septal surface into the olfactory cleft. In an anatomically averaged human nasal cast (Figure 4), GST can deliver over 90% of the administered formulation to the defined olfactory region under controlled in vitro conditions.4 Formulation deposition performance is maintained across a practical range of device orientations, and the impaction force is comparable with marketed pressurised nasal saline products.4,5 Collectively, these findings establish GST as a clinically viable, non-invasive platform ready to progress into R&D and human studies to further knowledge in this field. Conclusion Nasal systemic drug delivery is evolving into a major growth segment of the pharmaceutical industry, driven by strong clinical and commercial momentum across emergency and rescue medicines, metabolic and cardiovascular disorders, mental health, and CNS-targeted therapies. As pharmaceutical innovators increasingly seek rapid, noninvasive, and patient-friendly treatment options, device performance and usability are becoming critical determinants of success. Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary REFERENCES 1.
KEY POINTS High olfactory deposition for targeted CNS delivery Directionally stable liquid stream technology Robust performance in simulated clinical settings Ready to support next-generation CNS therapeutics
Figure 3: Guided Stream Technology
Through platforms such as UniSpray, DuoSpray, and Guided Stream Technology, Nemera is enabling the next generation of nasal therapies by combining robust delivery performance, regulatory readiness, and patient-centric design to support improved treatment access, adherence, and outcomes.
Mentions: BAQSIMI® is a registered trademark of Amphastar Pharmaceuticals Inc. NARCAN® is a registered trademark of Emergent Operations Ltd. SPRAVATO® is a registered trademark of Johnson & Johnson. ZAVZPRET™ is a registered trademark of Pfizer Ireland Pharmaceuticals.
2. 3.
4.
5.
Evaluate PharmaWorld Preview 2024, Outlook to 2030: Leading Intranasal Therapies Market Analysis, published 2024 FDA News Release FDA Approves First Over-theCounter Naloxone Nasal Spray | FDA accessed 13 August 2026 Grand View Research, Inc. Epinephrine Market Size, Share & Trends Analysis Report By Type (Auto-injectors, Nasal Sprays, Pre-filled Syringes), By Application, By Region, And Segment Forecasts, 2025 – 2033, published 2025. Sensitivity Analysis of Guided Stream Technology for Targeting The Olfactory Area Using an Anatomically Relevant Nasal Cast Foliard, T., Rabiller, S., Regard, A. DDL 2025 poster 108 Nemera unpublished data
Sophie Conte Sophie Conte is Marketing Category Manager for the Nose and Dermal franchises at Nemera. Sophie’s marketing experience spans diverse segments of the healthcare industry, including medical marketing, excipient manufacturing, digital health solutions and combination device manufacturing. At Nemera, she drives the new device innovation programmes, R&D collaborations and go-to-market strategies. Email: sophie.conte@nemera.net
Elsie Thomas Elsie Thomas is Marketing Category Manager for the Ear, Nose and Throat (ENT) franchise at Nemera. She leads strategic marketing initiatives for nasal drug delivery systems, supporting both established products and new combination device developments. Her experience spans pharmaceutical devices, bioequivalence driven generic programmes and global go to market strategies, working closely with R&D, regulatory and commercial teams. She contributes to portfolio positioning, customer centric value propositions and the launch of innovative nasal delivery solutions for international markets. Figure 4 – Nemera CUBO nasal cast showing delivery of a coloured liquid formulation to the representative olfactory zone using the GST device with an automatic actuation, in a controlled experimental setting www.international-pharma.com
Email: elsie.thomas@nemera.net
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Subsection: Nasal & Pulmonary
When the Ground Shifts, So Must the Materials Why converging regulation, sustainability and biologics are rewriting the specification for pharmaceutical materials – and why no company will solve it alone The pharmaceutical industry is experiencing not one disruption but several at once. PFAS restriction, the propellant transition, expiring device patents and the relentless rise of biologics are colliding – and each is quietly asking the same question of the components that touch our medicines. The answer will not come from a single supplier, but from an ecosystem willing to innovate together. Walk the halls of CPHI or the Drug Delivery to the Lungs (DDL) conference this autumn and one theme follows you from stand to stand: change. For two decades the materials in our inhalers, injectors, vials and filling lines were treated as settled science. That stability is ending. A cluster of regulatory, environmental and clinical pressures is arriving at once, and beneath every one lies the same question: is the material of construction still fit for what we now ask of it? The honest answer is rarely “exotic materials everywhere.” For most components, metals, elastomers and commodity plastics remain perfectly adequate, and highperformance polymers have historically been reserved for a device’s few genuinely demanding corners – the high-pressure dosing chamber of a soft mist inhaler being the classic example. What is changing is that those corners are multiplying. A useful rule of thumb: when three demanding requirements must be met at once – strength, say, with chemical inertness and a tight, stable tolerance – a specialist polymer such as PEEK (polyetheretherketone) begins to earn its place. It is worth holding that test in mind through what follows – asking not only what each pressure breaks, but what might quietly fix it. PFAS: From the Seal to the Coated Stopper Fluoropolymers such as PTFE and PVDF are everywhere in pharmaceutical operations – in valve seats, seals, gaskets and O-rings on filling lines, in non-stick coatings, and, critically, in 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Figure 1: Inhalers, injectors and line components – the materials of construction now under simultaneous regulatory, clinical and environmental pressure.
the spray-coated stoppers and plungers that protect injectable biologics. As PFAS restriction tightens across Europe, forward-looking teams are mapping where those chemistries sit in their bill of materials. Substitution is not uniform: where PTFE is chosen for its lubricity and non-stick behaviour, it is hard to match without real development work. But where a fluoropolymer is doing a sealing or chemical-resistance job, credible nonfluorinated options exist. PEEK, for example, is used for seals, valves and connectors across temperature extremes – from cryogenic handling to high-temperature aseptic processing – and its very low leachables suit it wherever purity in contact with the drug matters most. The lesson: a bill of materials can be unpicked function by function, not all at once. The Propellant Transition Greenhouse gas emissions from the pressurised metered-dose inhalers (pMDIs) segment account for a significant proportion of the carbon emissions from the inhalers devices (ref – Asthma and Lung UK. How inhalers affect the environment. Available at: https://www. asthmaandlung.org.uk/conditions/asthma/ how-inhalers-affect-environment); however, for 30% of patients, it is not possible to replace them with other inhalers (source – IPI Issue 3 of Volume 17 from Autumn 2025). With the Kigali Amendment entered in force in 2019, the segment is undergoing its second most significant transition towards
sustainability since the Montreal Protocol in the 1980s, moving to moving to low-globalwarming-potential propellants such as HFO-1234ze(E) and HFA-152a.1 Each differs from the incumbents in density, vapour pressure and solvating power, altering spray force, valve behaviour and – crucially – the extractables and leachables profile of every polymer and elastomer it touches.2 In short, changing the propellant can silently change the requirements of the valve, the seal and the canister lining. Here the material, not the propellant, becomes the variable worth changing: a component that stays inert against a more aggressive chemistry, and sheds few leachables of its own, absorbs uncertainty that would otherwise land on the valve and seal. It is one reason PEEK is increasingly discussed for canister linings, valve components and coatings that must hold up against an unfamiliar propellant. Patent Cliffs and the Pull Toward Precision As originator patents lapse, the differentiated engineering migrates from the molecule to the device – and to the materials that make it work. Soft mist inhalers are a case in point: by using a mechanical spring rather than a propellant, they sidestep the propellant debate while improving lung deposition, but that benefit is bought with engineering. The dosing components must withstand pressures of the order of hundreds of bar, hold micron-level tolerances, and remain inert in direct contact with the formulation. Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary
Figure 2. Larger volumes and higher viscosities demand more force through finer needles – pushing conventional device materials to their limits.
This is a corner where high-performance polymers already have a quiet track record: the dosing components of a class-defining soft mist inhaler were among the first places PEEK was adopted, because it could hold those tolerances under pressure, resist wear across thousands of actuations, and replace an assembly of small machined metal parts with one consolidated moulded component – taking out cost, weight and machining steps. As precision devices proliferate, that experience becomes more relevant, not less. The Biologics Effect on Injectors Nowhere is the pressure more visceral than in injectable delivery. The biologics boom – monoclonal antibodies, bispecifics and GLP-1 therapies – is pushing self-injection well beyond its comfort zone. Where autoinjectors once delivered up to 1 mL of a low-viscosity solution, developers now target 2.0–2.25 mL of formulations reaching 50 centipoise or more.3 Higher volume and viscosity mean one thing mechanically: more force, applied for longer, through finer needles. Device engineers describe conventional drive springs as reaching their practical limits, prompting ultra-thin-wall cannulae and alternative energy sources.4 Two things follow, and both play to a polymer’s strengths. First, thin-walled, load-bearing parts need a high strength-to-weight ratio, and properties can be tuned to the task: carbon-fibre-reinforced PEEK adds stiffness and strength without adding bulk, where every millimetre of device real estate is contested. Second, as these devices migrate from clinic to kitchen table, they must stay robust and dimensionally stable through drops, temperature swings and repeated use. Connectivity compounds www.international-pharma.com
it: as devices gain onboard electronics for adherence telemetry and charging, designers want to cut metal content, free up space and manage the electrical interface – another set of simultaneous demands a strong, dimensionally and dielectrically stable polymer can reconcile. Five Pressures, One Question Step back and the pattern is unmistakable. The surface questions differ – can our seals and packaging be re-specified? our valves tolerate new chemistries and forces? our components survive higher forces and viscosities? – but underneath lies the same one: are the materials of construction still fit for purpose, and if not, what can safely take their place? The recurring answer: a material chosen to satisfy several demands at once, not to optimise just one.
From Material Supplier to Innovation Partner By this stage PEEK has surfaced in almost every story, which is rather the point: it is not a universal answer but an unusually versatile tool in the kit, combining strength, chemical resistance, low moisture absorption, dielectric stability and high-temperature performance with injection-moulding to micron tolerances – and, as a non-fluorinated thermoplastic, standing in for certain fluoropolymers in specific sealing and thin-film roles.5 What turns those properties into advantage is evidence: a pharmaceutical-contact grade tested against USP Class VI, USP <87> and USP <661> reassures manufacturers that the part will meet endpart compliance testing, reducing risk and, potentially, time to market. The clearest proof is already in patients’ hands. In one classdefining soft mist inhaler, a metal dosing chamber that had to withstand roughly 340 bar was re-imagined in PEEK, preserving the performance of metal while remaining safe in direct contact with the formulation6 – and, on a life-cycle basis, consolidated moulded parts can carry a markedly lower carbon footprint than the machined metal they replace. The more important shift, though, is one of posture. The old model – specify a material, buy it by the kilogram, move on – sits poorly with an era in which changing one component can trigger extractables and leachables re-testing, stability restarts and regulatory resubmissions across a whole product. What is needed is not simply a supplier but a development partner: one that brings decades of evidence from other regulated sectors and engages early enough to de-risk the choice rather than merely fulfil it. It Takes an Ecosystem None of these pressures can be solved by any single link in the chain: the drug owner controls
Figure 3. High-performance polymers earn their place where three or more demanding requirements – strength, chemistry, precision, temperature, compliance – must be met at once. INTERNATIONAL PHARMACEUTICAL INDUSTRY 73
Subsection: Nasal & Pulmonary
2.
3.
4.
5.
6. Figure 4. Controlled innovation: change coordinated across drug owner, device developer, CDMO, packaging and material partners – so the whole ecosystem is enabled to adapt.
the formulation and dossier, the device developer the mechanism, the CDMO scaleup and fill-finish, the suppliers the parts that touch the drug, and the material scientist what a given polymer can, and cannot, be asked to do. Re-specifying a material ripples through all of them at once – attempt it in isolation and you invite delay, failed qualification or supply risk; approach it together and disruption becomes orderly progress. That is the essence of controlled innovation: change introduced deliberately, evidenced thoroughly and coordinated across the value chain, so uncertainty is reduced at every step rather than transferred downstream.
weather system, whose common denominator is the component that touches the medicine. Teams that treat material selection as a strategic, early and collaborative decision – not a late procurement line item – will convert that turbulence into differentiated, compliant and more sustainable products. The industry does not have to face this alone: the materials, the evidence and the manufacturing routes largely exist. Handled deliberately and early, this upheaval becomes the moment the ecosystem chooses to innovate in a controlled way – moving from disruption to genuine confidence about the medicines, and the patients, that depend on getting the materials right.
From Disruption to Confidence The market is telling us, from several directions, that materials of construction can no longer be an afterthought: PFAS, propellants, patents and biologics are not separate storms but one
REFERENCES 1.
