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5: EDITOR’S DESK Spring Budgets and Wegovy Once Again.
6: A SMALL DOSE
Covering the latest big pharma developments.
14: COVER STORY
Nandu Deorkar, Ph.D., and George Marquez of Avantor discuss advancing clinical trials manufacturing from pilot to production.
8: MANUFACTURING & PROCESS SOLUTIONS
Nigel Smith, CEO, TM Robotics explores how advanced automation is shaping the future of medical device production.
10: CLINICAL TRIALS
Paul Knight, Managing Director, CME Automation Systems postulates on how to implement automated ‘just-in-time’ clinical supply chains.
12: COMMENT SECTION: UK SPRING BUDGET
Following Jeremy Hunt’s Spring Budget, we spoke with voices across the industry to get their thoughts on how this budget will impact the world of UK pharma.
17: CONTRACT SERVICES
Mike Ludlow, Market Development Manager, Element Materials Technology looks at the factors to consider in critical assessment of contract research organisations.
18: CLINICAL TRIALS
Didier Haguenauer, CMO, CellProthera covers optimising time-to-market for innovative cell therapy trials.
20: Q&A
We caught up with old friends Lonza once again, this time touching on artificial intelligence and machine learning.
23: CONTRACT SERVICES
Miroslav Hlaučo, Apheresis Network Manager, SCTbio highlights the key considerations for effective apheresis cell collection.
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Given we at EPM Magazine cover the latest developments and innovations across Europe and, despite our name, the rest of the world too, it feels a little self-indulgent to start this editor’s note discussing UK specific news, however, despite my slight reticence that is exactly what I am going to do.
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European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd.
European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals.
Volume 24 Issue 2 Mar/Apr 2024
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On March 6th this year, Former Secretary of State for Foreign, Commonwealth and Development Affairs of the United Kingdom and current Chancellor of the Exchequer Jeremy Hunt released the UK Spring Budget in what was evidently his best attempt at regaining some semblance of dignity that the Tory party has lost over the last five years
– although some may argue over the last 14 years. Within this budget, issues ranging from the abolition of class two national insurance to the digital simplification of HMRC’s digital services to support Income Tax Self Assessment taxpayers seeking to pay tax in instalments (exciting, I know) were presented. Yet, most importantly for us and those within the pharma and life sciences industry, the budget included a significant AI funding, a £360 million R&D package, and perhaps most significantly for UK pharma, an announcement that AstraZeneca will be investing £650 million across two of their UK facilities. £450 million of their investment will
presence in Cambridge, employing over 1,000 people. Turn to page 12 to get the thoughts of leading UK pharma and life science individuals to the 2024 UK Spring budget.
Turning away from the UK, the last month has been yet another busy one for Novo Nordisk, as the Scandinavian giants forked out up to €1.025bn to acquire Cardior Pharmaceuticals with the aim of strengthening their pipeline of projects in cardiovascular disease. Additionally, when Novo Nordisk is mentioned, it is becoming increasingly inevitable that Wegovy will be mentioned too. The Company announced in early March that headline results from their kidney outcomes trial FLOW demonstrated that Wegovy showed a statistically significant and superior reduction in kidney disease progression as well as cardiovascular and kidney death of 24% for people treated with semaglutide 1.0 mg compared to placebo. A hugely significant finding all but adding to the efficacy and potential popularity of Novo’s leading drug.
go into research, develop, and manufacture vaccines in Speke, Liverpool, a facility which will be operationally net zero with power supplied from renewable energy sources and a further £200 million investment announced to expand AstraZeneca’s
Finally, and in keeping with news close to home, Astellas Pharma recently announced the breaking of ground on a new €330 million facility in Kerry, Ireland. The new facility, due to be operational by 2028, aims to accelerate the expansion of Astellas’ inhouse production capabilities and ensure a stable supply of high-quality medicines globally. A hugely significnat investment for Irish pharma.
As always, we at EPM HQ aim to keep you as up-to-date with the latest developments throughout the pharma industry. To ensure you never miss a beat, make sure you sign up to our free newsletter over on our website and follow us on LinkedIn. Enjoy this issue!
Johnson & Johnson have announced that it has successfully completed the acquisition of Ambrx Biopharma, a clinicalstage biopharmaceutical company with a proprietary synthetic biology technology platform to design and develop next-generation antibody drug conjugates (ADCs), in an all-cash merger transaction for a total equity value of approximately $2.0 billion, or $1.9 billion net of estimated cash acquired. The transaction will be accounted for as a business combination.
“We’re pleased to welcome Ambrx’s talented scientific team and proprietary ADC platform to Johnson & Johnson. We look forward to continuing the development of ARX517, which represents a potential first- and best-
in-class PSMA-targeting ADC for the treatment of metastatic castrationresistant prostate cancer,” said Yusri Elsayed, MD, MHSc, PhD, Global Therapeutic Area Head, Oncology, Johnson & Johnson Innovative Medicine. “This significant opportunity sets the
stage for advancing next generation ADCs with the aim of delivering differentiated solid tumor therapies that improve patients’ lives.”
The acquisition presents a distinct opportunity for Johnson & Johnson to design, develop and
IFM Therapeutics have announced that Novartis has exercised its option to acquire all of the outstanding capital stock of IFM Due, a subsidiary company of IFM.
Launched in February 2019, with a focus on developing small molecules that inhibit the cGAS-STING pathway, the company entered into an option and collaboration agreement with Novartis in September, 2019 whereby Novartis made fixed payments sufficient to fully finance IFM Due’s research and development costs for the cGAS-STING
program in exchange for the option to acquire the IFM Due subsidiary (link). Under the terms of the option exercise, IFM received $90 million in upfront payment and will be eligible for up to $745 million in milestone payments, adding up to $835 million in total consideration.
The acquisition provides Novartis with full rights to IFM Due’s portfolio of STING antagonists, which have the potential to treat an array of serious inflammationdriven diseases characterised by excessive interferon
elimination of cancer cells without the prevalent side effects typically associated with chemotherapy.
commercialise targeted oncology therapeutics. Ambrx’s proprietary ADC technology incorporates the advantages of highly specific targeting monoclonal antibodies securely linked to a potent chemotherapeutic payload to achieve targeted and efficient
“The Ambrx team has developed a promising pipeline and ADC platform that will be a strong complement and strategic fit to our oncology innovation strategy,” said Biljana Naumovic, Worldwide Vice President, Oncology, Johnson & Johnson Innovative Medicine. “ADCs are transforming the solid tumour treatment paradigm by leveraging antibody-antigen interactions to release cytotoxic payload directly to tumour cells. This acquisition underscores our ambition to deliver enhanced, precision biologics to transform the treatment of cancers, including prostate cancer.”
and other pro-inflammatory cytokine signalling.
“The acquisition of IFM Due represents the culmination of a highly productive, four-year preclinical collaboration between Novartis and IFM to develop novel small-molecule STING inhibitors with the potential to treat a spectrum of inflammatory diseases,” said Richard Siegel, global head of immunology research at Novartis. “We are excited to advance IFM Due’s STING program and leverage our deep expertise in inflammation science to bring forward transformative medicines that address major unmet patient needs.”
