EPM Nov/Dec 2022

Nov/Dec 2022 | Volume 22 Issue 6

REGULARS

5: EDITOR’S DESK: Go green or go home.

6: A SMALL DOSE: A brief round-up of some of the latest developments in the industry.

8: PERSPECTIVE ON PHARMA: Cytiva reflects on the developments of the biotech industry in 2022 and the increasing focus on sustainable solutions.

14: COVER: Natoli examines the optimal settings for your tamper-style encapsulation systems.

30: OPINION: Recursion delves into digital transformation within drug discovery and the power of AI platforms in therapeutics.

42: TALKING POINTS: Stories to consider and what to look out for in EPM over the coming weeks.

FEATURES

10: AI & AUTOMATION: Withers & Rogers explains the power of AI approaches in biomarker discovery, breaking new ground in personalised medicine.

16: LYOPHILISATION & COLD STORAGE: Tower Cold Chain discusses the current challenges in pharma cold chain and how to ensure safety throughout.

18: ORAL SOLID DOSAGE: Aenova explores the challenges of development and commercial manufacturing of OSD from a CDMO perspective.

26: TESTING & INSPECTION: Lonza discusses a more sustainable route to future-proof testing and QC in pharma.

34: BIOPHARMA & MANUFACTURING: Q&A with AmerisourceBergen on the increasing market for cold chain products.

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Volume 22 Issue 6 Nov/Dec 2022

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GO GREEN OR GO HOME

supply chains and 45% from patient care. Some of the exciting action plans that have got underway include: leveraging digital solutions to decarbonise clinical trials and reducing supply chain emissions with green heat solutions.

Approaching the end of the year – and the final EPM issue of 2022 - calls for a time of reflection. And in terms of pharma, it’s been a year of progression.

Advancements in technology and automation has seen a reduction in labour and energy costs. Whereas, fewer supply chain disruptions have ensured patient access to life-saving treatment without delay or issue.

Despite that pharma manufacturers are under pressure to adhere to stricter

regulatory requirements whilst meeting demand, the hot topic of incorporating greener-based strategies is looking like it’s here to stay.

It’s safe to say that biopharma has seen achievement in sustainability this year. For one, the 2022 EcoAct Annual Performance Report found biopharma among the top performing sectors for sustainability: GSK rose to the top of the FTSE 100 ranks for climate reporting, with AstraZeneca finishing close behind in the top 10. Together with Sanofi,

EDITOR’S DESK

all three companies were recorded as the highest performing companies for corporate climate action and reporting.

On top of that, seven CEOs among companies such as, Roche, Merck, Novo Nordisk and GSK are all uniting to accelerate the pathway to net zero healthcare - a sector that contributes 50% of its emissions from its

I then saw it showcased for myself at CPhI Frankfurt. Catching up with industry experts solidified the notion that sustainability is now an essential element across pharma companies rather than a USP.

And interestingly, sectors across the pharma supply chain are each doing their part. Packaging providers are dedicating their efforts to minimising virgin plastic, logistics and distribution suppliers are focusing on energy-saving costs in medical product transport, and formulation scientists are seeking strategies to limit the environmental impact of API waste.

But undoubtedly, there’s still much more to be done.

It’s not enough for pharma companies to say they’re doing their part. They also need to prove it. Sustainability metrics are expected to be contractually mandatory within the next five years and a key criterion for investment opportunities. The responsibility and accountability of our actions has never been more so, and so it should be.

The new year will likely come with its own challenges and demands for pharma manufacturing – positively allowing for innovative solutions - but what should be considered at every corner is the action to do so sustainably. The answer lies in a delicate balance between the two.

REBEKAH JORDAN

A small dose

PIVOTAL PARTNERSHIP SEEKS TO TRANSFORM CYSTIC FIBROSIS RESEARCH

LifeArc, a national medical research charity, is joining the Cystic Fibrosis (CF) Antimicrobial Resistance (AMR) Syndicate in a strategic partnership alongside Cystic Fibrosis Trust and Medicines Discovery Catapult (MDC).

The CF AMR Syndicate aims to address unmet patient needs by linking people with CF with leading experts across industry, academia and the NHS.