AstraZeneca / Honeywell announcement on development of respiratory inhalers with nearzero-GWP propellants; Bespak (Zephex®) and
Solstice® Air (HFO-1234ze(E)) commercial-scale programmes. Aptar Pharma. “Leachables assessment: new pMDI with low-GWP propellants” (2023) – comparative leachables of HFA-134a, HFA-152a and HFO-1234ze(E). Fontanellaz T, Jost R, Schneider A. “Subcutaneous drug delivery: adapting to high-viscosity, largevolume demands.” ONdrugDelivery, Issue 166 (Oct 2024). Roberts BC et al. “Novel cannula design improves large-volume auto-injection rates for highviscosity solutions.” Drug Delivery 2021; and Subcutaneous Drug Delivery & Development Consortium industry perspectives (2025). Victrex. VICTREX™ PEEK and VICTREX PC™ pharmaceutical-contact grade technical literature; PEEK as a PFAS-free alternative in selected sealing, coating and film applications. Wachtel H et al. Pulmonary Therapy 2017; 3:19–30; Iwanaga & Tohda, Clinical Drug Investigation 2019; 39:1021–1030 (soft mist inhaler / Respimat), reproduced with permission of Boehringer Ingelheim.
Yann Treguier Yann Tréguier is Pharmaceutical Market Development Manager with Victrex plc., a specialist in high-performance PEEK polymers for the medical and pharmaceutical industries. He works with drug owners, device developers and the wider supply chain to position advanced materials as enablers of faster, lower-risk and more sustainable product development. Email: yann.treguier@victrex.com
Sophie Versavaud Sophie Versavaud is Strategic Technology Manager, Pharmaceutical Segment, at Victrex. She works with drug owners, device developers, CDMOs and component manufacturers to identify where high-performance materials can address emerging challenges – from PFAS-free alternatives and low-GWP propellant compatibility to next-generation inhalation and injectable devices – and to translate that potential into evidenced, lower-risk solutions across the value chain. Email: sversavaud@victrex.com
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Autumn 2026 Volume 18 Issue 3
Application Note
Alternative Drug Delivery Routes:
Opportunities, Challenges, and How to Overcome Them Topical formulations are often preferable compared to oral and injectable options because they reduce systemic side effects, can efficiently target local delivery, eliminate the need for needles, and can improve patient adherence. These formulations, such as creams, gels, lotions, solutions, sprays, dissolvable patches, and foams, present a more complex medicine as the ‘vehicle’ is an integral part of the drug product. Topical therapies must be optimised to deliver the required clinical efficacy while providing the desired mix of physical properties that will make the product appealing to the patient, otherwise adherence will be hindered. At MedPharm, we define topical drug delivery as the application of a product directly to an epithelial surface – including the skin (intact or wounded), eye (corneal, intravitreal, and transscleral), respiratory tract (pharyngeal, pulmonary, and nasal), as well as oral, rectal, bladder, nail, and vaginal (including cervical) routes. Each of these delivery pathways presents unique biological and formulation challenges, requiring specialised expertise to navigate successfully and bring products to market with confidence. Opportunities and Unmet Needs of Alternative Delivery Routes The topical drug delivery market was estimated to be between $125 billion and $150 billion in 2024, depending on how ‘topicals’ are defined by route of administration. The dermal/skin route of delivery represents most of the market (approximately 40%–50%), primarily driven by the increasing prevalence of skin diseases such as acne, psoriasis, rosacea, atopic dermatitis, and fungal concerns. The ophthalmic route represents about 15% of the market, driven by the rising global prevalence of eye diseases such as macular degeneration, diabetic retinopathy, presbyopia, glaucoma, and eye infections. The nasal route of delivery is a growing area representing about 12% of the market driven by new therapies targeting allergic rhinitis, central nervous system (CNS) disorders, migraines, and vaccines. The oral topical market or delivery to the cheeks and gums www.international-pharma.com
represents about 8% of the market which provides opportunities for oral mucositis, ulcers, and gum diseases. Women’s health is another growing area, where about 10% of the market accounts for vaginal drug delivery, focusing on applications such as infections, hormonal therapies, and contraception. The remaining ‘other’ topical delivery represents about 15% of the market such as rectal, urethral and bladder. This series examines the advancements and emerging opportunities within the topical drug delivery market. The first article will focus on nasal delivery, examining how to design a robust formulation strategy that addresses the unique barriers and clearance mechanisms of this route. We will also discuss how MedPharm’s preclinical models can be used strategically to de-risk your development program, accelerate timelines, and boost confidence in your product’s success. Understanding the Route of Delivery and its Unique Barrier The nose has evolved to prevent foreign material in inhaled air from gaining access to the body. To this end, the nose has a multilayered system of defences. The innermost layer of this defence is comprised of specialised epithelial cells. These cells are tightly connected to each other to form a continuous, living, and responsive barrier between the air and the inside of the body. These cells are coated in a thin layer of constantly replenishing mucus, which serves
to trap foreign particles such as dust, pollen, and microbes. Between the mucus and the cells are microscopic hairlike structures called cilia, which project from the surface of the cell layer. These cilia wave back and forth in a coordinated fashion to move mucus (along with trapped particulates) up and out of the nose for removal from the body, typically either by swallowing or coughing. Together, this barrier poses some unique formulation challenges. As with any topical formulation, optimising the movement of the active pharmaceutical ingredient (API) from the formulation to the tissue is important. In the nose, however, the epithelium is expected to react to the presence of formulation and attempt to remove it. Unless checked or accounted for, the physical interaction with the epithelium will accelerate mucociliary transport through increased cilia beat frequency and the efflux of water into the nose through the epithelial layer, diluting the mucus and further increasing the speed of clearance. From a drug delivery perspective, the overall structure of the nose can be divided into five regions of interest. Going from the outside in, the first of these regions is the nasal vestibule or nostrils. This region has a different epithelium, transitioning from the mucosal layer of the interior of the nose to the dry, tough skin of the exterior. Behind that is the nasal cavity, which is characterised by three rigid, shell-shaped structures called turbinates. These serve to filter, warm, INTERNATIONAL PHARMACEUTICAL INDUSTRY 75
Application Note and humidify inhaled air. The convoluted surface of the turbinates serves to slow the air and induce a turbulent flow, depositing any suspended particles or droplets to the mucus layer for removal before they can reach the lungs. Above the nasal cavity is the olfactory cleft. This small structure is densely packed with olfactory receptors and is connected to the olfactory nerve. The fourth region of interest is the nasopharynx, the region at the back of the nose where the respiratory tract temporarily merges with the oesophagus. Finally, the sinuses form a series of interconnected chambers throughout the nose. Although these are not directly airconducting, they can serve as targets for certain formulation types.
prevent harmful compounds from entering the body, require additional ingredients to aid in delivery.
Each of these regions acts as a unique target for delivery. Formulations intended for rapid absorption into the bloodstream should be delivered to the highly vascularised surface area of the turbinates. Formulations delivered to the olfactory bulb can be directly absorbed into the central nervous system, bypassing the blood-brain barrier. Vaccines are most commonly delivered to the nasopharynx. The combination of API, formulation, and delivery device determines where in the nose a formulation will be delivered. Understanding these interactions is a critically important component of any nasal drug delivery technology.
Nasal formulation development at MedPharm initially involves preformulation work to determine drug solubility, stability (in excipients suitable for nasal use) and characterisation of the drug substance (e.g., particle size for drugs in suspension). This preformulation work provides vital information to understand degradation pathways/stabilisation strategies, drug loading and the most suitable excipients for use during development of prototype formulations.
Formulation Strategies MedPharm’s formulation strategy is consistent across the different epithelium, where the formulation and excipients or ingredients are specifically designed around the drug, the site of action and the target product profile to optimise for drug stability and delivery to the site of action. The site of action may be local to the different epithelium (i.e. skin, nasal, eye, etc.) or systemic delivery to the bloodstream (i.e. transdermal/transepithelial). The excipients or ingredients included in the formulation are specific to the unique barrier properties for the different types of epithelia. For example, formulations interfacing with the skin’s protective barrier, which has evolved to
Topical skin formulations tend to be the most complex (e.g. creams) and often require the most development time. Other routes of delivery, such as nasal, may involve less ingredients but will require a device/drug combination adding a different set of complexities. In all dosage forms, it is preferable to select ingredients already approved for the intended delivery route (e.g those on the FDA inactive ingredient list) to minimise safety concerns, reduce regulatory hurdles and avoid the need for extensive and costly toxicological work.
Prototype formulations are then developed with close consideration of the target site. The drug solubility data versus required drug loading is used to determine whether a drug in solution or drug in suspension is required. Drug-in-solution systems are simpler, but drug loading may be limited. In contrast, drug-in-suspension formulations are more complex and require control of the drug particle size, both as a drug substance but also in the final product, to ensure effective delivery and to mitigate the risk of irritation in the nose/delivery to the lung, which may afford a higher drug loading. The higher drug loading can enhance drug delivery provided the formulation is designed to improve residence time on the cilia and/ or mucous. For both drug-in-solution and suspension formulations it is vital that the device is considered at an early stage and throughout the development to ensure the formulations developed are suitable for use with the device.
optimal site-specific delivery. Formulation characterisation throughout the development such as particle/droplet size distribution, physical stability, rheology, mucoadhesion assessment, osmolality, cascade impaction, suspension redispersibility and sedimentation, is important to enable selection of the most suitable formulations for short-term stability prior to assessment in preclinical models to enhance the chance of success later in the development pathway. Use of Preclinical Models for Alternative Delivery Routes Historically, nasal formulation performance has been assessed using frozen excised tissue from animal cadavers, byproducts of the agricultural industry. Formulation was applied to the apical side (facing the air) of the tissue, and samples were collected from the basolateral side (facing inward) at different timepoints to assess the performance of a given formulation. This model has proven quite successful in the development of nasal drug formulations for decades, and MedPharm has used it with many clients in the development of several drug products. It has been said that all models are wrong, but some are useful. At MedPharm, we believe that all models are wrong, but some are more useful than others. And there’s always room for improvement. This philosophy gave birth to our reconstructed nasal epithelial model (RNE). This model system uses primary human nasal epithelial cells regrown on permeable
The drug, formulation, and device can impact particle size and droplet size. For more targeted delivery to the back of the nose, with the intent to bypass the blood-brain barrier through the olfactory bulb, requires a device that orients the spray and may include carefully designed particles to enable 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Autumn 2026 Volume 18 Issue 3
Application Note dependent on your formulation and device combination, therefore giving a closer to ‘real world’ analysis of the drug product. How We Can Help You Develop a Product for Alternative Routes of Delivery MedPharm is an end-to-end CDMO that specialises in topical, transdermal and transepithelial drug product development and commercialisation.
Charles Evans inserts and stimulated to develop into a welldifferentiated nasal epithelium. A big part of this stimulation is the culture at an air-liquid interface (ALI). The top side of the tissue is exposed to air, with the bottom side exposed to media. This causes the reconstructed tissue to polarise, forming cilia, producing mucus, and forming tight junctions that make the respiratory barrier unique. In the past few years, multiple methods of assessing formulation distribution into the nose have been developed in the form of nasal casts that simulate the internal structures of the nose, broken down into the more common regions of interest (e.g., nares, turbinates, olfactory region, and pharynx). Formulations are loaded into devices and sprayed into physical models of the interior of the nose. These models are then disassembled, and drug is extracted from each piece. This can help determine where the drug is being delivered by the device. Again, these models have proven useful and have shown room for improvement. First, these are made from a single material (e.g., aluminium). Different formulations and APIs
would be expected to adhere, and be extracted from, aluminium at different efficiencies. A low adherence efficiency could allow formulation to transfer from one region to another during disassembly. A low extraction efficiency could affect detection limits, missing places where drug had been delivered. Also, these models are limited to the regions that can be investigated. The pre-ordained regions are useful for development, but there is always room for improvement. To address these limitations, MedPharm has developed the MedCastTM nasal cast model based on head CT scans. Because the MedCastTM is 3D printed, casts can be quickly made with regions of interest specific to a given delivery strategy. 3D printing also allows for the construction of the MedCastTM from a variety of materials. Part of our method development strategy is to test each of these materials with the formulation to evaluate how well the API adheres to the material, and how efficiently it can be extracted. We can then select the most compatible material for the construction of the MedCastTM. This model allows quantitation of the drug from specific regions within the nasal cavity
Charles Evans is Senior Vice President of Pharmaceutical Development at MedPharm, with more than 20 years of experience advancing complex drug products across topical, inhalation, transepithelial, and injectable delivery platforms. He leads global formulation development strategy and has played a key role in the development of MedPharm’s proprietary MedSpray® technology.
Jon Lenn Jon Lenn is Chief Scientific Officer at MedPharm, where he leads global research and development for complex topical and transepithelial drug products. With more than 20 years of pharmaceutical experience, Jon has helped advance innovative biological models, novel test systems, and formulation strategies supporting challenging routes of delivery and product development.