“We have been steadfast in our belief that selectively targeting STING to block the cGAS-STING pathway has the potential to deliver a powerful therapeutic option for patients with serious chronic illnesses,” said H. Martin Seidel, Chief Executive Officer of IFM. “Novartis has been an outstanding collaborator, and the program couldn’t be in better hands. Today, as IFM Therapeutics marks the third major acquisition by a global pharmaceutical company, we cannot be more proud of our team’s accomplishments and look forward to seeing our vision of precisely targeting the innate immune system to address a variety of serious inflammation-driven diseases become a reality for patients in need.”
In the years since the COVID-19 pandemic catalysed the demand for medical devices, business analyst Mercer Capital reports that the growth trend continues due emerging global markets, an ageing population and more. But how can medical device manufacturers meet this rising demand while also keeping up with stringent and evolving regulations about how these products are made?
Mercer Capital’s Five Trends to Watch in the Medical Device Industry report cites several factors behind the growing demand for medical devices. They include an increasingly large ageing population and emerging economies and governments’ efforts to curb rising medical costs. However, companies developing novel medical devices face stringent regulations as outlined in The National Academy of Medicine’s paper on The Changing Economics of Medical Technology. These regulations emphasise accountability, device traceability, post-market surveillance and performance studies, underscoring the need for adherence to quality system regulations.
There is also mounting pressure to accelerate the production of medical devices and it is vital for uninterrupted production to meet hourly production targets. There is also a growing emphasis on advancing manufacturing processes to accommodate new materials with enhanced properties. To meet the demand for faster production while maintaining quality standards, automation and robotics are indispensable. Industrial robots, particularly 6-axis robots, play a vital role in loading and unloading tasks for plastic injection moulding machines.
Injection moulding, a prevalent
How advanced automation is shaping the future of medical device productionNIGEL SMITH, CEO OF TM ROBOTICS
manufacturing process expected to reach a value of $56.5 million by 2027, presents an efficient solution for producing medical devices. This method is already employed in manufacturing monitoring devices and infusion pumps and is poised to accommodate the production of devices using advanced materials like bioplastics.
This drive extends to utilising bioplastics, which offer a more environmentally sustainable alternative to traditional plastics derived from sources like corn, sugar cane, or sugar beets. Bioplastics are increasingly favoured for their potential to improve mould flow and increase impact strength in medical device manufacturing.
To ensure seamless operations, stringent standards are necessary to govern the efficient loading and unloading of moulds, as well as to facilitate smooth collaboration between human workers and automated systems. Automation and robotics emerge as indispensable tools in meeting these demands for efficiency and productivity.
actuator, further enhancing its versatility. These robots seamlessly integrate with Shibaura Machine’s injection moulding machines, such as the SXIII range, which offers faster injection speeds and enhanced performance, thereby increasing throughput. The user-friendly design of these robots facilitates easy installation and programming, reducing training costs and promoting collaboration between machines and operators on injection moulding lines.
TM Robotics, a key distributor of Shibaura Machine (formerly Toshiba Machine), specialises in integrating robots with injection moulding devices, offering a range of 6-axis robots tailored for these applications. Shibaura Machine’s latest series of 6-axis robots boasts features such as low headroom and extended reach, enhancing productivity in industries including automotive, medical, packaging, and pharmaceuticals.
They include the latest TVM range of efficient and dependable robots tailored for various sectors such as automotive, medical, packaging, and pharmaceuticals. The flagship model, TVM1500, boasts an impressive reach of 1,715 millimeters. Following closely, the TVM1200 offers a reach of up to 1,418 millimeters, while the compact TVM900 provides a maximum reach of 1,124 millimeters.
Additionally, each model’s operational scope can be extended by attaching the robot to an optional linear
When paired with a high-speed 6-axis robot for loading and unloading tasks, manufacturers can expect a significant increase in production efficiency. These machines are engineered with enhanced versatility and performance, featuring a sleek design that enables quicker loading and unloading operations.
Furthermore, these robots are meticulously designed for easy plug-and-play installation, simplifying programming for operators and reducing training costs. This encourages seamless collaboration between machines and operators on injection moulding lines, effectively integrating industrial robots into existing manufacturing processes.
The importance of expanding automation cannot be overstated in ensuring the cost-effectiveness and superior quality of tomorrow’s medical devices. Despite stringent regulations, industrial robots provide manufacturers with innovative avenues to introduce new medical advancements to the market, thus propelling patient care towards a promising future.
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One of the biggest challenges facing the life sciences industry is how to implement automated ‘just-in-time’ clinical supply chains that will increase speed, flexibility, and efficiency in clinical trial drugs manufacture.
It’s clear that these are exciting times for the clinical trials sector. As demand grows for innovative treatments, especially in areas such as gene therapies or personalised medicines, so too does the value of the global market – which could be worth potentially as much as $100 billion by 2030, according to one forecast.
With this opportunity, though, comes a sizeable challenge: scalability. Getting new drugs into worldwide circulation is a painstaking process, to ensure regulatory compliance and – most importantly – patient protection. Efforts are being made to minimise any delays in this process. For example, the Medicines and Healthcare products Regulatory Agency (MHRA) has announced plans to streamline approvals. Cited as the biggest overhaul in UK clinical trials regulation in over 20 years, the aim is to make it faster and easier to run trials. This is great – but without investment, innovation, and collaboration elsewhere in the supply chain, the benefits will be moot. Regulatory bottlenecks are compounded by the logistical challenges involved in smallbatch production. As therapies become ever more tailored, there will be a lot of drugs competing for production lines, packaging infrastructure and cleanroom space.
The key question then becomes how to deliver the growing number of clinical trials in the first place. Finding a solution to this will help overcome long lead times for supplying medicines, avoid wastage, and make it easier to respond to patient demand. Any student of manufacturing will know that the hardest bridge for clinical trials to cross is moving from a ‘just in case’ (JIC) model to a ‘just in time’ (JIT) process.
It’s no surprise that, today, pharmaceutical manufacturers are planning with caution and, therefore, holding a larger inventory of stock. It can be difficult to predict patient demand with any degree of accuracy, while delays in recruitment to trials are commonplace. Equally, though, there’s a tricky balancing act in clinical trials manufacture between consignment sizes volumes and cleanroom conditions. Changeovers can be complex and costly, and a JIT model isn’t practicable based on existing manufacturing techniques. The grail in this situation is a more agile and responsive supply chain, geared towards developing a transformative shift that makes JIT manufacturing a reality.
Such is the importance of this quest that it has been officially adopted as one of two ‘Grand Challenges’ by the UK-based Centre for Process Innovation (CPI). Grand Challenge 2 (“Delivering Automated Just-In-Time Clinical Supply”) is a multi-partner collaboration, whose ambition is “to develop a supply chain of the
future which can drastically reduce current timescales of over 300 days to 30 days.”