Together, this crosssector consortium is identifying and tackling drug discovery hurdles to accelerate the development of CF antimicrobials and infection diagnostics and the speed at which they can reach the people who need them.

For the estimated 10,800 people in the UK living with CF, the lungs are one of the most commonly affected organs, where people with the condition experience a build-up

of thick sticky mucus, which is difficult to clear. The development of frequent and persistent infections that are difficult to treat leads to a progressive decline in lung function. Treatment failure due to the development of resistance is frequently seen in people with CF, and the consequences of this can be devastating.

With microbes becoming increasingly resistant to the current medicines and no new antibiotics being brought to market in over 25 years, AMR is a critically important and worldwide health concern. It remains one of the biggest issues faced by the CF community and is an area that faces significant drug discovery and development challenges.

This critical unmet patient need is something that the drug discovery and diagnostics expertise of both Medicines Discovery Catapult (MDC) and LifeArc –combined with expert insight from Cystic Fibrosis Trust – will seek to address, delivering a collaborative approach which could prove pivotal in unlocking future treatments and breakthroughs.

Dr. Beverley Isherwood, partnership lead for Infectious Disease at MDC, commented: “LifeArc, Cystic Fibrosis Trust and MDC have an aligned vision of lifting the limits of medicines R&D, accelerating the development of CF antimicrobials and diagnostics, and speeding up new treatments for people with CF. By bringing the CF research community together with people with the condition, we have identified barriers to the discovery of medicines and built a programme to overcome them.

Dr. Catherine Kettleborough, Chronic Respiratory Infection lead at LifeArc, said: “We’re delighted to join the CF AMR Syndicate as a managing partner. LifeArc helps accelerate scientific discoveries into new clinical solutions for patients. Working with CF Trust and MDC, we’ll provide in-house science capabilities, translation expertise and funding to fast-track the development of antimicrobials and diagnostics to bring new and effective treatments to people living with CF faster.”

Eisai clears all-case study requirement for antiepileptic agent Inovelon

Eisai Co. has received notification from Japan’s Ministry of Health, Labour, and Welfare (MHLW) that the “all-case study” specified postmarketing observational study condition required at the time of approval of antiepileptic agent Inovelon Tablets 100 mg and 200 mg (rufinamide) as an adjunctive therapy to

other antiepileptic drugs (AEDs) for treatment of Lennox-Gastaut syndrome (LGS) has been cleared.

In March 2013, the MHLW approved Inovelon as an adjunctive therapy with other antiepileptic drugs for tonic and atonic seizures associated with LGS showing insufficient response to other antiepileptics, with the

MOUTHWASH

ELUDRIL mouthwashes are among the first oral hygiene products in Europe to benefit from this type of packaging. This achievement is the result of a prospecting process conducted with ten different suppliers of recyclable PET in order to find the solution meeting the requirements of Pierre Fabre in terms of machinability, safety for the consumer, aesthetics and regulatory compliance. In addition to the use of recycled plastic, the new packaging is also lighter than its old packaging, which reduces the consumption of raw materials. Thanks to this innovation, more than one ton of plastic will be saved each year.

This initiative reflects the shared commitment of the two companies to sustainable development,

BORMIOLI & PIERRE FABRE DEVELOP 100% RECYCLED PET PACKAGING FOR

following condition: “Because of the very limited number of subjects included in the Japanese clinical trials, the applicant is required to conduct a postmarketing observational study in all patients until data from a certain number of patients is accumulated after its launch in the market, in order to identify the background information of patients treated with the product and collect safety and efficacy data on the product in the early post-marketing period, and thereby take necessary measures to ensure proper use of the product.”

Based on the safety data in 702 patients and efficacy data in 495 patients submitted to the MHLW as the results of analyses of this allcase study, the MHLW has concluded that the all-case study was conducted properly and the necessary measures to ensure proper use of the product were sufficient to lift the condition.