Jon Volmer Jon Volmer is Senior Director of Research Biology at MedPharm, with more than 15 years of experience in biotechnology and preclinical drug development. He leads MedPharm’s cross-functional Research Biology team, supporting the development of biological models, analytical approaches, and instrumentation for complex topical and transepithelial drug delivery applications.
www.international-pharma.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 77
Subsection: Nasal & Pulmonary
The Upcoming Inhaled Biologics Therapies: A Data-Driven Analysis of the Inhaled Biologics Clinical Pipeline In Short The pipeline is filling up fast. 346 trials registered in 2025 and more than 100 already in 2026, with 127 InhBioX candidates now in Phase II and III. Infectious disease leads, and vaccines dominate. Infectious disease and COPD are the main indications, and 60% of Covid-19 trials are vaccines. Synthetic peptides top the molecule list, followed by recombinant proteins and recombinant vector vaccines. The device gap is the opportunity. Nasal accounts for 57% of the delivery choice because of late phase COVID vaccines, and there is not a single portable inhaler candidate in Phase III: this is a huge opportunity. Terminations of clinical trial are rarely about the science. Of 68 discontinued trials, 33% stopped for recruitment challenges and 19% for business or strategic reasons. Adverse events, lack of efficacy and regulatory issues accounted for just 10% each. Biotechs are the creation engines, while Big Pharma has specialised in filing and commercialisation. The inhaled biologics field is no longer emerging; it has emerged. A structured interrogation of commercial and clinical trial databases identified 346 inhaled biologic trials commencing in 2025 and over 100 already registered in 2026, with 117 candidates in Phase II and III. Biologics now represent 58% of the inhaled clinical pipeline: biologics lead inhaled pipelines. Three molecule classes lead, commanding 40% of the pipeline between them: i. synthetic peptides (16%), ii. recombinant proteins (14%), and iii. recombinant vector vaccines (10%). The pipeline concentrates on two mechanistic strategies: a. receptor agonism and, b. ionchannel activation. Infectious diseases dominate the indications, with cystic fibrosis, RSV and 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY
idiopathic pulmonary fibrosis, the principal unmet needs. Innovation is, above all, a small-biotech story: 57% of Phase I trials are led by private companies. Analysis of discontinued programmes (N=68) shows that inhaled biologics do not fail on science: recruitment (38%) and regulatory issues (14%) dominate terminations, while adverse events and lack of efficacy together account for only 19%. Biologic drugs have transformed the treatment of chronic and infectious disease, but their delivery has remained dominated by injection because large molecules do not survive the gastrointestinal tract.1 Two upstream forces are now reshaping this position. First, the science of inhaled biologics, mechanisms, targets and the behaviour of macromolecules in the airway, has been studied intensively. Second, the pace and expertise of biologics manufacturing have accelerated, allowing candidates to be produced at scale. Inhalation and nasal delivery offer a credible alternative route for local delivery to the respiratory epithelium, and for systemic exposure where it is required.
GlobalData database. All figures are drawn from published or publicly verifiable sources, and no proprietary or non-public data are relied upon. Scale and Shape of the Pipeline Inhalation at large is highly active: 346 new inhaled trials commenced in 2025, 162 completed, and 88 approvals were recorded. Of these approvals, 80 were Chinese generics and 99% were low-molecular-weight molecular entities. Against this backdrop the key finding is unambiguous: the present is low-molecularweight entities, and the future is biologics (58% of the inhaled clinical pipeline). The field spans more than 680 therapies across over 350 active organisations. Development is young and front-loaded. Approximately 100 InhBioX trials were registered in 2026. Across all InhBioX trials registered in 2025 and 2026, 34% are in Phase I and 32% in Phase II. Above all, innovation is a small-biotech story. Sponsorship reveals a consistent hand-off: 57% of Phase I trials are led by private
The objective of this work was to quantify the public and searchable inhaled biologics clinical landscape from clinical and commercial databases to establish, on the evidence, what therapies might be coming and when. We looked at volume, molecule classes, targets, indications, sponsors, delivery routes and the specific therapies being advanced. Methods For brevity, inhaled biologics are referred to throughout as “InhBioX”. Commercial and clinical trial datasets were extracted from GlobalData’s market and clinical intelligence platforms.2 Records were verified against public sources (regulatory registers, company disclosures and the peer-reviewed literature) and checked against drug names and sponsoring organisations. Candidates were classified by molecule type, biological target, therapy area, development phase, sponsor type and geography, and delivery route. Phase II candidates were mapped against published Phase Transition Success Rates to weigh their probability of advancing, as defined by the Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary #
Molecule type
Programmes
Share
1
Synthetic peptides
19
16%
2
Recombinant proteins
17
14%
3
Recombinant vector vaccines
12
10%
4=
Live-attenuated vaccines
9
7%
4=
Monoclonal antibodies
9
7%
6
Gene therapies (mRNA + viral vector)
8
7%
7
Exosomes / extracellular vesicles
6
5%
–
Unclassified / undisclosed
18
15%
Table 1. InhBioX candidates by molecular class (Phase II/III). A further 24 programmes (20%) could not be assigned to a class and are not listed.
companies, whereas 74% of Phase II and III trials are led by institutions. Many of these trials are part of a COVID tail-off, hence the dominance of institutions. Small biotechnology companies and academic groups originate and create these programmes; large pharmaceutical companies buy assets late and act principally as the regulatory and commercial or marketing vehicle that carries them to market. The United States leads by trial count, but growth is concentrated in Asia-Pacific, and innovation is now genuinely global, exemplified by the outlier NeuroEPO, Cuba’s intranasal therapy for Parkinson’s disease. The Therapies Now Advancing A cohort of named InhBioX candidates is progressing towards the clinic and market (Table 2). They are a heterogeneous group: Rein Therapeutics’ LTI-03, a first-in-class Caveolin-1 peptide for idiopathic pulmonary fibrosis; Nano24’s EXO-CD24 exosome for ARDS; and two nasal candidates, Blue Lake’s PIV5-vectored BLB-101 for COVID-19 and Ethris’s IFN-λ mRNA ETH47 for asthma and COPD.
A distinct cystic fibrosis gene-therapy race is under way – ReCode’s CFTR mRNA RCT2100, and the AAV programmes SP101 (Spirovant) and 4D-710 (4DMT). Not all survive: Boehringer Ingelheim’s lentiviral BI 3720931 for cystic fibrosis was discontinued in 2026, a reminder that this is a real pipeline with real casualties. Delivery Routes 57% of Phase II/III candidates use the nasal delivery route, with strong regional variation (Europe 71% nasal; Asia-Pacific leaning pulmonary). This is highly skewed by COVID vaccines: when all clinical trials are considered, and only trials specifying a route are counted, the nasal route drops to 22.8% and the inhaled route to 24% (unspecified inhaled 17.2%, nebulisers 5%, DPIs 1.8%). Among Phase III candidates, the identified routes are nebuliser, nasal spray and a single sublingual product; no portable inhaler candidate was identified among the novel biologics. This is a legacy pattern from COVID trials rather than an optimal or future one. Nebulisers are chosen by default not by design: they are the entry point for Phase I, not Company / Programme
the destination, and are routinely dismissed from Phase II onwards, forcing programmes to repeat and bridge earlier studies at avoidable cost and delay. This is a costly and poor strategy that does great disservice. As a delivery technology for chronic therapy they belong to the last century, providing neither the formulation stability across manufacturing and storage nor the portability and adherence that these medicines will require at scale. The history of inhaled delivery is one of maturation, with pressurised metered-dose inhalers and nebulisers giving way to dry powder and portable devices as each molecule class stabilised, and there is little reason to expect inhaled biologics to be an exception. The absence of a portable inhaler in Phase III is therefore best read as a lag that will close, not a permanent feature: once a biologic can be stabilised in a portable format, as synthetic peptides and spray-dried proteins increasingly show, the route follows the molecule – a spray-dried, room-stable oxytocin powder for postpartum haemorrhage being one such example among several. Inhaled biologics do not, for the most part, fail on the science. Of 68 discontinued programmes only 21 record a specific reason. Among those, recruitment challenges are the single largest cause at 38%, followed by regulatory issues at 14%. Adverse events and lack of efficacy together account for 19%, half the recruitment figure. This pattern is consistent with the sponsorship hand-off above: programmes originated by small companies and carried by larger pharmas are exposed to recruitment difficulty and shifting strategic priorities far more than to any failure of the molecule. Summary & Conclusions Analysis of clinical and commercial databases shows that the inhaled biologics pipeline
Molecule
Indication
Route
Phase
Nano24 / EXO-CD24
CD24 exosome
ARDS
Nebuliser
IIb
Blue Lake / BLB-101
PIV5 vector
COVID-19
Intranasal
IIb
Ethris / ETH47
IFN-λ mRNA
Asthma/COPD
Intranasal
IIa
Rein Ther. / LTI-03
Caveolin- 1 peptide
IPF
DPI
II
4DMT / 4D-710
AAV (A101 capsid)
Cystic fibrosis
Nebuliser
II
Spirovant / SP-101
AAV, CFTR transgene
Cystic fibrosis
Nebuliser
I/II
ReCode / RCT2100
CFTR mRNA
Cystic fibrosis
Nebuliser
Ib
Table 2. Selected advanced and upcoming InhBioX candidates www.international-pharma.com
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Subsection: Nasal & Pulmonary
is real, substantial and moving on defined timelines: 346 trials in 2025, over 100 in 2026, and 117 in Phase II/III. Biologics now represent 58% of the inhaled clinical pipeline: biologics lead inhaled pipelines. The field is led by three molecule classes (synthetic peptides, recombinant proteins and vector vaccines, 40% between them) and concentrates on two target strategies, receptor agonism and ion-channel activation.
Innovation is a small-biotech story: private companies and institutions originate these programmes, while large pharmaceutical companies buy late-stage assets and act as the regulatory and commercial vehicle. Critically, inhaled biologics do not fail on the science; recruitment and regulatory issues, not efficacy or safety, are the dominant reasons programmes are stopped. A cohort of named therapies is advancing towards patients.
Those late-stage candidates are today tethered to nebulisers, a last-century technology chosen by default rather than by design and, on the evidence of how every previous inhaled class has matured, an interim step rather than the endpoint. The inhaled biologics therapies are coming: named, dated, and largely on schedule. REFERENCES 1. 2. 3. 4.
Liang W et al, “Pulmonary Delivery of Biological Drugs”. Pharmaceutics, 2020, Vol 12(11), Article 1025. GlobalData Plc, Pharmaceutical Intelligence Center – clinical trials and drug sales databases, London, UK. Accessed 2026. Rogueda P et al, “[Inhaled biologics landscape review – Part I]”, 2026. Rogueda P et al, “[Inhaled biologics landscape review – Part II]”, 2026.
Philippe Rogueda Philippe co-founded Merxin Ltd in 2015. His expertise spans across multiple facets of the inhalation field, particularly with dry powder and soft mist inhalers. Philippe's passion lies in the development of soft mist inhaler technology, particularly for biologics, which he believes holds immense potential to revolutionise the delivery of inhaled therapies. With over a decade of experience in the inhalation sector, Philippe's deep knowledge and innovative approach to inhalation technologies make him a key figure in advancing medical device development for improved drug delivery systems. MERXIN LTD, WE MAKE INHALERS
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Autumn 2026 Volume 18 Issue 3
WE WILL LAUNCH YOU We M a k e I n h a l e r s . Merxin Ltd specialises in designing and supplying inhaler devices, including dry powder and soft mist inhalers, for evaluation through to commercial supply. Our expertise spans therapeutic categories, from biologics and small molecules to generic and novel therapies. W e W i l l L a u n c h Yo u . O u r D N A i s i n t h e p h a r m a i n d u s t r y . We a re c o m m i t t e d t o d e l i v e r i n g q u a l i t y , reliability, and efficacy. Our reputation is built on excellence. Make It Better. We a re c e r t i f i e d a s m e e t i n g t h e re q u i re m e n t s o f I S O 1 3 4 8 5 : 2 0 1 6 f o r t h e Design, Development, and Supply of inhalers. Our goal is to improve your molecule’s efficacy and improve patient outcomes worldwide.