As implied by the title of Grand Challenge 2, the project’s success will lie in automation. Just as automated technology enables the pharmaceutical industry to deliver medicines both at speed and at scale, the aim here is to achieve the same responsiveness for smaller trial shipments.
As therapies become ever more tailored, there will be a lot of drugs competing for production lines, packaging infrastructure and cleanroom
space.
There are many factors to consider – otherwise such a model would already exist. This is why the CPI has invited several organisations from across the clinical trials supply chain, including CME Automation Systems, to collaborate on developing a viable solution, which is being tested at the Medical Manufacturing Innovation Centre (MMIC) in Strathclyde.
CME’s key role in the project has been to build a faster, more agile supply chain while still maintaining cleanroom conditions. Without a sterile manufacturing environment, the efficacy of any trial product may be compromised – or at the very least, data on its performance will be undermined.
Against this, the trend is towards more, not less, diversity of packed products, due to the
rise in late-stage customisation and single-patient ordering. With unlimited space, it would of course be possible to build giant cleanrooms. However, for financial as well as environmental reasons, this is hardly viable. The goal is that multiple products can be packed in the same small footprint as any mass-market, JIT medicine.
Accordingly, the solution we have developed, and which is currently deployed at MMIC utilises a multi-product modular automation line, known as PACE. The system is designed to deliver the production, packaging and labelling of multiple drugs in the same facility without crosscontamination. In other words, to enable faster changeovers and late-stage customisation while maintaining tight clinical protection.
The PACE system fills bottles with OSD in either tablet or capsule format, or fill finish into vials, without the risk of cross contamination, whilst maintaining complete traceability throughout the system.
It all takes place on a single line in a Good Manufacturing Practice (GMP) environment with real-time quality checks,
resulting in less waste, risk, and cost while maximising speed to patient.
A key innovation is the patented design of the filling station. This enables a single line to incorporate a series of subsequent humidity and temperature-controlled drug filling stations, each configured as a fully functioning independent unit. They are designed to allow quick changeover of pharma product types, for example to dispense tablets or capsules of differing drug types and strengths.
The filling stations sit at the centre of a full line solution, comprising handling, filling, sealing, weighing, marking, labelling, and packing. It is digitally enabled to provide real-time connectivity for greater accuracy and speed in verification, via QP dashboard, and ongoing data insight using digital twin technology. Rigorous checking processes along the line reject any bottle that fails, and these are logged so that that specific order can be fulfilled at the next available opportunity.
With PACE now in operation at MMIC, we are seeing how the use of automation, carefully controlled in cleanroom
conditions, will enable a clinical supply chain that can rapidly and responsively process material on a truly demanddriven basis, both actual and short-term. Benefits include the acceleration of trial supply availability, reduced need for over-production, and improved responsiveness to changes in trial strategy.
Ultimately, the shift towards a JIT manufacturing model for clinical trials medicines will result in a faster, more agile supply to patients. By balancing speed, flexibility and efficiency, this transformative model will help the industry to realise the huge growth potential in the market without compromising on clinical protection or resorting to greater cleanroom footprints.
Progress to date has reinforced the viability of the system, while ongoing interactions with regulatory bodies are ensuring alignment with their expectations. For the clinical trials industry, these capabilities open the door for more trials per year, as well as more diverse trials – for example, by trialling multiple doses and strengths simultaneously. A future where new products can be delivered faster, more flexibly and cheaper than before is now within sight.
As the seemingly soonto-be-out Conservative Party looks to claw back any semblance of dignity following a consistent litany of underwhelming polling results and by-election losses, Jeremy Hunt MP, Chancellor of the Exchequer, delivered the 2024 UK Spring Budget on March 6th.
Discussing a range of topics from a tax on vaping, a 2% decrease in National Insurance, and most significantly for this publication, a £360m investment in R&D, Hunt will be hoping that this budget places his party on some longed-for stable footing. To best analyse the budget with respect to the pharma industry, we at EPM HQ thought it best to collect a variety of opinions from across the industry and compile them here, for you dear reader:
AstraZeneca Chief Executive Officer, Sir Pascal Soriot, said: “AstraZeneca’s planned investment would enhance the UK’s pandemic preparedness and demonstrates our ongoing confidence in UK life sciences. We will continue to support the UK in driving innovation and patient access, building on the strong foundations which have been put in place. This year marks 25 years since the merger of UK-based Zeneca Group and Swedish Astra AB. We are proud of our British roots and how far we have come over that time – we are now a truly global company that has transformed the lives of millions of patients throughout the world with a
relentless focus on science and innovation.”
Justin Wilson, partner, and cell & gene therapy sector specialist at European intellectual property law firm, Withers & Rogers, commented: “This is a major investment which will further vital scientific research at an exciting time when some very promising new
medicines are being trialled. The UK has a world-leading reputation for life sciences R&D, with strategic hubs such as the Cambridge Biomedical Campus, positioning research scientists’ shoulder to shoulder with clinical centres of excellence, including the worldrenowned Addenbrooke’s Hospital. AstraZeneca’s investment, as well as increased Government support for medical research, will support the delivery of new vaccines and further the development of new cell and gene therapies for patients with rare diseases and hard-to-treat cancers. These therapies have the potential to revolutionise the treatment of diseases for which there is currently no cure.”
Karim Budabuss, Director of Grant Advisory at ForrestBrown, said: “The Government has dedicated large financial investment to encourage onshoring and inward investment by pharmaceutical businesses to boost manufacturing resilience in the UK, with application windows open from this summer. The UK is a world leader in life sciences, but the COVID-19 pandemic has exposed major weaknesses within the UK’s manufacturing supply chain and this announcement shows that lessons have been learned.”
Chris Allen, CEO, Broughton commented: “This announcement is a doubleedged sword. We do not want to see an increase in prices that provides smokers with another reason not to switch. Greater taxes on those products with a higher nicotine strength will hit the heaviest smokers the hardest. Still, they may encourage a reduction in nicotine consumption and potentially initiation from nonnicotine users. The balance between efficacy and abuse liability is difficult to get right. At least the proposed duty will go through consultation, and I hope a sensible balance can be achieved. The current perception of such products is a greater concern than the price point. The results from the 2023 ASH survey indicate that 12% of smokers switch to save money, whilst 39% of smokers believe that vaping is as harmful or more harmful than smoking. Another 25% are unaware of the relative safety. If the funds raised can be used to help (i) effectively promote the benefits of reduced-risk products and (ii) strengthen and, most importantly, enforce regulations, then this will only stabilise and enhance the category in the future.”
Andrew Blevins, Senior Vice President, Prologis UK, said: “This budget announcements fall perfectly in line with the work we are delivering at Cambridge Biomedical Campus (CBC). Following the full letting of 1000 Discovery Drive at CBC, Prologis UK is continuing to invest in life sciences, R&D and manufacturing in Cambridgeshire and further afield, with an additional 200,000 sq. ft. of speculative lab and office space planned. AstraZeneca’s further investment is a testament to the
strength of the location we are operating in, and we are certain that this budget will spark further life sciences major players to join us at CBC.”