Eisai will continually strive to promote the proper use of Inovelon and provide information about the product, thereby making further contributions to increase the benefits to patients and their families.

a fundamental pillar for both Bormioli Pharma, which has committed to manufacture 50% of its products from materials with low environmental impact by 2025, and for Pierre Fabre, who has pledged as part of his Green Mission that 50% of his dermo-cosmetic and oral hygiene portfolio will be ecosocial-designed by 2023.   Roberto Valenti, head of Materials Development Bormioli Pharma, said: “The historic collaboration with a group as important and recognised as Pierre Fabre is a source of pride and inspiration for us. We are delighted with the excellent results we have achieved together on the new packaging for ELUDRIL, one of Europe’s best-selling oral care products, which could well pave the way for the widespread adoption of recycled PET in this sector.”

A majority of Bormioli Pharma’s packaging used by

Pierre Fabre is manufactured in the Saint-Sulpice (Tarn) factory, less than 50km away from Pierre Fabre’s main dermo-cosmetic production factory. This short circuit reduces CO2 emissions and road pollution caused by the transport of packaging.

Frank Legendre, Packaging, Innovation and Development director of Pierre Fabre said: “With our teams, we conduct a daily reflection to eco-design our packaging in order to improve its environmental performance from the design and throughout its life cycle. Our partnership with Bormioli Pharma reinforces our common commitment to implement concrete and measurable actions in favour of sustainable development, an approach at the heart of our responsible innovation approach, carried with the Pierre Fabre Green Mission.”

PERSPECTIVE ON PHARMA

Making headway

2022 was another major year for the biotechnology industry. Although nations were slowly starting to emerge from two years of public health measures related to COVID, the science and innovation never stopped. In 2020, the scientific community cracked the code on mRNA technology and has since been applying that knowledge to try and solve other global health challenges. The US FDA approved two gene therapies in 2022, giving hope to patients who historically had few options. However, advancing and accelerating the development of mRNAbased therapeutics, vaccines, and gene therapies can only be done if manufacturing challenges are addressed. As

AUTHOR - Emmanuel Abate, president Genomic Medicine and head of Sustainability, Cytiva.

the industry works to develop the tools and technologies needed solve these issues, we can’t lose sight of environmental concerns. Solutions must be sustainable.

OVERCOMING THE CHALLENGES OF MRNA MANUFACTURING

mRNA was catapulted into the spotlight during the COVID-19 pandemic as an exciting technology that could change the future of medicine. While we may not have another breakthrough for some time, the scientific community must now address the process and manufacturing challenges for any potential mRNA vaccine or therapeutic to reach its potential.

Adapting the process remains one of the key hurdles, as most current processes are designed and optimised for other molecules. mRNA manufacturing has not yet been standardised, leading to challenges with operations, personnel, process, quality control, and contamination. mRNA is on a much smaller scale than traditional cell-based modality manufacturing which presents another challenge for its development. While this results in considerable space and cost savings, it does require manufacturers to think differently about their space.

Another key challenge is DNA linearisation and purity at various stages of the process. Due to their size and varying impurity profiles, traditional chromatography resins don’t always interact well with mRNA molecules. Greater flexibility in purification technologies and allowing process development scientists to mix and match media, based on the specific characteristics of the molecule, are two ways to deal with this challenge.

The key to success for mRNA manufacturing is flexibility. Ensuring equipment is scalable and supporting the transfer from process development to GMP manufacturing will be a crucial success factor in building out the mRNA manufacturing ecosystem.

Gene therapy is here to stay, but manufacturing isn’t there yet

There are many gene therapy candidates in clinical development and more global regulatory approvals anticipated over the coming years.

However, we are not yet in a place where the industry could manufacture to meet patient demand.

Most gene therapy products are manufactured using individual steps that are manual and involve open operations. As such, efficiency is affected, and the risk of product contamination increases significantly. The solution to reducing these risks is scalable, automated, and closed platform manufacturing.

Through adding single use technologies to the closed system, this can further save time, reduce risk, and lower overall manufacturing costs. By reducing cleaning and validation time, set-up time, and in process hold steps for an operator to oversee equipment, has led to anywhere from a couple of days to a couple of weeks being saved. Closed systems are also more compatible with automation, which can further reduce timelines and cost, and, perhaps most importantly, ensure consistent product quality.

Implementing an integrated solution involves all the unit operations working together in a continuous manner resulting in all consumables being compatible. It is important to not only optimise each unit of operation, but also to consider

how all these units fit together and could reduce process steps. This solution will also ensure the process will run the same way each time.