www.merxin.com www.international-pharma.com
info@merxin.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 81
Subsection: Nasal & Pulmonary
From Molecule to Market, Faster: Solving Nasal Drug Delivery's Biggest Development Bottlenecks Formulation, device and manufacturing decisions need to work together, yet they are often made separately, with expertise spread across multiple suppliers. As a result, problems may only become clear once development is well underway: the chosen device may not suit the final formulation, late changes can lead to costly rework, or scale-up risks may not have been addressed early enough. For developers of complex nose-to-brain and systemic therapies delivered nasally, this can mean delays, added cost and regulatory uncertainty. To address these challenges, Bespak®, along with Upperton, and Resyca®, have brought together their expertise in a new collaboration to provide a more connected approach from early feasibility and formulation development through to device engineering, clinical supply and commercial manufacture for liquid spray, soft mist and dry powder. We sat down with Bespak CEO Chris Hirst, Upperton CEO Nikki Whitfield, and Resyca CEO Deborah Jones to discuss why this approach is needed and how it could help customers make better decisions earlier, reduce development risk and move promising CNS therapies towards the clinic faster. What market need led you to form this strategic partnership, and what makes your combined offer different? Chris Hirst: Interest in nose-to-brain and systemic delivery via the nasal route is growing because of the possibilities it could open up for patients. But these are complex products to develop, and molecule developers need the right support from early formulation work and device selection through to clinical supply and commercial manufacture. Too often, those decisions are made in silos, with different suppliers responsible for different parts of the programme and no one looking across the whole pathway. That is when mismatches arise, rework causes 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY
delays and scale-up risks are identified too late. We formed this partnership to address that gap. By bringing formulation development, device selection and optimisation, fill-finish and product supply into one network, we can give customers a clearer, more connected route from molecule to market. Deborah Jones: The nasal delivery landscape has changed significantly over the past decade. The focus has expanded beyond local conditions such as allergies and sinusitis towards systemic and CNS therapies. Nose-tobrain delivery could create new ways to treat serious conditions, including those where potentially effective medicines struggle to reach the target area. At the same time, these therapies place much greater demands on the delivery system. For example, reaching specific regions of the nasal cavity requires precise control of deposition, while sensitive molecules such as biologics need to remain stable during delivery. At Resyca, our Ultra Soft Nasal™ platform was developed with these challenges in mind, but the device is only one part of the product. That’s why we formed this partnership which pools our respective expertise in soft
mist technology with formulation expertise, and advanced tools such as deposition modelling to help customers make informed deciusions earlier in development and reduce risk in later program develivery. The partnership allows customers to work with a unified team that truly understands the complexity in the entire nasal development customer journey. Nikki Whitfield: To echo Chris and Deborah, we are also seeing interest extend well beyond traditional local nasal products – into systemic delivery, peptides, biologics and CNS therapies, including those with potential for nose-to-brain delivery. That creates a real formulation challenge, because each molecule brings its own stability, solubility, dose, particle engineering and manufacturability considerations. For nasal products, early formulation decisions have a major influence on device compatibility, deposition, scalability and ultimately clinical performance, so it is essential that formulation development is not treated in isolation. By combining Upperton’s formulation development and GMP clinical manufacturing expertise with Bespak’s liquid and powder device capabilities and Resyca’s soft mist technology, we can help customers make
Complex challenges from molecule to market Turning breakthroughs into next-generation nasal drug-device products means navigating a complex interplay of factors including: Formulation
Regulation
• Managing stability, solubility and dose • Optimising particle engineering and deposition • Addressing manufacturability from the outset
• Generating the data needed to support regulatory submissions • Navigating complex and evolving regulatory landscapes • Managing drug-device combination product requirements
NASAL DRUG DELIVERY
Manufacturing
Device • Selecting a device compatible with the formulation • Achieving consistent dose and delivery performance • Designing for patient usability and real-world use
Anatomy • Variable nasal anatomy and physiology • Rapid mucociliary clearance limits nasal residence time • Targeting the olfactory region or trigeminal nerve for nose-to-brain delivery
• Handling complex molecules and sensitive formulations • Identifying manufacturing complexities before commercialisation • Maintaining product quality and stability through scale-up
Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary the right decisions earlier and move more efficiently from feasibility through to clinical supply and commercialisation. For developers evaluating nasal delivery for complex and innovative molecules, that joined-up expertise can make a significant difference.
Our role is to help determine when soft mist is the right approach and tailor its performance to the needs of the product. By bringing deposition science and device performance into the conversation early, we can help customers make better-informed development decisions.
What expertise does each partner bring, and how does it come together as one offer?
Nikki Whitfield: At Upperton, we support customers by bringing deep expertise in the formulation development of nasal products across the full development pathway, from early pre-clinical feasibility through to latestage GMP manufacture.
Chris Hirst: Bespak has decades of experience manufacturing nasal drug-device combination products, from multi dose aqueous sprays to powder systems. That expertise spans our sites too, combining established nasal spray and powder fill-finish capabilities at Holmes Chapel with novel device development at King’s Lynn. We apply this experience to help partners move through development more efficiently. For example, our modelling and virtual simulation capabilities help us identify potential design issues early, while rapid prototyping allows us to test and refine solutions quickly. The partnership adds Resyca's soft-mist technology to Bespak's liquid and dry powder portfolio, encompassing both unit dose and multi dose formats. This means we can recommend a platform based on the needs of the molecule, formulation and patient, rather than asking customers to commit to a device before the science is settled. The real value lies in connecting these choices to the wider development pathway. Customers can access connected support from pre-formulation through to clinical and commercial manufacture, wherever they are in their programme. Deborah Jones: As Chris says, bringing these capabilities together gives customers a much broader choice of nasal delivery platforms. Resyca adds specialist expertise in soft-mist delivery, aerosol science, device development and regulatory support. At the heart of our Ultra Soft Nasal™ technology is a proprietary spray nozzle that generates a slow-moving, low-shear aerosol. This can help protect sensitive molecules, including biologics, while supporting targeted deposition within the nasal cavity. The platform is also designed to reduce sensitivity to differences in insertion angle and depth. Combined with its slower, more controlled actuation, this can support more consistent delivery in real-world use. www.international-pharma.com
One of the ways we help overcome early obstacles is through our UpperNose™ platform, which enables rapid formulation screening and assessment of nasal product performance at an early stage. This helps customers make better-informed decisions around formulation strategy, device compatibility and manufacturability before significant time and cost have been committed. A major benefit of this collaboration is that customers do not have to manage multiple disconnected vendors or navigate time-consuming and costly transfers between organisations. Instead, they work with a closely aligned, integrated team from start to finish. That continuity improves decisionmaking, reduces development risk and ultimately helps accelerate innovative nasal medicines towards the market and into the hands of patients. From start to finish, what does the process look like for a customer, and what's actually different about it? Nikki Whitfield: The vision for the collaboration is to offer customers a breadth and depth of knowledge that would be difficult to access through a fragmented development model. By bringing together Upperton’s formulation development, analytical, stability and GMP manufacturing expertise with Bespak’s device capabilities and Resyca’s soft mist technology, we can help ensure each product is developed using scientifically robust approaches and with a clear pathway to the clinic and beyond. Deborah Jones: Successful CNS nasal therapies need an integrated approach from day one, because the physiology of the nose creates challenges at every stage: •
Spray droplets need to sit within a specific size range to reach the trigeminal
• •
nerve or olfactory region rather than being inhaled Rapid mucociliary clearance limits how long a drug stays in contact with nasal surfaces Large biological molecules are often unstable once delivered
We start by evaluating the molecule, therapeutic objective and patient population to define a clear target product profile, including which regions of the nasal cavity need to be targeted, so formulation, device performance and usability requirements are aligned from the outset rather than reconciled later. As programmes move through preclinical and clinical development, we generate the performance data needed for regulatory submissions while refining the product for patient use, then shift focus to manufacturability, scale-up and commercial readiness once clinical proof of concept is established. The benefit for customers is a single team that understands the entire journey from early-stage development through to commercial supply, fewer handovers, fewer gaps for things to fall through, and a faster route to a clinic-ready product. Chris Hirst: Our goal is to reveal that complexity early, rather than let it surface once a programme is already underway, allowing life-changing CNS-targeted products to have a clearer run to market. With that in mind, we have set out to make our partnership as simple for our customers as possible. In practice, every customer is assigned a single commercial lead as their touchpoint from early pre-formulation through to scaleup and manufacture. Whichever partner they approach first, they get access to the full network. As such, decisions about target device, scalability, and regulatory and manufacturing requirements are made together and early, not bolted on after the fact. By aligning the formulation and device thinking from day one, we can avoid potential hurdles six months down the line. What does this actually mean for customers and the wider industry, what's the tangible benefit? Chris Hirst: In practice, this means that when formulating a nasal therapy, a framework is in place to make sure this is being done with a view toward the target nasal device, INTERNATIONAL PHARMACEUTICAL INDUSTRY 83
Subsection: Nasal & Pulmonary device expertise, formulation capability and established regulatory support, alongside manufacturing and commercialisation pathways, with the flexibility to choose whichever delivery technology actually fits their molecule. The aim is a seamless journey that gets therapies to patients faster. scalability, regulatory and manufacturing requirements, and so on. By engineering our recommendations and process specifically around our customer’s specific drug molecule, we are able to improve efficiency and the speed a programme progresses towards the market. For customers, this translates into faster decisions, because there's no back-and-forth between disconnected suppliers, and reduced risk because the same team that helped shape the formulation is still there at scale-up. It means fewer surprises late in development, less rework, and a faster, more predictable route to a clinic-ready product. But underneath that, what we're really offering is a partner committed to getting a molecule to patients, not just a supplier for one part of the journey. Nikki Whitfield: For customers, the ultimate goal of the collaboration is to provide expertise and programme delivery across all of the individual aspects of nasal product development within one integrated project team. A CNS or nose-to-brain therapy does not move through development in a simple linear sequence; formulation, device selection, analytical methods, stability testing, manufacturability, regulatory strategy and clinical
supply all influence one another. Our role is to ensure those workstreams are connected from the outset. The value of working through this helps customers avoid the silos that can slow programmes down or introduce unnecessary risk. In a fragmented model, a product can move from one vendor to another several times, creating complex technical transfers, potential gaps in product knowledge and, in some cases, the need to repeat work at a new site. That can add time, cost and uncertainty. By contrast, our collaboration provides a closely aligned team that manages the programme from start to finish. Product knowledge is retained, decisions are made with the full development pathway in mind, and each stage builds on the work that came before it. That integrated approach helps customers move more efficiently from early formulation thinking through to clinical development and ultimately commercialisation. Deborah Jones: As Nikki says, customers increasingly want integrated solutions that reduce complexity and development risk, rather than having to coordinate multiple suppliers themselves. Through this partnership, customers get access to the Ultra Soft Nasal™ technology, specialist soft mist
An accelerated route to commercialisation: Engineered around you
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Clinical supply
Nikki, CEO of Upperton, brings 30 years of pharmaceutical and CDMO leadership experience across small molecules and biologics. She has led drug development programmes from early formulation through to late-stage development and pre-launch, overseeing technical strategy, manufacturing, scale-up, regulatory submissions and clinical supply. Her senior leadership roles span biotech, pharma and CDMO organisations.
Chris Hirst Chris, CEO of Bespak, brings 25 years of experience in the pharmaceutical sector. Previously a member of Recipharm's Executive Committee and Head of its Advanced Delivery Systems business unit, he has led the development and commercialisation of pMDI, DPI and nasal drug delivery technologies, with a strong focus on innovation and sustainability.
Deborah Jones
Bringing complementary expertise together across the value chain to support your nasal drug-device programme.
Device platforms, device engineering, product development and commercialisation capabilities
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Commercialisation
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Deborah Jones, Ph.D., CEO of Resyca, brings more than 20 years of executive leadership experience in life sciences technology. She specialises in commercial growth, international expansion and strategic partnerships, with particular expertise in inhalation and nasal drug development. She has a strong track record of advancing innovative aerosol and spray technologies to enable more patient-focused drug delivery.