Nigel Theobald, CEO, N4 Pharma added: “We welcome any new investment in medical research and manufacturing in the UK. However, Covid demonstrated the impact of significant investment into a major health challenge, with the UK developing the first approved vaccine. If the same kind of resource were put into tackling devastating diseases such as cancer, we could save millions of lives and endless future NHS funds. The investment needs to not only go to the big pharma players, but to come down to the smaller companies, such as N4 Pharma, who are innovating and represent future opportunities to treat and cure disease.”
Yogan Patel, Head of Life Sciences at MHA, explained that: “It is great news that the Chancellor announced £360m investment into UK R&D and manufacturing. However, the challenge is that HMRC is taking a much longer time to approve claims and, more importantly, to release the refunds, which can be reinvested into R&D projects. It is encouraging to see that Canary Wharf will be a new hub for Life Sciences in the coming years and that AstraZeneca has planned to invest the £450m in Liverpool. But that must be balanced by ensuring that the skills shortage we have is overcome, so these investments become a success. Universities must be incentivised and supported so that talent can be attracted into the Life Sciences sector, which was one of the fastest growing sectors in 2023 for investment.”
Ivan Wall, Head of the Advanced Centre for Advanced Therapies Manufacturing Training at the University of Birmingham added: The budget brings some welcome announcements on investment in life sciences. Support for early career medical researchers will enable continued innovation that benefits patients, whilst investment in manufacturing should lead to jobs creation and growth of a technical skills pool to support the UK’s biomanufacturing capability, which is critical for future pandemic preparedness. Taken alone, investments are a drop in the ocean, but the win for the sector is in the ability to leverage private investment, coupled with initiatives to drive skills and talent growth, to fill these roles and build the life sciences ecosystem.
AstraZeneca's planned investment would enhance the UK's pandemic preparedness and demonstrates our ongoing confidence in UK life sciences.
The historic pace of new therapy development has challenged biopharmaceutical manufacturers to find new ways to make processes more efficient and ensure safe treatments get to patients faster — and the stakes are high. To capitalise on the opportunities new therapies offer and advance them to market without delay, manufacturers must address numerous challenges, from pilot to production, starting with clinical trial materials manufacturing.
Because of their typically small sizes, Phase I and Phase II trials do not require large quantities of manufacturing materials or equipment capable of handling large volumes. While volumes may not be high, absolute rigor is required in early-stage phases to maintain quality within production and storage cycles. Every effort must be taken to ensure patient safety. In addition, early phase outcomes will determine whether development of the drug continues. Any quality issue early on can generate false results, misinforming development investment decisions and the potential of advancing lifechanging medicines to market.
Scaling materials manufacturing is also a challenge. As trials move from clinical Phase I to Phase III to commercialisation of drug products, the volume and quality requirements increase. In certain cases, the in-house quality raw material may be acceptable in early clinical development. However, the same raw material quality may need to be controlled using cGMP manufactured raw materials.
Likewise, each time a trial changes equipment, material of construction or cGMP requirements during scaleup, the change may require additional testing, production process verification and
Nandu Deorkar, Ph.D., MBA, Senior Vice President, Research & Development, Biopharma Production; and George Marquez, Vice President, Operations, Avantor.
documentation to validate sterility, consistency and performance. Any of these delays creates the potential for increasing costs and even compliance issues if the changes are made after product development.
Manufacturers who can incorporate flexible processes position themselves to advance production to avoid delays and
move therapies to market faster. For example, patient participation levels may change during the trials as patient retention rates vary, impacting material volume needs. Likewise, sometimes a patient will drop out of a trial after receiving the Investigational Product. When a new patient joins, material resources will need to support the addition of a new patient starting the trial from the beginning.
Building flexibility into every
aspect of the process, from manufacturing to kitting to storage, allows drug developers to not only adapt to changing conditions but scale up as needed through each phase and into commercial production. The ability to remain flexible also positions developers to scale up in unexpected situations, such as cases in which a first-in-class molecule receives conditional approval to treat broader or larger patient populations.
Clinical trial material manufacturing presents different
challenges than manufacturing for large-scale production. A Phase I clinical trial is the first time that the investigational product will be used in a human. That makes it critical to consider quality systems early, as well as the regulatory guidelines established to prevent cross-contamination and environmental contamination. Even more stringent guidelines must be followed for clinical trial materials used in monoclonal antibodies (mAbs), biologics and cell and gene therapy (C>) products.
Early planning is the foundation for creating a scalable, compliant process.
Navigating raw material supply:
Insufficient material planning can lead to inefficiencies, validation failures and market delays. The use of cGMP grade materials, like reagents, from the start of a clinical trial can ease the transition to later trial phases and larger-scale manufacturing. The material will maintain its quality and viability across the full workflow and eliminate material requalification due to unavailable grade or quantity after transfer.
In addition to creating a more seamless path to commercial production, the use of cGMP materials in early clinical Phase I can help minimise contamination risk, provide material traceability, ensure product consistency and regulatory compliance.
Use of cGMP materials is not always possible during development of advanced
therapeutics, such as C> therapy. Labs sometimes use a unique material or ingredient that has been successfully used in the lab but has not been used in manufacturing processes. It is critical to conduct a risk assessment to establish a quality standard. It is also important in advanced therapeutics trials to have a plan to acquire cGMP-quality materials.
Likewise, investigators must consider the quantity of materials early in the process to avoid potential delays and bottlenecks. An early production run may only require a small amount of a specific material, so it’s common to assume that quantity will be easy to acquire. However, the supplier may have already allocated their current supplies to another customer. In addition, the value of considering larger amounts of raw material for production in later phases cannot be underestimated. Ordering supplies early —regardless of the quantity — helps minimise costly delays.
Another important materials consideration is planning for cGMP documentation. If a lab uses a material before acquiring documentation, a supplier may not be able to supply the documentation for a variety of reasons, such as the material is not assessed for a specific requirement. Risk assessment during the trial planning phase is an ideal opportunity to identify and prepare for these future needs and avoid delays.
Leveraging technology to scale production: Technology can be a key tool to help avoid setbacks as production scales. A platform approach that uses a fluid handling system can help de-risk and improve processes during the transition from development to final production volume.
For example, peristaltic
pumps used in research and development require much lower flow rates. Smaller labscale units cannot support the transition from bench to full-scale production. To ensure a project can scale quickly, it’s faster and more efficient to use the same pump technology in the lab as when it is time to transition to equipment that can handle higher flow and volume.
Considering automation platforms during the clinical trial material manufacturing process can also ensure seamless scale-up. Peristaltic pumps with built-in automation capabilities ensure technicians can set and recall commonly used programs and continuity in controls.
Likewise, single-use technology can be key to processing clinical trial materials. Single-use offers customised, scalable technology with a wide range of component choices, from filters and connectors to tubing and bags. By engaging early on in single-use technology with smart industrial design, an open architecture approach with as many agnostic components as possible, manufacturers can ensure their processes have the agility and secure scalability to support later product volumes.