ACCELERATING THERAPEUTICS SUSTAINABLY

While we work to address manufacturing challenges, we must do this sustainably. The use of plastic is integral to accelerating therapeutics. While there continues to be a need for plastic, one solution doesn’t fit all applications. As such, it’s essential that the biotechnology industry considers its approach on how to create more sustainable alternatives.

The industry’s dependence on plastic can impact the environment, and so starting to introduce circular models into product design processes can help. Sustainability should be built into the product lifecycle from the start through to end of life. To ensure that this is a reality, companies need to implement a framework that engages teams to think of ways to reduce, reuse, and recycle throughout the design process. For example, could recycled plastic be used instead of virgin plastic when sourcing materials? Or could the product be recycled at the end of its life? If the industry can learn to look at product design through a sustainability lens, then the environmental benefit could be huge.

There are also sustainable opportunities to be pursued

in advanced recycling, where technologies are currently being developed to meet rising demand. This process enables the transformation of used plastics into new products that can be repeatedly recycled. Although there’s a high demand for this type of solution, there’s a limited availability of advanced recycling facilities.

This restricts the speed of implementation. Ultimately, the biotechnology industry will need to accelerate its sustainability efforts, and start to support academic institutions researching advanced recycling of contaminated plastics.

The adoption of smart logistics is another solution which can reduce environmental impact. This could look like a rethink of packaging materials, using more direct and shorter routes, as well as changing transport modes. Through smart logistics companies can cut carbon emissions and transportation costs.

THE BIG PICTURE

The world needs advanced therapeutics to solve some of the greatest health threats from potential pandemics to cancer to rare diseases.

Addressing the manufacturing challenges they pose, is only part of the solution. Developing technologies that can advance therapeutics sustainably will help preserve the planet while providing patients with the medicines they need.

If the industry can learn to look at product design through a sustainability lens, then the environmental bene t could be huge.

BREAKING NEW G ND

PATENTING A NEW FRONTIER IN PERSONALISED MEDICINE WITH AI-POWERED BIOMARKER DISCOVERY

In the past five years, there has been a boom in the patenting of biomarkers as diagnostics and targets for use in personalised medicine. Research scientists have been capitalising on advances in the application of AI, especially deep learning, to find new, improved, or repurposed treatments and therapeutics for specific diseases.

A biomarker is a naturally occurring molecule, gene or clinical characteristic that may denote a pathological or physiological process. These biomarkers can be an indicator of disease, but they can also inform clinicians about disease progression and clinical efficacy. Once identified, they can be used to develop treatment pathways for specific patient groups, facilitating a more personalised treatment plan.

Prior to the advances in AI, the process of finding new drugs and treatments, or repurposing ones already in circulation, was time-consuming and expensive. The learnings from focused clinical trials tended to be more limited and often geographically spread, which made it difficult to spot signs that certain treatments were, for example, more effective in groups of patients with a particular gene or other physiological identifier. This led to a ‘one size fits all’ approach to medicine, which is not always effective or optimal for everyone.

ACCELERATING DISCOVERY WITH AI

By harnessing the power of AI approaches such as deep learning, it has been possible to accelerate the process of biomarker discovery. AIpowered approaches can lead to more accurate and reliable outcomes than is possible from a more traditional analysis of the fewer data points available from patients in separate clinical trials. AI algorithms developed for specific purposes are able to analyse large

datasets from a variety of sources, correlating multiple biomarkers, confounding variables and different outcomes simultaneously. Such algorithms do not require these correlations to be preprogrammed, and so are able to find features currently unknown or poorly utilised in science. For example, they might be used to find out why a particular group of patients might react to a drug in a certain way and expose potential pathways for more effective treatments.

Author: Abbie Fisher, associate at European Intellectual Property Firm, Withers & Rogers.

The sheer volume of data that is now available to biotech companies, pulled from many different resources, can help to de-risk the costly process of finding new drugs and therapies. It can also help to identify opportunities to repurpose existing ones. Through the analysis of many layers of data, AI algorithms can extract the fine details of where and how a drug works in a treatment pathway, providing better insights about what dosages or other clinical interventions will be most effective.