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Subsection: Nasal & Pulmonary
Beyond Propellant Replacement: A More Intelligent Development Pathway for Low-GWP pMDIs The transition to low-global-warmingpotential (low-GWP) propellants is one of the most significant changes to pressurised metered dose inhaler (pMDI) development in decades. The environmental driver is clear. The pharmaceutical challenge is considerably more complex. A pMDI is not simply a drug formulation packaged with a propellant. It is a coupled formulation – container closure – device system in which the propellant contributes directly to metering, atomisation, plume formation, evaporation, and aerodynamic behaviour. Changing one of the fundamental physical components of that system can therefore affect formulation behaviour, device interactions, aerosol generation, dose delivery, regional deposition, and ultimately the evidence required to demonstrate acceptable product performance. The EMA’s current lowGWP pMDI guidance reflects that breadth, covering quality, non-clinical, and clinical considerations rather than treating propellant replacement as a narrow formulation change.1 The development objective is therefore not simply to demonstrate that a reformulated product produces acceptable analytical results. It is to understand whether the aerosol journey remains appropriate from device to patient. That requires a broader set of questions: How does it fly? Where does it land? What arrives? These are connected questions, but they are not answered by the same measurement. That three-part framework sits at the centre of the current Proveris low-GWP scientific strategy. The low-GWP transition creates an opportunity to reconsider when those questions are asked. Rather than relying heavily on a full, expensive, compendial test package early in development when formulations, valves, actuators, and instructions for use may still be changing, a more efficient strategy is to generate a greater density of rapid, mechanistic, and comparative information first. More resource-intensive testing can then be concentrated on candidates that have already been characterised and understood. This is the principle behind Proveris by Design™ (PbD): generate actionable evidence early, follow the 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY
mechanism, add realism where its required, and confirm the selected product rigorously. Low-GWP Reformulation Changes a Connected System The scientific challenge begins with aerosol generation. Following actuation, a metered volume of pressurised formulation passes through the valve and actuator and undergoes rapid pressure reduction, flash evaporation, and atomisation. The aerosol then continues to evolve after leaving the device as droplets or particles interact with surrounding air and volatile components evaporate. Low-GWP propellants do not have identical thermophysical properties to the currently used HFA-134a. Reviews of HFA-152a and HFO1234ze(E) have highlighted these differences and their potential consequences for formulation and atomisation.2 Recent experimental studies reinforce the point. Duke and colleagues compared solution pMDIs formulated with HFA-134a, HFA-152a, and HFO-1234ze(E) using APSD, laser diffraction, and high-speed imaging. In the systems studied, HFA-152a produced greater actuator and throat deposition and different plume behaviour, while HFO-1234ze(E) was more similar to HFA-134a in APSD but still showed differences in plume development.3 A subsequent suspension study demonstrated that the presence of suspended drug further modifies the relationship between propellant properties and spray structure, including flash-evaporation behaviour and plume width.4 Proveris and collaborators have examined related variables experimentally, including spray characteristics of P-134a and P-152a systems with and without ethanol, and
methods for quantifying evaporation fraction and evaporation rate in HFA-134a and HFA152a formulations.5,6 These studies support the broader development premise that the propellant change can alter the physical processes that generate the aerosol. The Proveris framework treats formulation, device, aerosol, and patient-facing variables as an interconnected system. The Cost of Understanding Too Late This problem has a long history in spray and aerosol development. In 2013, Proveris described the “Merry-Go-Round”: repeated cycles of testing, unexpected results, modification, and re-testing when data had not been converted into sufficient product knowledge to direct the next action.7 The concept remains relevant because low-GWP pMDI development creates exactly the conditions in which trial-and-error can become expensive. A single propellant change can cascade into uncertainties about formulation, valve, actuator, canister and closure materials, labelled shaking and firing instructions, analytical strategy, deposition behaviour, and the evidence needed for progression. If a candidate differs from the reference in a compendial result, several explanations may be plausible. The formulation may not redisperse in the same way. Valve delivery may differ. The candidate may be more sensitive to shaking or shake-to-fire delay. There may also be other formulation, device, method, or handling related factors contributing to the observed difference. The result alone does not identify the cause. This is also where timing becomes economically important. Early development
Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary offers flexibility. Formulation composition, actuator geometry, valve choice, and preparation parameters can still be changed. Later, the same changes can affect stability, scale-up, analytical validation, PK, clinical work, or submission strategy, at greater consequence and cost. Proveris by Design: More Learning Before More Commitment Proveris by Design provides a framework for putting that principle into practice. The approach is consistent with Quality by Design thinking: understand the variables; build evidence around the development question with constant analysis; and use the results to guide the next experiment rather than executing a fixed battery of tests regardless of what the data show. Proveris formally describes PbD as a stepwise roadmap for in vitro characterisation of orally inhaled and nasal drug products.8,9 The first step is to understand the product that is being changed or reproduced. For a reference product, that means more than establishing nominal DDU and APSD values. The baseline should include normal batch, device, and shot variability; sensitivity to shaking, delay, and orientation; dose delivery through canister life; aerosol formation and temporal behaviour; and, where relevant, upper-airway or regional deposition. The target is product performance, not meeting a single specification. The second step is to generate rapid controlled evidence with enough statistical
power to distinguish real differences from noise. This is where more data earlier can be more cost-effective. Rapid screens can investigate multiple formulation and device variables before the programme commits large quantities of product, analyst time, and instrumentation to a full suite of expensive resource-intensive confirmatory methods. This does not mean “do every possible test early.” It means selecting measurements according to the uncertainty. If the question is whether the device meters consistently, investigate valve delivery and DDU; if the question is whether the aerosol event has changed, interrogate spray pattern, plume geometry, velocity, duration, or evaporation; or if the question is whether the difference remains relevant when the product interacts with a patient, then add breathing, anatomy, or deposition. Early mechanistic evidence also creates a defensible record of why development decisions were made and can support later root-cause investigation if stability, scale-up or manufacturing introduces a change. How It Flies The first scientific layer is how the aerosol is generated and evolves. For low-GWP pMDIs, this is especially important because changing the propellant changes the physical conditions under which atomisation and evaporation occur. “How it flies” includes plume formation, velocity, particle or droplet size, trajectory, duration, and evaporation. These variables are dynamic and interdependent.
Plume-Front Velocity, for example, provides information about how rapidly the aerosol moves away from the actuator. Evaporation measurements depicted help determine how the aerosol changes after emission. Spray Pattern and Plume Geometry provide spatial information about the developing aerosol. There are published methodologies addressing both emitted aerosol velocity and evaporation as additional characterisation variables.6,10 The value is mechanistic. If two products have different deposition behaviour later, understanding how each aerosol was generated can help explain why. Conversely, if mechanistic differences are detected early, the development team can determine whether those differences persist or disappear as the evidence chain progresses. Where It Lands After leaving the device, the aerosol interacts with airflow, the mouth and throat, and the branching respiratory tract. At the same time, droplets may continue to evaporate and change size. The combination of velocity, particle or droplet size, trajectory, breathing profile, and anatomy influences where drug is likely to deposit. The Proveris framework makes this relationship explicit: an evolving aerosol is being inhaled into a complex airway, and the two processes together determine deposition. Regional deposition therefore asks a different question from dose delivery or particle-size characterisation. A product may
Figure 1: Plume Front Velocity (PFV) images and corresponding distance-versus-time plots. www.international-pharma.com
INTERNATIONAL PHARMACEUTICAL INDUSTRY 87
Subsection: Nasal & Pulmonary deliver the expected amount of drug while distributing that dose differently through the respiratory tract under more representative conditions. Human-relevant deposition models can provide additional context. For example, INVIDA® combines human-relevant oropharyngeal geometry with programmable breathing profiles and regional HPLC quantification to assess deposition across the mouth/throat, tracheal and lung regions. Olsson and colleagues used anatomically correct inlet throats with actual inhalation flow profiles and measured the fraction of drug passing beyond the throat. That ex-throat fraction was shown to predict typical total lung deposition across a range of inhaled products in healthy adults.11 During development, the priority is to understand which formulation, device, administration, and physiological variables influence product performance, and to investigate those relationships while the product can still be changed.
Figure 2: Evaporation measurements determined from Spray Pattern images taken at specified distances from a pMDI mouthpiece.
Once those relationships are understood, standardised methods provide the controlled and reproducible framework needed for activities such as release, stability, and routine product control. Human-relevant experiments are therefore most useful during development when they help explain an observed difference or determine whether it is likely to matter under representative use conditions. The principle is simple: add realism when it can affect the decision. What Arrives Once drug has reached a region of the respiratory tract, a further question remains: what has actually arrived, and in what state is it available to continue toward its intended local or systemic action? How is it absorbed? For conventional small-molecule pMDIs, dissolution may be one important part of this question. For more complex products,
Schematic of Proveris Scientific’s INVIDA platform.
the relevant evidence may eventually include molecular integrity, aggregation state, payload association, or other measures of functional integrity. The framework therefore extends “where it lands” into “what arrives”: postdeposition behaviour, dissolution, integrity, and availability. For low-GWP pMDIs, this does not mean every programme requires an extensive post-deposition package. It means that 88 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Autumn 2026 Volume 18 Issue 3
YOUR PARTNER…
FROM DEVELOPMENT TO APPROVAL
Scientific expertise and testing strategies for innovator and generic OINDPs • Hand Actuation Parameter Design Studies
• In Vitro Testing
• Root Cause Analysis
• IVBE Studies
• OOS/OOT Investigations
• Device and Formulation Screening
• Development Stability Testing & Storage
• Method Development
• Method Validation & Transfer
• Spray Characterization Studies
• Device Reliability Studies
• Product Consultation when Design, Supply Chain or Manufacturing Changes Occur
• Regional Deposition Studies (Human Realistic)
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Subsection: Nasal & Pulmonary the evidence strategy should be capable of following the drug further when deposition alone does not resolve the uncertainty. Compendial Testing as Confirmation, Not Discovery Established compendial and regulatory tests remain essential. DDU, APSD, and other required measurements provide controlled, standardised, and widely accepted evidence of product quality and performance. A full compendial package can be time, material, and analytically intensive. During early screening, when multiple formulations and device configurations remain in play, running the entire package repeatedly may be less efficient, and more costly, than first using faster measurements to establish which candidates are robust and which mechanisms need investigation. PbD therefore places the larger compendial and confirmatory package later in the learning sequence, after formulation, device, and aerosol behaviour have been characterised and after humanrelevant questions have been addressed. The proposed development strategy is therefore formulation screening, devicefunction screening, aerosol-formation screening, human-relevant evaluation, and finally compendial/confirmatory evidence. The objective is to avoid discovering fundamental product behaviour for the first time when the programme has already reached its most resource-intensive and expensive tests. From the Laboratory Question to the Development Decision The same philosophy explains the evolution of Proveris Laboratories. The laboratory was built because customers repeatedly asked for help beyond operating an instrument: method development, troubleshooting, reference-product characterisation, workflow automation, and interpretation of unexpected results.
Those questions often cross analytical boundaries. A problem first observed in a compendial result may originate in formulation, device function, actuation, aerosol formation, or deposition. A laboratory designed around the question rather than the test is therefore able to move through the evidence chain until the uncertainty is resolved. The output is not simply more data. It is a better development decision. Low-GWP pMDIs as a Model for Better Development Science The low-GWP transition is an environmental necessity, but it also exposes a broader weakness in conventional development thinking. Endpoint results can provide erroneous reassurance before the system that produced them is fully understood. The transition challenges the industry to preserve patient-facing performance while changing a fundamental component of the aerosolgeneration process. That cannot be addressed efficiently by asking one test to answer every question. A more rational pathway is to understand the reference product, generate highinformation evidence early, manage formulation and device variables as a system, follow the aerosol as it is generated and evolves, determine where it lands, investigate what arrives, and then enter compendial and confirmatory testing with a product that is already substantially better understood. This is the core proposition of Proveris by Design. More data earlier does not mean more indiscriminate testing. It means generating mechanistically useful evidence while change is still possible, escalating complexity when the evidence justifies it, and using confirmatory methods when they provide greatest value. The environmental objective and the patient objective must succeed together. The new propellant must reduce climate impact, but the product must still deliver the medicine appropriately. The most effective way to de-risk that transition is to understand earlier, connect the evidence across the whole aerosol journey, and make each experiment earn its place in the next development decision. REFERENCES 1.
90 INTERNATIONAL PHARMACEUTICAL INDUSTRY
European Medicines Agency. Questions and answers on data requirements when transitioning to low global warming potential (LGWP) propellants in oral pressurised metered
2.
3.
4.
5.
6.
7.
8. 9.
10.
11.
dose inhalers. EMA/477469/2023 Corr. 1. Updated 3 October 2024. Buttini F, Glieca S, Sonvico F, Lewis DA. Metered dose inhalers in the transition to low GWP propellants: what we know and what is missing to make it happen. Expert Opin Drug Deliv. 2023;20(8):1131–1143. Duke DJ, Rao L, Myatt B, et al. In-vitro evaluation of solution pressurised metered dose inhaler sprays with low-GWP propellants. Pharm Res. 2025;42:385–400. Duke DJ, Rao L, Myatt B, et al. The role of low global warming potential propellants on suspension metered dose inhaler sprays. AAPS PharmSciTech. 2025;26:154. Jordan L, Johnson S, Chand R, Thurston G, Jones D, Webster V, Stanford S. Comparison of spray characteristics of P-134a and low GWP P-152a pMDIs with and without ethanol. Respiratory Drug Delivery 2023. pp. 311–316. Jordan L, Chand R, Eldam MM, Farina DJ. Methodology for measurement of evaporation fraction and evaporation rate: a comparison of HFA-134a and HFA-152a pMDI formulations. Respiratory Drug Delivery 2024. Vol. 1:379–383. Proveris Scientific Corporation. How to Get off the Merry-Go-Round and Get Your Spray or Aerosol Product to Market: 7 Questions to Ask to Accelerate Spray or Aerosol Product Development. Proveris Scientific Corporation; 2013. International Council for Harmonisation. ICH Q8(R2): Pharmaceutical Development. 2009. Liao L. Proveris by Design™: A Roadmap for In Vitro Characterization of Orally Inhaled and Nasal Drug Products. Proveris Scientific Corporation; 2020. Liao L, Ramos K, Farina D. A novel characterization of emitted aerosol velocity profiles from metered dose and soft mist inhalers. Poster presented at Drug Delivery to the Lungs; Edinburgh, UK; 2019. Olsson B, Borgström L, Lundbäck H, Svensson M. Validation of a general in vitro approach for prediction of total lung deposition in healthy adults for pharmaceutical inhalation products. J Aerosol Med Pulm Drug Deliv. 2013;26(6):355–369. doi:10.1089/jamp.2012.0986.