Collaborating with solutions partners: From selecting qualified products to storing materials in cGMP-compliant biorepositories, manufacturers must balance a myriad of considerations on the path to commercial production. Choosing solutions partners with pilot-to-production expertise, deep regulatory understanding and a comprehensive portfolio can be key for scale-up success and allow researchers to spend more time on science.
For example, experienced, cGMP-compliant kitting suppliers are well positioned to offer flexible services that
scale as the trial progresses, no matter how simple or complex the kit or logistics required. By collaborating with a partner early in the process, drug developers can provide solutions that conform with all internal and external protocols as well as regulatory requirements.
Safe and secure storage of production materials and patient samples are also essential for supporting clinical trials and commercial manufacturing as they scale. cGMP-compliant biorepositories help ensure proper asset management across the full chain of custody. During the planning state, consider how much storage of bulk manufacturing material will be needed as the clinical trial progresses, as well as any specific storage requirements, such as temperature or humidity control.
Trial planning for therapeutics like C> creates unique challenges compared to more standard biopharmaceutical clinical trials. For example, since each specimen is used to create the therapy, it must be stored and returned under the most stringent safety and cryopreservation conditions and aligned with regulatory requirements. In addition to the extraordinary care a biorepository must provide, it must also support the stable, multiyear storage C> trials demand.
Careful planning during clinical trial materials manufacturing can ensure flexibility and compliance as processes scale. From high-quality raw materials to innovative equipment technology to long-term storage, drug developers can leverage these opportunities to advance production, focus more time on science and move treatments to market faster.
The growth in demand for outsourced services from the pharmaceutical industry has led to an upsurge in the number of Contract Research Organisations (CROs) providing support to the sector.
The scope of services provided by these CROs is extensive and their role in ensuring the safety, efficacy, and quality assurance of pharmaceutical products throughout all stages of the drug development process is crucial. It’s vital therefore for pharmaceutical and biopharmaceutical companies to critically evaluate potential service providers before selecting a CRO.
Typical examples of outsourced analytical support include:
• Method development, validation, and transfer
• Quality control and stability testing
• Characterisation of impurities / structural identification
• Root cause analysis
• Technical consultancy and training services
The requirements for assessing the suitability of outsource partners for the provision of analytical testing services can be influenced by a variety of key factors:
Expertise – Recent downsizing in the pharmaceutical sector has created a significant skills-gap in areas such as analytical science and problem solving. The level of experience required to support pharmaceutical testing is significant and often lies outside the remit of R&D focused organisations.
during routine QC analysis. The potential impact of halting a production process can be financially considerable and may ultimately prevent a patient from access to critical medication.
The competition in the CRO space increases the need for excellent levels of customer focus, reducing any potential barriers to service delivery. A client-centric approach to logistics and associated administrative aspects is vital and all the systems relating to customer on-boarding should be as painless as possible, with defined processes for finalising commercial, technical, and quality agreements.
Regulatory compliance expertise is another important consideration. Robust and well-maintained quality systems are required to meet relevant regulatory authorities’ requirements.
Capacity – The demand for analytical support can vary significantly throughout the drug development process so managing workflow and maintaining delivery of testing can be challenging for organisations to manage completely in-house. CROs can provide additional flexibility and scalability.
Technology – The range and costs associated with analytical instrumentation required to support pharmaceutical testing is outside the scope of most organisations. This, together with the qualifications and routine maintenance required for high-end analytical instrumentation, mean that it’s often much more cost effective to use an external supplier.
The nature of pharmaceutical analysis, particularly the support of problem-solving type activities, means that a CRO needs to be able to provide this expertise and technology in a cost effective and agile manner. The supply of rapid response testing services can be critical, for example where an unexpected impurity is detected
The process of attaining approved supplier status with any large organisation can be a significant obstacle for new suppliers and service providers so it’s critical for CROs to minimise any potential barriers as much as is practically possible.
In conclusion the critical factors to consider in the assessment of potential CRO providers include the following:
Expertise – Does the CRO have the relevant technical expertise and experience to deliver?
Capacity – Can the supplier deliver within the agreed timelines / budget and adapt to changing priorities when necessary?
Technology – Does the equipment and instrumentation available match requirements?
Across the biopharmaceutical industry, many have expressed concern about the protracted timelines for drug development, which on average are getting longer when most stakeholders insist the timeto-market (TTM) needs to be shorter. Nowhere is this clearer than with new modalities, particularly cell therapies that are often personalised and manufactured starting from a patient’s own cells.
Stakeholders see many advantages to reduced timelines. For one, it may enable a company to be first to market and establish a beachhead. Investors push TTM optimisation for a higher return on investment, higher net present values, and higher market cap. Plus, it can be beneficial for patients in urgent need of innovative therapies for severe diseases, thereby garnering regulatory support as well. However, trading quality for speed is not an option in healthcare for ethical and regulatory reasons. In the cell therapy space specifically, developers, manufacturers, and regulators are still learning best practices as we move toward standardisation.
There are efforts underway to optimise several stages of development but some approaches that impact other therapies do not meet the specialised needs of cell therapies. For example, advances that can abbreviate the discovery stages like high-throughput and in silico screening may not be as impactful on advanced
therapies. Additionally, the field has struggled to develop animal models with greater relevance to outcomes in humans, meaning that we are unlikely to see dramatic TTM gains based on advances impacting early-stage development any time soon. This puts greater emphasis on innovating the clinical phase, already the longest part of development.
Unfortunately, the duration of clinical trials continues to increase, primarily due to ever-extending patient recruitment periods. The reasons for this are related to the substantial size of the cohort, increasingly complex protocols, limited resources of hospital centres, and the concentration of clinical trials in the same indications among the same expert recruitment sites.
The introduction of new trial designs could change this paradigm, such as those incorporating adaptive design and innovative non-parametric statistical methods (e.g., generalised pairwise comparison). Regulators have been increasingly open to the use of surrogate endpoints that are predictive of clinical outcomes,
like biomarkers and imaging. Surrogate endpoints are especially critical in chronic diseases, where it can take years to tell directly if a therapy has truly altered progression. This is part of our approach at CellProthera, where we are working to advance cell-based therapy into late-stage trials to prevent heart failure in patients following acute myocardial infarction. Severe heart attacks often lead to chronic heart failure and a life expectancy of only 50% after five years, but the use of surrogate endpoints, if sufficiently predictive of the underlying disease, would allow for earlier market authorisation.
The use of real-world evidence as an external control group, although still requiring consensus and standardisation, is also gaining ground and can reduce recruitment duration. Between their openness to such novel approaches, a growing collaborative spirit, and the multiple accelerated development pathways offered by regulators like the U.S. FDA and the European Medicines Agency, agencies have become critical partners for expediting clinical trials
Another aspect of clinical development ripe for acceleration is chemistry, manufacturing, and controls (CMC) activities, which must be conducted to make a product ready for phase 3. Here, prior experience helps to reduce the process characterisation workload and shortens both time frames and investment. CMC changes – to improve on cost or speed, for example –are still possible post-approval, allowing a degree of flexibility in the clinical phase that can make fast-to-market approaches easier to implement.