Joanne Mather Joanne Mather is Senior Director of Marketing at Proveris Scientific, she focuses on translating complex scientific and regulatory challenges into practical solutions that help companies in the OINDP space accelerate development and ensure product quality. With a strong background in analytical science and a customer-centric approach, she is dedicated to supporting the industry in bringing effective and reliable aerosolised drug products to market.
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INTERNATIONAL PHARMACEUTICAL INDUSTRY 91
Subsection: Nasal & Pulmonary
A Pioneer's Path to Transition: How HFO-1234ze(E) Is Shaping the Future of Sustainable Pressurised Metered Dose Inhalers The pharmaceutical respiratory inhalation sector is entering its second major propellant transition. In response to the Montreal Protocol requirements, the first transition moved pressurised metereddose inhalers (pMDIs) away from ozonedepleting chlorofluorocarbons (CFCs such as CFC-11) to hydrofluoroalkanes (HFAs), principally HFA-134a and HFA-227ea. These HFAs eliminated the ozone-depletion concern but unfortunately retained high global warming potential (GWP). Climate change regulation is now driving a further transition. Following the Montreal Protocol, the Kyoto Protocol and the related Kigali Amendment established a global hydrofluorocarbon phasedown trajectory, implemented regionally in the EU through Regulation (EU) 2024/573, which removed the previous quota exemption for HFA-based pMDIs, and in the United States through the American Innovation and Manufacturing (AIM) Act and its implementing allowance programme at 40 CFR Part 84.1,2,3 For pMDIs, the challenge is to decarbonise without compromising patient access, inhaler performance, or therapeutic continuity. This review summarises HFO-1234ze(E) as a successfully approved next-generation propellant, assessing its physical properties, formulation compatibility, toxicological profile, clinical evidence, and regulatory readiness. Technical and Formulation Considerations Medical Propellant HFO-1234ze(E), GMP is a hydrofluoroolefin propellant for pMDIs, reducing propellant greenhouse gas emissions by up to 99.9% relative to the incumbent HFAs.4,5 Its liquid density of 1.17 g/ mL is comparable to HFA-134a at 1.22 g/mL so that suspension sedimentation and creaming behaviour carry across the transition without wholesale reformulation, in contrast to the substantially less dense HFA-152a.4,5 HFO1234ze(E) exhibits no vapor flame limits under standard test conditions and is classified nonflammable under EC Testing Method A11, ISO 10156 and the US DOT standard (ASTM E681), and in the ASTM flame projection, ignition distance and enclosed-space ignition tests.4 A narrow flammable range can be observed 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Physical Property Comparison of Common pMDI Propellants Property
HFO-1234ze(E)
HFA-134a
HFA-152a
Chemical formula
CF3-CH=CHF
CF3-CFH2
CHF2 -CH3
Molecular weight (g/mol)
114.0
102.0
66.1
Boiling point (°C)
-19.0
-26.1
-24.0
Density at 21.1 °C (g/mL)
1.17
1.22
0.91
Vapour pressure at 21°C (psia/bar)
64.2 / 4.42
85.8 / 5.92
77.0 / 5.31
Vapour pressure at 54°C (psia/bar)
161.7 / 11.15
213.4 / 14.71
190.6 / 13.14
Water solubility (ppm)
225
2200
1700
Flame limits in air at 20°C (vol%)
None
None
3.7-16.9
GWP (100-year ITH, AR6)
1.37
1530
164
Atmospheric lifetime
19 days
14 years
1.6 years
No ATEX required
No ATEX required
ATEX required
Manufacturing requirements
Table 1. Physicochemical, environmental, and manufacturing properties of common pMDI propellants. The data presented in Table 1 are drawn from the supplier’s technical data sheet and product literature and the propellant property comparison presented at Respiratory Drug Delivery 2022.4,5,6
only where temperature is at or above 30°C, relative humidity at or above 50%, and a high-energy ignition source is present.7 The propellant is thermally and hydrolytically stable, showing no breakdown and no effect on metals after two weeks at 200°C in the presence of water and metals, and remaining within specification after several years of storage in steel cylinders. Compatibility has been demonstrated with aluminium, tin plate and PET-lined canisters and with common valve gasket materials including grades of butyl rubber, Buna and neoprene, with pMDI valve compatibility testing conducted by Aptar Pharma.4 Nonetheless, the best approach is to conduct confirmatory testing with the specific container closure system used. Formulation studies further demonstrate the suitability of HFO-1234ze(E) across both suspension and solution pMDI formulations. Using static multiple light scattering, salbutamol sulphate suspensions in HFO1234ze(E) were more physically stable than the equivalent HFA-134a suspensions, with lower migration rates (52 versus 64 mm/hour propellant-only, and 40 versus 53 mm/hour at 5% ethanol); ethanol addition reduced both flocculation and sedimentation, with the benefit plateauing above approximately 5% w/w.8 In higher drug-load suspension work, ethanol at 2–5% w/w brought mean delivered
dose onto a 180-microgram target with acceptable uniformity and fine particle doses of 89–114 micrograms per actuation, exceeding marketed comparators, while 15% ethanol reduced fine particle dose to 49 micrograms through increased throat deposition.9 Solution formulations of beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide delivered doses at or above their reference listed drugs with dose uniformity meeting USP 601, and reducing actuator orifice diameter to 0.22 mm raised beclomethasone fine particle dose from 44.1 to 80.2 micrograms and fine particle fraction from 48.0 to 83.7% while lowering MMAD and geometric standard deviation; storage at 40 degrees C/75% RH for 12 weeks produced no statistically significant change in delivered dose and little change in aerodynamic particle size distribution.10 Compatibility extends beyond simple substitution. Budesonide, marketed only as a suspension because of solubility limits in HFA propellants, formed clear solutions in HFO1234ze(E) at 14–16% w/w ethanol, meeting USP 601 dose uniformity criteria with higher fine particle dose (51.1 versus 40.6 micrograms), higher fine particle fraction (46.5 versus 36.3%) and markedly finer mass median aerodynamic diameter (MMAD) 1.48–1.56 versus 3.75 micrometres than the suspension Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary reference product.11 Fluticasone propionate, previously the least characterised active in this propellant because of its hydrophobicity and aggregation tendency, was successfully formulated as a suspension at 2% ethanol with either oleic acid or magnesium stearate, delivering 94.9–105.9% of label claim against the reference at 85.4% with acceptable uniformity and comparable aerodynamic performance.12 Standard excipients including ethanol, oleic acid, magnesium stearate, citric acid and propylene glycol perform as expected in these systems.6 Taken together, the combination of near-zero GWP, non-flammability, HFA-134alike density and demonstrated container closure compatibility, alongside formulation profiles closely comparable to existing HFAbased products supports HFO-1234ze(E) as a technically viable near drop-in replacement for HFA-134a that can often be implemented using similar materials, excipients, device platforms, and manufacturing approaches. Modest cosolvent adjustment and actuator orifice selection are the principal levers for aligning in vitro performance, and in the case of poorly HFA-soluble actives, HFO1234ze(E) offers formulation opportunities that were previously difficult to achieve with conventional HFAs. Toxicology and Safety Assessment A comprehensive toxicological programme has been conducted for HFO-1234ze(E), covering repeated-dose toxicity, safety pharmacology, genetic toxicology, carcinogenicity, reproductive and developmental toxicity, and local tolerance.13, 14, 15, 16 Pharmacokinetic investigations showed very limited metabolism (below 1% of the administered dose) and rapid systemic clearance following inhalation exposure, with peak blood concentrations occurring immediately after dosing and declining rapidly thereafter.13 Safety pharmacology evaluations demonstrated no adverse effects on cardiovascular, respiratory or central nervous system function in rats or dogs, and a cardiac sensitisation study in dogs was negative.14 HFO-1234ze(E) was generally well tolerated in repeat-dose inhalation studies of up to 3 months in mice, 6 months in rats, and 9 months in dogs.14 In repeat-dose rat studies, the propellant exacerbated progressive cardiomyopathy, a known spontaneous background lesion in this species.15 These effects were observed principally at exposures of approximately 15,000 ppm, did not increase in severity with longer treatment duration, and www.international-pharma.com
were not seen in mice or dogs. The 6-month rat study established a NOAEL of 5,180 ppm (4,280 mg/kg/day).14 A multigeneration reproductive toxicity study identified deaths and neurological findings in lactating female rats exposed to 19,400 ppm (approximately 23,000 mg/kg/ day). These events were confined to the late lactation period and were not observed in males, non-lactating females, or in any other repeat-dose study.14 The parental toxicity NOEL was 4,820 ppm, while reproductive performance and offspring development were unaffected at all tested exposure levels. Embryo-foetal development studies in rats and rabbits demonstrated no maternal, reproductive, developmental or teratogenic effects.14 The propellant showed no genotoxic potential across a complete battery of in vitro and in vivo studies, including bacterial reverse mutation assays, chromosomal aberration assays, micronucleus tests, and unscheduled DNA synthesis assessments.15 Two-year inhalation carcinogenicity studies in mice and rats showed no treatment-related neoplastic or non-neoplastic findings, indicating that HFO-1234ze(E) is not carcinogenic under the OECD test conditions of those studies.16 The non-clinical data support a favourable safety profile.14,16 The compound exhibits low systemic toxicity, rapid clearance, negative genotoxicity and carcinogenicity findings, and no adverse effects on fertility or development. The effects observed were limited to high-dose rat studies at exposure levels substantially exceeding those anticipated in clinical use. Key NOAELs were 29,000 mg/kg/day in mice (3 months), 4,280 mg/kg/day in rats (6 months), 5,760 mg/kg/day in the rat reproductive study, and 3,620 mg/kg/day in dogs (3 months).14 Clinical Experience Clinical characterisation of HFO-1234ze(E) advanced during 2025 with two randomised, double-blind studies.17, 18 Both were designed around the same premise: because nonclinical work showed the propellant appears in blood only transiently and produced no risk at pMDI exposure levels, its effects were expected to be primarily airway-based, making the potential for bronchospasm the key tolerability consideration for a new inhaled excipient.14, 17, 18 Pleasants et al. addressed airway sensitivity directly in a Phase IIIb, randomised, doubleblind, single-dose crossover study in adults with well-controlled or partially controlled
asthma (NCT05850494), using propellantonly inhalers containing no active drug at four inhalations per dose, twice the exposure anticipated for a combination product. HFO1234ze(E) met non-inferiority to HFA-134a for change from baseline in FEV1 AUC0-15 min against a margin set at the minimum FEV1 change classifiable as reversible and consistent with asthma, and no bronchospasm event occurred in either arm in a study powered to detect such events at a rate of 5% or greater. Both propellants were well tolerated, with no serious adverse events, no adverse events of special interest, and no discontinuations.17 Usmani et al. then evaluated the propellant in its intended commercial configuration in a Phase 3, randomised, double-blind, parallel-group, active-comparator study at 92 sites across nine countries (NCT05573464), comparing budesonide/glycopyrronium/ formoterol fumarate dihydrate delivered by HFO-1234ze(E) or HFA-134a in moderateto-very-severe COPD over 12 weeks, with a prespecified cohort continuing to 52 weeks. Adverse event incidence was balanced at both timepoints, and respiratory adverse events of special interest, selected as most relevant to an inhaled propellant with very limited systemic exposure, showed no difference between groups. Continuous Holter monitoring covering the first inhaled dose, serial ECGs, clinical laboratory tests and vital signs showed no clinically meaningful differences; exploratory lung function and health status indicated comparable therapeutic effect; and no new or unexpected safety signals emerged.18 The two studies are complementary. The crossover isolates the propellant in a susceptible airway population at supratherapeutic dosing and finds no effect on lung function and no bronchospasm.17 The Phase 3 study confirms that this neutrality holds in the finished product across chronic dosing to 52 weeks in an older, comorbid population, consistent with earlier Phase 1 findings of systemic and lung bioequivalence for the active ingredients formulated with either propellant.19 Taken together, the evidence indicates a similar benefit-risk profile for both propellants and supports substitution of HFO-1234ze(E) for HFA134a, with real-world evaluation identified as the next step.18 Regulatory Approval Journey and Timeline The regulatory pathway for HFO-1234ze(E) in pMDIs reflects a progression of international environmental agreements, agency-level scientific engagement, and initial product approvals spanning nearly four decades. INTERNATIONAL PHARMACEUTICAL INDUSTRY 93
Subsection: Nasal & Pulmonary
Figure 1. Transition and regulatory approval journey for HFO-1234ze(E): environmental agreements, agency engagement and first pMDI product approvals, 1987 to 2026.
Figure 1 above traces this journey, mapping the key environmental, scientific and regulatory milestones from the 1987 Montreal Protocol through to the first pMDI approvals containing HFO-1234ze(E) in 2025 and 2026. The 2025 MHRA approval of Trixeo Aerosphere with HFO-1234ze(E) in the United Kingdom represents the first regulatory authorisation of a pMDI product using this next-generation ultra-low-GWP propellant, establishing a precedent for subsequent EU and global submissions.22 As of mid-2026 the propellant is approved for patient use in the United Kingdom, the European Union, Australia and New Zealand.23,24,25 Evolving Regulatory Landscape In the United States, the FDA 2018 draft quality guidance for MDIs and DPIs remains the primary reference for CMC expectations, covering delivered dose uniformity, aerodynamic particle size distribution, spray pattern, leachables and related critical quality attributes.26 The Agency has not yet issued dedicated final guidance for the lowGWP propellant transition. The 2024 FDA and CRCG public workshop addressed scientific understanding of low-GWP propellants, product performance considerations, and data requirements for both innovator and generic transition programmes, but binding regulatory pathways remain product-specific.21 FDA supports the transition to low-GWP 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY
propellants while expecting a sciencebased demonstration of safety, quality and performance, and has signalled interest in reducing unnecessary testing where confidence in reformulated product safety and effectiveness can be maintained. The EU and UK framework is more developed. The EMA Q&A on data requirements for transitioning to low-GWP propellants sets expectations for a novel propellant, comprising full novel excipient quality, toxicology and pharmacokinetic data, local tolerance assessment covering ciliary function and airway sensitivity, clinical safety evaluation, and pharmacokinetic bioequivalence demonstrating therapeutic equivalence. Once a propellant has been used in an approved product, the package for subsequent applicants narrows to product quality and demonstration of therapeutic equivalence.20 The EMA draft guideline on the pharmaceutical quality of inhalation and nasal medicinal products (EMA/ CHMP/20607/2024) consolidates inhalation product quality expectations and incorporates the Medical Device Regulation, requiring risk-based demonstration of quality, safety and performance comparability, including consideration of therapeutic equivalence and device changes.27 International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) has published proposed pathways for US FDA approval of low-GWP propellant transitions, providing an industry
reference in the absence of dedicated FDA guidance.28 HFO-1234ze(E) is now supported by a coherent scientific and regulatory evidence base: an AR6 GWP of 1.37, an atmospheric lifetime of approximately 19 days, nonflammable classification under recognised international test methods, a comprehensive non-clinical safety package including twoyear carcinogenicity studies in mice and rats, demonstrated formulation compatibility across suspension and solution systems, clinical tolerability data in asthma and COPD populations, and regulatory approval of the first pMDI products incorporating this propellant in four jurisdictions. Adoption should nonetheless proceed through disciplined product-specific comparability, quality-by-design development, and early regulatory engagement. Sponsors must generate evidence across formulation performance, container closure compatibility, extractables and leachables, stability, delivered dose uniformity, aerodynamic particle size distribution, and clinical bridging where required. The strongest case for HFO-1234ze(E) rests on its combined ability to reduce inhaler climate impact while preserving the clinical utility, usability, and patient access advantages that define the pMDI platform. Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary REFERENCES
10.
1. 2.
11.
3. 4. 5. 6. 7. 8. 9.
UNEP. Kigali Amendment: HFC Phasedown. 2016. EU Regulation 2024/573: Fluorinated greenhouse gases. 2024. US EPA. HFC Phasedown, 40 CFR Part 84. Solstice. HFO-1234ze(E) GMP: Technical Data Sheet. 2026. Solstice. HFO-1234ze(E) GMP: Product Brochure. 2026. Hulse R, et al. A journey to net zero using Solstice Air. RDD. 2022:97-102. Close J, et al. HFO-1234ze(E): flammability characterization for MDI manufacturing. RDD. 2023:211-216. Boldt E, Smith G. Physical stability of salbutamol sulfate suspensions in HFA-134a and HFO1234ze(E). DDL. 2023;34. Boldt E, Smith G. Single-actuation salbutamol sulfate MDI using HFO-1234ze(E). RDD. 2024:244247.
12. 13. 14. 15. 16. 17. 18.
Boldt E, Smith G. Beclomethasone, formoterol, and glycopyrronium formulations in HFO1234ze(E). RDD. 2025. Smith G, et al. Budesonide solution formulations in HFO-1234ze(E). RDD. 2026:221-225. Smith G, et al. Fluticasone propionate suspension formulations in HFO-1234ze(E). RDD. 2026:226-230. Schuster P, et al. Biotransformation of HFO1234ze. Toxicol Appl Pharmacol. 2009;239:215-223. Giffen PS, et al. Nonclinical assessment of HFO1234ze(E). Int J Toxicol. 2024;43:4-18. Rusch GM, et al. Toxicology of HFO-1234ze. Drug Chem Toxicol. 2013;36:170-180. Giffen P, et al. Two-year inhalation studies of HFO-1234ze(E). Int J Toxicol. 2026;45:247-257. Pleasants RA, et al. Lung function following HFO1234ze exposure in asthma. J Aerosol Med Pulm Drug Deliv. 2025;38:275-283. Usmani OS, et al. Budesonide/glycopyrronium/ formoterol with HFO-1234ze vs HFA-134a. eClinicalMedicine. 2025;87:103402.
19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Aurivillius M, et al. Relative bioavailability of triple therapy with low-GWP propellants. Pulm Pharmacol Ther. 2023;83:102245. EMA. LGWP propellant transition: data requirements. 2023. CRCG/FDA. Navigating the Transition to LGWP Propellants. 2024. AstraZeneca. Trixeo Aerosphere UK approval. 2025. EMA. Trixeo Aerosphere EPAR. TGA. Breztri Aerosphere. ARTG 475305. Medsafe. Breztri Aerosphere Data Sheet. FDA. MDI and DPI Drug Products: Quality Considerations. 2018. EMA. Quality of Inhalation and Nasal Medicinal Products. 2024. IPAC-RS. Transition to LGWP Propellants in MDIs. 2024.
Dr. Nilesh Wagh Dr. Nilesh Wagh is Global Lead, Product Stewardship & Regulatory at Solstice Advanced Materials, covering ultra-low GWP propellants and pharmaceutical packaging. He holds a Ph.D. in Pharmaceutical Chemistry and works across chemical and pharmaceutical regulatory compliance and on CMC within the drug approval process.
Dr. Sandeep Mukhi Dr. Sandeep Mukhi, Ph.D., DABT, is a boardcertified toxicologist with more than 20 years of experience in toxicology, risk assessment, product stewardship, and regulatory science. He currently serves as Global Lead for Toxicology and Risk Assessment at Solstice Advanced Materials.
Dr. Rahul Parakhia Dr. Rahul Parakhia leads Product Stewardship for the Americas at Solstice Advanced Materials. With more than a decade of experience in regulatory compliance and toxicology across multiple industries, he serves as a member of the Society of Toxicology and several industry workgroups including IPAC-RS.
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Subsection: Nasal & Pulmonary
Soft Mist Inhalers: Enabling the Next Generation of Complex Inhaled Therapies The inhaled medicines pipeline is changing, expanding from conventional small molecules towards proteins, peptides, nucleic acids and other complex therapeutics. Pulmonary delivery could broaden the opportunities for complex therapeutics, supporting both local treatment in the lung and systemic delivery. New therapeutics require new approaches to delivery. Preserving drug integrity through storage, aerosolisation and administration is becoming as important as generating the right aerosol and achieving efficient lung delivery. Delivery technology is therefore becoming an early strategic development choice. Soft mist inhalers are particularly well positioned to address these emerging requirements and potentially enable the next generation of complex inhaled therapies. Emerging Opportunity for Pulmonary Delivery of Biologics Pulmonary delivery of biologics is moving beyond recombinant proteins towards a broader range of therapeutic modalities with five biologics currently approved for direct airway delivery.1 Specifically, inhaled genetic medicines is emerging with multiple programmes exploring mRNA and viral-vector approaches for cystic fibrosis (CF) and primary ciliary dyskinesia (PCD).2 While growth in biologic therapies remains dominated by injectable products, pulmonary delivery offers an attractive alternative for selected biologics, enabling both direct treatment of the respiratory tract and systemic delivery. The lung’s large surface area, thin epithelial barrier and extensive vascular network can support rapid absorption while bypassing gastrointestinal degradation and first-pass hepatic metabolism. As the broader biologics pipeline is predominantly formulated as liquids, liquid inhalation appears to be a natural route, also reflected by in 79% of current inhaled biologic programmes using nebulised delivery.2,3 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Yet pulmonary administration brings its own challenges. Formulation stability, aerosol generation, device compatibility, dose delivery and regional deposition are closely interconnected, and a biologic stable in its primary container may not retain its integrity during aerosolisation. For advanced biologics, the delivery system should therefore be considered an integral part of therapeutic development rather than a downstream device or packaging decision. New Therapeutics Demand New Delivery Technologies Biologics place specific demands on delivery: proteins are susceptible to aggregation, denaturation and degradation, while mRNALNP formulations require preservation of both the nucleic acid payload and nanoparticle structure.3,4 The choice of formulation and delivery technology is therefore closely linked. Dry-powder approaches may improve stability but introduce mechanical and thermal stresses during processing, while liquid delivery avoids some of these steps but requires careful control of stability, sterility and aerosolisation compatibility. Device selection consequently becomes part of the formulation strategy. The challenge is not simply to generate a respirable aerosol, but to do so while preserving integrity and biological function. For complex biologics, delivery technology is an early development choice with consequences for formulation, CMC and programme progression. Low-Shear Aerosolisation Becomes a Critical Quality Attribute For sensitive mRNA-LNP and other nano-
particle formulations, aerosolisation must generate a respirable aerosol while minimising mechanical and interfacial stresses that can disrupt the carrier and compromise the encapsulated payload.⁵ Soft mist inhalers offer an attractive alternative to conventional nebulisation, with the aerosol-generation mechanism playing an important role in preserving formulation integrity. Collidingjet systems such as Respimat® form droplets through impinging liquid jets, whereas Rayleigh-based systems such as the Resyca PFSI® exploit the natural instability of micronscale liquid jets to generate the aerosol.5,6 These fundamentally different aerosolgeneration mechanisms also differ in the energy and mechanical stress imparted to the formulation. High aerosolisation energy has been associated with increased lipid-carrier disruption, loss of encapsulated material and mRNA degradation, while low aerosolisation energy such as for Rayleigh breakup has shown improved preservation of nanoparticle size, encapsulation, mRNA integrity and biological functionality compared with the other nebuliser and SMI technologies (Figure 1).7–9 Current evidence remains predominantly in vitro and formulation-specific, but as payloads become more complex and sensitive, aerosolisation stress should be considered. Device performance must therefore extend beyond aerosol characteristics: the relevant question is not only whether a device produces the required aerosol, but whether it preserves and delivers the functional therapeutic. Lowenergy Rayleigh breakup offers a promising approach where biologic and nanoparticle integrity is critical.
Figure 1: Impact of aerosol-generation mechanism on the integrity and biological functionality of sensitive mRNA-LNP formulations. Comparison of LNP aggregation, mRNA delivery and encapsulation efficiency following aerosolisation using Rayleigh- and colliding-jet SMIs and nebuliser technologies. Aadapted from.7 Autumn 2026 Volume 18 Issue 3
Subsection: Nasal & Pulmonary Sterile Primary Packaging and Drug Product Compatibility Preserving biologic integrity extends beyond aerosolisation to storage and administration, making primary packaging an integral part of the delivery-system strategy. Biologics typically require sterile, well-characterised containerclosure systems and are often preservativefree, with established formats such as vials and prefilled syringes (PFS) supported by extensive development experience and supply chains. Transferring these products into a dedicated inhalation reservoir can introduce additional compatibility, stability and fill-finish requirements. One approach is to integrate an established sterile primary container directly into the inhaler, serving as both primary container and drug reservoir. In a PFS-based SMI, a sterilised prefilled syringe can connect directly to the aerosol-generation system through a closed fluid path designed to maintain containerclosure integrity (CCI). This minimises product transfer between fill-finish, storage and administration, while supporting refrigerated and frozen supply chains commonly used for biologics. While this approach can simplify the drug-product pathway, product-specific stability, container-closure compatibility and extractables and leachables assessments remain essential. Building the SMI around established biologics packaging can avoid a bespoke inhalation reservoir and potentially reduce packaging-related development risk and complexity. Manufacturing Scalability Beyond simplifying drug-product architecture, primary packaging has important implications for manufacturing scalability.