Additional efforts to accelerate TTM involve reducing the workload on hospital centres and the burden on patients. Everything that can be done outside the hospital should be carried out at home, or at least in a facility closer to the patient. New advances in telemedicine, AI, and wearables are making this transition easier. When in-person interactions are required, the integration of more patient-accessible recruitment centres can facilitate recruitment later, especially since sponsors tend to tighten patient inclusion criteria to maximise the chances of treatment success.
The challenges faced for trials of cell therapies require exploiting all the above for clinical acceleration. Approved cell-based therapies have demonstrated unique efficacy and even curative potential, making this one of the fastestgrowing areas in biopharma. However, the space is far from standardised, with few examples’ successful pathways through the clinic.
As such, innovative technologies are being tested and implemented at a high rate, ranging from ways to edit and modify genes to manufacturing advances related to automation platforms. Yet, finding clinicians with the right expertise can be difficult. One solution is to add production facilities and manufacturing slots, which can give these expert sites more flexibility by allowing extra time to schedule hospital procedures.
This also helps address the issue of overburdened hospitals as recruitment sites. Through the nature of cell therapy manufacturing, we are effectively transferring part of the CMC workload from the trial sponsor to the sites. Asking them to add responsibilities like collecting patients’ cells or perform final conditioning are not standard practice for trial sites, and many are understaffed with high turnover rates, meaning cell therapy trials automatically carry extra risk with heightened potential for slow recruitment.
In some cases, it may not be possible to identify qualified research teams at sites with lower turnover rates, and even additional training may be an imperfect solution as bust investigators often lack availability. For this reason, it becomes crucial to alleviate the burden on physical sites
by reducing required exams to the minimum and performing as much of the trial as possible closer to the patient – meaning satellite sites when necessary and at-home interactions when possible. This has the added benefit of lowering the burden on patients themselves, which can boost recruitment and retainment.
Accelerating clinical trials cannot compromise quality, and the complexity of cellbased therapy trials makes this balance more delicate. One way to strengthen quality is to add rigor in the patient selection process, based on stringent criteria. For us, this means taking steps like waiting a brief period after heart attack to make sure we do not include patients who recover spontaneously without treatment. While this can add some time to the trial, we feel it is a necessary step to ensure results are robust.
Another quality risk is when variability from one patient’s or donor’s cells to the next contributes to differences in starting material that result in doses that are out of specification, preventing their administration. Here, developing robust methods and implementing automation as appropriate can both shorten the manufacturing process and minimise process variability. We decided early on to develop our own automated equipment to ensure process robustness across several decentralised production sites.
Especially in the bespoke world of cellular therapies, it should be no surprise that we lack a simple, one-sizefits-all solution to accelerating TTM through optimising the clinical phase. However, innovation clearly is not limited to the therapies themselves –creative solutions can help the field bring better therapies to more patients, faster.
Lonza has had a busy opening to 2024, most notably the company announced that it has had a $1.2b offer accepted by Roche Pharmaceuticals to acquire the Genentech largescale biologics manufacturing site in Vacaville, California. This acquisition aims to significantly increase Lonza’s large-scale biologics manufacturing capacity to meet demand for commercial mammalian contract manufacturing from customers with existing commercial products, and molecules currently on the path to commercialisation within the Lonza network.
Lonza plans to invest approximately CHF 500 million in additional CAPEX to upgrade the Vacaville facility and enhance capabilities to satisfy demand for the next generation of mammalian biologics therapies. The products currently manufactured at the site by Roche will be supplied by Lonza, with committed volumes over the medium term, phasing out over time as the site transitions to serve alternative customers.
Over the final half of 2023, we caught up with a vast range of Lonza SMEs discussing everything from the process and benefits of spray-dried dispersion technologies to the key targets of Lonza’s Micronisation Centre of Excellence. This year, we plan to stay in the Lonza loop once again by continuing to speak with some of their internal leaders, pushing the industry ever-further forward.
In our first interview series of the year with Lonza, we spoke with Dr. Simon Wagschal, Associate Director, Advanced Chemistry Technologies, Lonza Small Molecules Global R&D and Dr. Aaron Johnson, Manager, Cheminformatics & Data Science, Lonza Small Molecules Global R&D.
Jai: For Lonza, we know the company aims to remain at the forefront of innovation. In what ways has the company been able to capitalise on Machine Learning and what have been the standout developments thus far?
Dr. Simon Wagschal: The biotech and pharmaceutical industry continues to evolve and Lonza is harnessing innovations in Machine Learning (ML) to meet our customers’ needs and help bring their innovations to market. At Lonza, ML is used in synthetic process route design, process optimisation, toxicological assessment of new chemical entities, and formulation design.
While all the above-mentioned applications are driving efficiencies in our ways of working, we have recently appreciated ML-driven gains in our Early Phase service offerings. Small molecule API process route scouting is one example. In this aspect of INDenabling work, process chemistry SMEs devise prospective synthetic pathways from commercially accessible starting materials, through successive intermediates of increasing molecular
complexity, to arrive at a target active pharmaceutical ingredient. After prioritising the possible routes for alignment with clinical and commercial manufacturing ideals, the team experimentally assesses the performance of the top-rated options. The advent of computer-aided synthesis planning technologies (CSPTs) with route prediction capabilities has materially impacted this workflow. Virtually all CSPTs use a subset of machine learning, called Monte Carlo Tree Search, to quickly prioritise computationally predicted synthetic routes. This heuristic search approach, in our context, prioritises prospective routes by iteratively computing probabilities of reaction success at each step in a proposed pathway between starting materials, intermediates, and target API. The resulting prioritised routes are served to the SMEs for consideration and further adaptation. Guided by our process chemistry SMEs, this has spurred larger volumes of prospective strategies and a higher incidence of shorter API syntheses.
Jai: What role does artificial intelligence (AI) play regarding route design, cost-effective modifications, and overall timelines for route scouting?
Dr. Aaron Johnson: Lonza is also using AI to help address the growing need to develop therapies faster and more efficiently – ultimately reducing time and cost for customers.
One area where AI is being leveraged is the manufacturing of active pharmaceutical ingredients (APIs).
APIs are continuing to grow more complex, impacting speed-to-clinic. These longer synthetic pathways present challenges for process chemists hoping to achieve an efficient API manufacturing process.
Dr. Aaron Johnson
Overcoming these challenges is crucial to mitigate delays and expenses associated with bringing new drug candidates from early development to commercial production.
To address these obstacles, we are leveraging predictive route design technology integrated with a highly curated and expansive supply chain database. This combination yields time and cost savings for developing complex APIs. As the industry encounters more drug candidates requiring over 20 synthetic steps on average, AI-powered predictive route design technologies have become indispensable for designing efficient retrosynthetic routes. However, these tools have primarily been designed for early phase discovery phases, often producing retrosynthetic routes not optimised for commercial-scale production realities. To bridge this gap, we have merged leading AI-powered predictive route design models with proprietary supply chain data spanning raw material costs, availability, and comprehensive supply chain intelligence. This integrated technology empowers process chemists to rapidly pinpoint not merely the shortest pathways, but those most commercially viable by factoring in real-world constraints. By providing this holistic view, these cutting-edge AI solutions streamline route scouting and ultimately accelerate the transition from research and development to robust manufacturing processes.