Figure 2: From fill dose to functional mRNA lung delivery. Illustration of how device output, mRNA integrity following aerosolisation and pulmonary deposition collectively determine the predicted functional mRNA dose delivered to the lung for Rayleigh SMI and mesh nebuliser technologies. Adapted from.11 www.international-pharma.com
Emerging inhaled biologics often progress through early development with uncertain future demand, making investment in dedicated filling infrastructure, proprietary cartridges and inhalation-specific manufacturing processes a significant development and commercial risk. A PFS-based SMI offers a different pathway by leveraging existing infrastructure. Prefilled syringes are widely established across the biologics industry, supported by global fill-finish networks, mature processes and scalable supply chains. Using the PFS as both primary container and inhaler reservoir allows drug-product manufacture and aseptic filling to remain within this infrastructure. This allows the same primary packaging and manufacturing strategy to be maintained from early clinical development through commercial supply, preserving flexibility while avoiding unnecessary technology transfer or premature investment in inhalation-specific filling infrastructure. By leveraging proven biologics manufacturing infrastructure, developers can limit upfront investment, reduce scale-up risk and potentially shorten the path to commercial supply. Platform Strategy: Balancing Standardisation and Adaptability A successful device platform strategy balances standardisation with product-specific adaptation. While a common delivery platform can simplify development and manufacturing, different biologics require the delivery system to match the formulation, therapeutic target and deposition profile. A configurable inhaler platform needs control beyond aerosol generation. Nozzle geometry and pore size should be tailored to droplet formation, while metered volume and spray duration should be adaptable to the required dose. Equally important is the interaction between aerosol and patient. Built-in airflow resistance can passively guide patients towards a more consistent, slow and deep inhalation, reducing patientto-patient variability and supporting high lung deposition, as demonstrated in studies with different SMI flow resistances.10 When these parameters are optimally configured, delivery efficiency becomes more than the fraction of drug leaving the device. For complex biologics, the relevant measure is the functional drug reaching the intended lung region. mRNA modelling illustrates this principle, showing how device output, post-aerosolisation integrity and lung
deposition together determine the predicted functional lung dose (Figure 2).11 Optimising this functional lung dose, rather than aerosol performance in isolation, should therefore be a central consideration in developing delivery systems for complex inhaled biologics. Patient-Centricity and Real-World Use Optimising functional lung delivery is only valuable if patients can reproduce it in everyday use. Poor inhaler technique, including insufficient inspiratory effort, actuation-inhalation coordination and inconsistent handling, remains an important source of dosing variability, particularly among elderly and paediatric patients and those with respiratory impairment. This is especially relevant for complex biologics, which are often high-value products and may require relatively high delivered doses, making it important to minimise losses and reliably deliver functional drug to the lung. SMIs are well suited to these challenges. They are compact, portable devices that generate aerosol mechanically rather than relying on inspiratory energy or external power. Their slow-moving, long-lasting aerosol cloud reduces the need for precise actuationinhalation coordination. Combined with passive flow guidance, these characteristics can reduce dependence on patient technique to support more reproducible lung delivery. These characteristics can also support broader patient-centric design, combining convenient handling and efficient drug use with options such as reusable devices and replaceable drug cartridges to reduce material consumption. For next-generation inhaled therapies, patient-centricity should therefore encompass not only consistent administration, but also portability, efficient use of valuable drug product, affordability and environmental impact. Regulatory Perspective Taken together, these interactions between drug product, delivery technology and patient use make the delivery platform an important development and regulatory decision for complex inhaled biologics. Developers may need to demonstrate not only consistent aerosol performance and dose delivery, but also that formulation, primary packaging and aerosolisation preserve critical quality attributes and biological functionality throughout storage and administration, without changes that could affect safety or immunogenicity. This makes early integration of the biologic and delivery system important. Formulation, INTERNATIONAL PHARMACEUTICAL INDUSTRY 97
Subsection: Nasal & Pulmonary primary packaging and device performance need to be developed together, with attention to stability, sterility, compatibility and preservation during aerosolisation. Identifying these requirements early can reduce the risk of later changes that trigger additional development, manufacturing or regulatory work. A platform-based SMI approach can help manage this complexity. Established sterile primary packaging, low-energy aerosol generation and a configurable device architecture can provide a common technical foundation across biologic products. Using the same platform from clinical development through commercial supply can reduce the need for changes in primary packaging or delivery technology as a programme progresses. While product-specific regulatory evidence remains necessary, established platform knowledge and manufacturing processes may be leveraged across programmes, reducing technical risk and unnecessary redevelopment. Looking Ahead The next generation of inhaled therapies will place different demands on delivery technology. As pulmonary development expands from small molecules towards biologic therapeutics, success will increasingly depend on preserving the drug product while providing efficient, reproducible and patientfriendly administration. This changes the role of the inhaler. the delivery platform becomes an integral part of the therapeutic product and should be considered from the outsety. Soft mist inhalers are well positioned in this landscape. Their compatibility with liquid formulations, mechanically generated aerosols and compact handheld delivery provides a strong foundation for complex therapeutics. Platforms combining these characteristics with low-energy aerosolisation, established sterile primary packaging and adaptable delivery parameters can extend the range of biologics suitable for pulmonary administration (Figure 3). Ultimately, the opportunity is not simply to develop a better inhaler, but to enable therapies that would otherwise be difficult to deliver effectively through the lung. REFERENCES 1. 2.
Giri N et al., Pulmonary delivery of biologics: a literature review. Drugs. 2026; 86:1187-1229. Shaibie NA et al., Inhaled biologics for
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Figure 3: Integrated drug–device development for complex inhaled therapeutics. Bringing molecule, aerosolisation, packaging, device, manufacturing and regulatory strategy together from early development to commercialisation.
3.
4. 5.
6. 7.
8.
9. 10.
11.
respiratory diseases: clinical potential and emerging technologies. Drug Deliv Transl Res. 2025;15:4098-4114. Cipolla D et al., Inhalable and Nasal Biologics: Analytical, Formulation, Development, and Regulatory Considerations. J Aerosol Med Pulm Drug Deliv. 2025;38(5):284-303. Matthews AA et al., Developing inhaled protein therapeutics for lung diseases. Molecular Biomedicine. 2020; 1(11). van Rijn CJM et al., Low energy nebulization preserves integrity of SARS-CoV-2 mRNA vaccines for respiratory delivery. Scientific Reports. 2023;13:8851. Komalla et al., Advances in soft mist inhalers, Expert Opinion on Drug Delivery. 2023; 20(8.). He P et al., Rayleigh-based soft mist inhalers preserve mRNA-LNP integrity for pulmonary delivery. J. Drug Delivery Science and Technology. 2026; 115. Biesel A et al., Soft mist inhaler nebulization by Rayleigh-breakup largely preserves functional integrity of liposomal mRNA in respirable aerosols. European J. Pharmaceutical Sciences. 2025;214. Klein et al., Degradation of lipid based drug delivery formulations during nebulization. Chemical Physics. 2021;547. Buchmann NA et al., Influence of device flow resistance on inhalation manoeuvre and predicted lung deposition using a soft mist inhaler. Respiratory Drug Delivery (RDD). 2024. Sibum I et al., A device screening method
for predicting delivery of inhaled mRNA via a nebuliser. Drug Delivery to the Lungs (DDL). 2023; 34:170–173
Dr. Nicolas Buchmann Nicolas Buchmann is Chief Technology Officer at Resyca B.V., where he leads the development and commercialisation of advanced technologies for inhaled and nasal therapies. With a background in aerosol physics and pulmonary drug delivery, his work focuses on translating innovative aerosol-generation and device technologies into practical drug–device combination products, with particular expertise in soft mist technologies, inhalation systems and complex-molecule delivery. He has held senior technology and development roles at Vectura, PARI and Resyca and has authored more than 60 scientific publications spanning inhalation science, aerosol delivery and fluid dynamics.
Autumn 2026 Volume 18 Issue 3
Your sensitive molecules are in safe hands By minimising shear stress during atomisation, Resyca’s soft mist platform supports the delivery of sensitive biologics and advanced formulations to the nose and lungs.
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Explore what soft mist could mean for your next-generation therapies.
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Events & Exhibition
CPHI Milan 2026 Showcases Collaboration and Transformation Industry leaders and ambitious innovators across the pharmaceutical supply chain will benefit from three days of talks and networking opportunities at CPHI Milan in October 2026. Taking place at Fiera Milano from 6–8 October, this year’s conference looks to build on the success of CPHI Frankfurt 2025, which attracted delegates from over 166 countries, with more than 2,900 exhibiting companies and 250 speakers. The 2026 event has expanded to meet the demands of today’s pharmaceutical landscape, introducing four new exhibition zones and a dedicated Sustainability Summit. Insights from Pharma Leaders Delegates will gather for three days of talks from leading pharmaceutical experts on themes ranging from biomanufacturing to investment, manufacturing, R&D and regulation. The agenda features a variety of keynotes and panels addressing some of the most important issues determining the pharma industry’s future, including: •
• • •
The manufacturing evolution of GLP-1 production and how companies can respond to fast-growing global demand for these therapeutics. The need to restore resilience in Europe’s antibiotic manufacturing and supply chains. How reforms in the EU and UK are transforming biosimilar development. Market shifts and the future of global active pharmaceutical ingredient manufacturing.
Delegates will hear from Edgardo Hernandez, Executive Vice President and President of Manufacturing Operations at Eli Lilly and Company, on “Manufacturing for the Medicines of Tomorrow.” This keynote will discuss how manufacturers are strengthening their supply networks to meet the demand for more complex medicines, as well as to address regulatory, geopolitical and market developments. CPHI will also feature talks from industry leaders such as Medichem SA CEO Elisabeth 100 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Stampa, United States Pharmacopeia (USP) CEO Ronald T Piervincenzi, and Steffen Saltofte, CEO of Zentiva and President of Medicines for Europe. CPHI Unveils New Sustainability Summit This year also marks the first year of the CPHI Sustainability Summit, a two-day event offering a forum for discussion and solutionsharing. Sustainability is now a core consideration for pharmaceutical companies globally, as teams adapt to new regulatory requirements and adopt more environmentally friendly processes. Attendees will explore how sustainability can be successfully integrated into operations throughout the supply chain. More than 20 roundtables, working groups and interactive discussions will address issues such as absorbing green costs across the value chain, embedding sustainability into process design and implementing sustainability at scale. Expanded Exhibition Space Increases Opportunities for Partnerships One of the key strengths of CPHI is that it offers a platform for industry leaders, suppliers and ambitious startups to meet, discuss opportunities and build lasting partnerships. This year’s conference offers four new exhibition spaces, each reflecting an important new facet of pharmaceutical operations. These new zones include: •
•
Contamination control: New international legislation such as EU GMP Annex 1 has increased the importance of contamination control systems in pharmaceutical development. This zone will showcase suppliers offering modular cleanrooms, environmental monitoring systems, air-filtration technologies, isolators and other solutions. Cold chain and logistics: Companies working with highly temperaturesensitive therapies such as biologics and vaccines will be able to meet with suppliers who specialise in fields such as transportation, warehousing, digital monitoring, risk management and specialist packaging.
•
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Labelling: The industry continues to explore the advantages of serialisation and track-and-trace technologies. This area will feature suppliers helping to ensure regulatory compliance and more effective anti-counterfeiting measures. AI and tech: AI promises several benefits in fields such as commercial intelligence, regulatory compliance, data integrity, smarter manufacturing and predictive maintenance. Delegates will be able to explore how these solutions could improve efficiency in their operations.
Tara Dougal, Event Director at Informa Markets, said: “Pharma is highly innovative, but also tightly regulated, so the challenge is to integrate AI responsibly into the systems on which the industry depends. The new AI and tech zone will give technology providers and pharmaceutical leaders a dedicated space to explore practical applications, build confidence and form the partnerships needed to scale these technologies.” Excellence Recognised at CPHI Pharma Awards The conference will also feature the CPHI Pharma Awards, which celebrate innovation and excellence in the pharmaceutical industry. These awards are presented to individuals and companies who have helped to advance drug development, re-shape manufacturing processes and encourage teams to adopt more sustainable measures. The categories for 2026 include individual awards for Future Leader and CEO of the Year, as well as awards for manufacturing excellence, sustainability, device innovation and start-up achievement. CPHI Milan takes place at Fiera Milano, Italy, from 6–8 October 2026. The CPHI Sustainability Summit runs from 6–7 October 2026.
Autumn 2026 Volume 18 Issue 3
Where pharma comes together 6-8 OCTOBER 2026. MILAN, ITALY.
Discover new ideas Meet new partners Create new opportunities
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Autumn 2026 Volume 18 Issue 3