Jai: The prominence of “Industry 4.0” has been immensely significant on the pharma industry, yet there are undoubtedly challenges that arise when implementing new technologies to enhance drug development. What challenges have Lonza faced and how have they been overcome?
Both: The prominence of Industry 4.0 has brought significant challenges for CDMOs like Lonza in implementing advanced technologies like AI to enhance drug development at a commercial scale. Some key challenges Lonza has faced include:
1. Adapting and modifying AI systems to provide meaningful insights for large-scale manufacturing operations.
2. Integrating and managing diverse data sources effectively.
3. Upskilling the workforce to leverage AI technologies effectively.
To overcome these challenges, Lonza has taken a strategic approach, including forging partnerships and collaborations, implementing AI through pilot projects and iterative rollouts, and providing comprehensive employee training. By addressing these hurdles, Lonza has successfully integrated AI and other Industry 4.0 technologies into its operations, leading to more efficient and data-driven decision-making, streamlined processes, and enhanced quality control in drug development and manufacturing.
At Lonza, machine learning is used in synthetic process route design, process optimisation, toxicological assessment of new chemical entities, and formulation design.
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In recent years, there have been an increasing number of clinical trials and research projects based on cell technologies that use cells from a patient or healthy donor as the starting material for their production. With the vast potential of these kinds of therapies to treat, or even cure, rare diseases, research, and investment is only set to intensify. However, the logistics, practicalities, and expense involved can be challenging for investors, sponsors, clinical trial management, and investigators to oversee.
Leukapheresis for cell therapies demands precise coordination among the clinical study site
investigator/manufacturers regarding protocol limits, the Apheresis Centre in relation to capacity, transport logistics, and the production laboratories for scheduling of production slots. Transportation options pose specific limitations, especially for distant destinations dependent on-air transportation.
Relatively fast and reliable transportation can be arranged by collaborating with various transportation companies using a combination of air, train, and road to transport leukapheresis, whether in ambient, cold, or deep-frozen mode.
Based on internal verification at SCTbio, if the target cell is a monocyte and the product is delivered for processing within about 24-30 hours, transporting it at ambient temperature is recommended. This approach aligns with existing data on the stability of leukocytes in PBMCs, as supported by the literature. In our opinion, this is because there is less activation and slower metabolism of platelets at higher temperatures, leading to fewer adherence issues with undifferentiated monocytes. Plus, platelets consume less oxygen and produce fewer metabolites of degradation, resulting in more stable monocytes with a higher ability to differentiate.
For chimeric antigen receptor (CAR)-T (lymphocyte-based) starting material, the transport temperature is usually maintained at 4-8°C. Freezing in liquid nitrogen using a cryoprotectant, such as Dimethyl Sulfoxide (DMSO) is also an option. Usually, leukapheresis products can be shipped from an EU based collection centre within 24 hours of collection within the EU and within 30 hours to most major US cities.
Apheresis Centres must be properly certified by the National Regulatory Authority for a collection, with the category and method of certification varying from country to country. Other requirements include a Quality Management System, adequately trained personnel, including Peripheral Blood Mononuclear Cells (PBMC), Mononuclear Cells (MNC) and Continuous Mononuclear Collection (CMNC) training for collection on a given separator. Proper equipment, effective documentation management, and the ability to perform mandatory testing of subjects under the local implementation of Directive 2002/98/EC and/or Directive 2004/23/EC (in the EU) are also necessary.
The success of leukapheresis depends on an objective assessment of the patient's condition at a separate visit one to seven days before the collection. The main points of this evaluation should include:
1. Control of subject's general state of health
2. Height and weight to calculate the total blood volume
3. Evaluation for systemic infection
4. Complete blood count and differential
5. Mandatory tests before leukapheresis and infectious testing (HIV, HBV, HCV, syphilis antibodies and additional tests need to be performed according to national or local regulations - e.g., HTLV I/II)
6. Control of subject's veins and evaluation of whether the subject can undergo collection via peripheral veins and/or via central line/catheter (CVC) is needed
7. Consultation on discontinuation of inappropriate medications, such as steroids, immune suppressors, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, anti-coagulants etc
8. It is important to inform the patient about what to expect and recommend appropriate preparation
Based on more than a decade of expertise at SCTbio, SPECTRA OPTIA (Terumo) and AMICUS (Fresenius Kabi) separators are the best instruments suitable for white blood cell (WBC) collections. Both CMNC and MNC modes can be used for SPECTRA OPTIA collections. The collection efficiency and cost-effectiveness of both separators are very similar. The Amicus can collect a product with less platelet contamination, but in the CMNC program of the Spectra OPTIA, the platelet proportion can be reduced by lowering the Packing Factor (from 4.5 to 4.0).
The volume of the product depends on the manufacturer's requirements (i.e. the number of cells required). Generally, four to seven x10 e9 peripheral blood mononuclear cells (or similar number of WBCs) are required. This corresponds to more than seven litres of processed blood.
Although the addition of plasma is not mandatory, the patient´s autologous plasma can be added to the concentrate for stability and to maintain cell viability between collection and the start of processing. For SCTbio related collections, we add 40-50 millilitres of plasma to the concentrate as standard for Amicus collections.
1. Keep the collection flowing. Interrupting the procedure will significantly reduce the yield and purity of the product. Ensure inlet and return flow rates are set to prevent interruptions in the flow of blood in and out of the separator. Running a slower inlet flow with a stable inlet is far more efficient than higher speed.
2. Clumping can be a possible cause of flow continuity failure. It may be related to the patient's condition (inflammation, high platelet concentration, fibrinogen levels, etc.) or problems in the separator channel (incorrectly positioned interface), or improperly inserted needle or CVC.
3. Ensure adequate anticoagulation by using an accommodative convergence (AC) ratio suited to the patient. Adjust the ratio according to clumping trends or patient status. Monitor the channel during the run for any evidence of clumping and respond promptly by lowering the AC ratio in response to any signs of clumping.
Critical factors for cell viability include temperature, cell concentration, storage time, transportation, and the influence of other cell populations (e.g., red cells and neutrophils). Our experience suggests that if cells are stored without further processing for up to 24 hours, the leukapheresis product is quite stable and maintains its viability both in 2-8°C mode and at ambient temperatures of 18-24°C. The choice of the cold regime and the maximum time between collection and processing depends on the desired cell population and cell quantity/concentration.
Factors that can have an impact on product quality include:
· Human variability: patient specific variables – status and diagnosis, age, blood count and differential, body (de)hydration and blood fluidity etc
· Patient/donor status and comfort during collection
· Apheresis device setting and collection course
· Venous flow (or central venous status)
· Product purity
· Added plasma
· Transport conditions and duration of transport
There are many considerations Apheresis Centres and investigators need to make when processing leukapheresis samples for cell therapies. It’s critical that careful management of the samples from patient to processing is in place, to maximise the quality, safety and potential efficacy of the eventual treatment.
The biologics market is growing at a compound annual growth rate (CAGR) of over 15% and, furthermore, 24% of biologic drugs newly approved by the FDA between 2017 and 2021 were in lyophilised form.1
These figures confirm the growing need for sterile filling in small batches. In addition, drug stability remains a major concern and ultra-low temperature storage cannot be the only answer from a handling and especially supply chain cost perspective, and it is often impractical. Ready-tofill containers, such as EZ-fill vials from Stevanato Group, have proven to be an excellent solution for small batch filling, but can nested vials also be used effectively for lyophilised products?
Stevanato Group, in collaboration with the Politecnico di Torino University (POLITO), has conducted a series of tests on freeze-drying pharmaceuticals in nested vials, the results of which are described in this article. 2, 3
INTRODUCING RTU
NESTED VIAL – A HIGHVALUE SOLUTION FOR LYO PRODUCTS
Nested vials are in a suspension frame “nest”, contrary to conventional loading where the vials are in direct contact with the freezedryer shelf. The suspended configuration according to ISO 21882 avoids glass-toglass contact during the filling phase and reduces mechanical stress which could lead to vial breakage.
The nested configuration may raise doubts about the heat transfer mechanism from the shelf to the vials.
The overall study results, performed on a 3ml ISO vial, not only confirmed the usability of nested vials for lyophilisation but, above all, demonstrated their potential as a high-value solution for freeze-dried pharmaceutical products.
The test series included primarily the following:
• Influence of the loading configuration on the temperature distribution of ice nucleation and on the morphology of the lyophilised product
• Influence on the residual biological activity
Nested vials tended to nucleate at higher temperature compared with vials resting on the shelf. It is known from the literature that the higher the nucleation temperature (i.e. the lower the degree of supercooling) and therefore the higher the sublimation rate, the larger the ice crystals and pores during the sublimation phase.
The average pore size of the sample in the nested vials was 170 µm compared with 75 µm for vials placed directly on the shelf.
A freeze-drying cycle of a 5% Mannitol solution was performed to compare the thermal behavior of the product during primary drying. Overall, the differences in temperature and time were very minimal.
The biological activity of the enzyme LDH (lactate dehydrogenase) was almost 30% higher in the nested vials after freeze-thawing and after lyophilisation. Nested vials exhibited bigger crystals and, consequently, a smaller interfacial area between the ice and the cryo-concentrated solution. This is the trigger for the denaturation of LDH, and the recovery of LDH bioactivity was always higher in nested vials.
BELOW: EZ-fill® Nested Vials
Main advantages of the EZ-fill nest configuration:
• Easier cycle scale-up and transfer to the final industrial site
• No significant impact on freeze-drying cycle time
• Reduction in interfacial stresses a biopharmaceutical product is exposed to during the freezing and drying phases
• Better recovery of LDH bioactivity
• Reduced intra- and interbatch variability
These results confirm the advantages of EZ-Fill vials for lyophilisation. Find more information at: https://www. stevanatogroup.com/en/ offering/drug-containmentsolutions/vial-systems/
1. Source: IQVIA and Stevanato Group internal analysis
2. Pisano R, Artusio F, Adami M, Barresi AA, Fissore D, Frare MC, Zanetti F, Zunino G. Freeze-Drying of Pharmaceuticals in Vials
Nested in a Rack SystemPart I: Freezing Behaviour. Pharmaceutics. 2023 Feb 14;15(2):635. doi: 10.3390/ pharmaceutics15020635. PMID: 36839958; PMCID: PMC9960346.
3. Artusio F, Adami M, Barresi AA, Fissore D, Frare MC, Udrescu CI, Pisano R. The Freeze-Drying of Pharmaceuticals in Vials
Nested in a Rack System-Part II: Primary Drying Behaviour. Pharmaceutics. 2023 Nov 2;15(11):2570. doi: 10.3390/ pharmaceutics15112570. PMID: 38004549; PMCID: PMC10674193.
Late last month, Bristol Myers Squibb announced a $400 million investment in their Dublin Cruiserath Campus towards the build and design of a Sterile Drug Product (SDP) facility, which will support the manufacturing and supply of existing medicines as well as serve as a launch excellence facility for pipeline assets. This will be BMS's first European SDP facility for biologics manufacturing and is currently in the design phase. Construction is expected to commence in March 2024, now that planning approval has been received, for completion in 2026.
Padraig Keane, Vice President, Cruiserath Biologics, said: “This is significant news and a proud day at Cruiserath Biologics as this SDP facility strengthens not only our capabilities on campus, but allows us to be agile
and responsive to patient needs across the globe. This investment will expand our capacity for aseptic drug products, reinforce stable production for global supply, and accelerate the development and commercialisation of innovative biologic therapies alongside other pipeline medicines. This year we celebrate 60 years of BMS in Ireland, across our three sites in Ireland we continue to play a critical role in the global production, development, and supply network.”
Michael Lohan, CEO of IDA (Industrial Development Agency), added: ‘’Bristol Myer Squibb’s decision to invest $400 million at their Cruiserath campus along with 350 new jobs is most welcome news and underscores the strategic importance of Ireland in their global operations. It is proof of the company’s future commitment to Ireland and a testament to Ireland’s continued attractiveness as a location for biopharma investment.''
The latest episode of The FemTech Series, featuring Dr. Chung Looi, CEO, Ablatus.
Novartis recently announced it broke ground for the expansion of its biopharmaceutical manufacturing plant in Singapore. The $256 million investment will facilitate Novartis in deploying digital and automation solutions to enhance manufacturing productivity, improve operational efficiency, and upskill the workforce. The expanded site will focus on manufacturing therapeutic antibody drugs to deliver breakthrough treatments to patients globally.
“In the next phase of growth for the biopharma sector, we should seek to make manufacturing more sustainable and productive, as well as to make products that are more targeted, precise and effective. This will require constant and persistent innovation. With Singapore’s biomedical investments over the years, we have built an ecosystem that is well-positioned to work with global partners like Novartis to deliver best-in-class and
innovative biologics products that can combat diseases and increase Healthspans, around the region and globally,” remarked Mr Heng Swee Keat, Deputy Prime Minister and Coordinating Minister for Economic Policies, in the opening speech.
Steffen Lang, President of Operations at Novartis, added, "Biotherapeutics now account for almost one-half of all recent drug approvals and have enormous potential to address unmet needs of patients across a wide range of diseases. To meet this increasing demand for biologics, the Novartis early-stage biologics portfolio has been growing significantly in terms of capacities and investment. Our new facility in Singapore, which will be operational by early 2026, is timely and will help in bolstering the biopharmaceutical manufacturing and supply chain across Asia as well as strengthen local capabilities and upskill talent in Singapore.”
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