In this field, patents can often relate to a novel correlation between a biomarker and a specific medical condition. Once identified, this can lead to further opportunities to patent

new or repurposed drugs for use in the treatment of a specific disease or patient sub-group.

A patent should never impede a medical professional from providing a diagnosis or treatment, and strategies for patenting, for example, new biomarkers and repurposed drugs targeting biomarkers, can be directed by your patent attorney. AI-powered biomarkers in drug discovery bring advantages such as an increased success rate of drug development, improved efficacy and safety outcomes, and a smooth manufacturing process - as the infrastructure for a known drug will already be in place.

Pembrolizumab (Keytruda), is a type of cancer immunotherapy

that is effective against several cancers including melanoma and classical Hodgkin lymphoma. Pembrolizumab has recently been approved in Europe for use in advanced solid tumors in patients with microsatellite instability-high or mismatch repair-deficient biomarkers. This previously marked the first example of regulatory approval by the US Food and Drink Administration for a treatment defined by pantumour predictive biomarkers. Another example of a biomarker-related patent is EP3036007B1, for Trichostatin A, and its use in the treatment of cancer. In this case, the drug is used if the patient has a raised level of aurora kinase A (AURKA), as part of a personalised treatment plan.

CONCLUSION

As these examples show, AIpowered biomarker discovery is breaking new ground and generating a wave of safe and effective treatments and therapies for patients around the world. This is a particularly hopeful time for patients with rare diseases, where initial investment, risk and available data were stumbling blocks. The fact that this can now be done much more quickly and cost-effectively than before is a bonus for both the biotech industry and patients.

As the scale tips further towards personalised medicine, it is likely that applications for AI-powered biomarker-related patents will soar, bringing in a new and exciting future of healthcare for all.

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TO FINISH

With more than a decade of success driven primarily by chimeric antigen receptor (CAR) T cell endpoints, the field of cell & gene therapy is seeing unprecedented growth globally. Europe has been positioning itself to facilitate the development of advanced therapeutics, recently courting Bristol Myers Squibb (BMS) to construct its CAR T cell therapy production centre in Leiden Bio Science Park in the Netherlands. To keep pace with the industry, developers in Europe would do well to consider the supply chain for their starting materials as well as the safety and efficacy of the final therapeutic product.

CHOOSING A RELEVANT STARTING PROVIDER

The quality of cell & gene therapy starting materials, such as leukapheresis products and purified immune cell subsets, reliably determines the success of generating an advanced therapy – whether it is in the research, development, or clinical manufacturing phase. Therefore, it is recommended that sponsors choose an experienced starting material provider with a strong reputation for quality. Ideally the chosen provider will have a GMP-compliant product line because it demonstrates not only the quality of their research-grade products, but also a firm understanding of quality and regulatory oversight as it relates to customers’ clinical requirements. A GMP

portfolio also guarantees an ability to scale with allogeneic therapy developers, as there is no need to transition from one provider to another when entering clinical trials.

The provider also needs to have access to a broad, diverse group of donors to test the limits of an advanced therapy production process and guarantee a reliable supply of specific types of donors for a single study. For example, autologous therapy developers are beholden to the age, HLA-type, and physical characteristics of the patient being treated for starting material. Their research and development programs should therefore test as many permutations of the above as possible to assure a robust manufacturing process to maximise patient access. Further, allogeneic therapy developers often identify characteristics of an “ideal” donor for their product’s starting material. As additional inclusion and exclusion criteria are added, such as those listed above plus exposure to certain pathogens such as cytomegalovirus, a starting material provider’s donor pools may quickly shrink from tens of thousands to dozens of eligible donors. To avoid delay in bringing therapies to market, therapy developers should articulate their ideal donor demographics upfront and work with providers who have characterised their donors to a level that can accommodate their customers’ needs.

THE CRITICALITY OF SAFETY ENDPOINTS

While approved cell & gene therapies on market have demonstrated their efficacy, safety profiles remain a critical consideration. Potential adverse reactions such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, off-target effects, and other complications remain areas of focus for therapy developers. Other, rare complications such as CAR-transduced B cell leukaemia cells – wherein a patient’s leukaemia cells erroneously transform and express CARs – further emphasise the criticality of safety endpoints. Accordingly, bioanalysis has become an important aspect of advanced therapeutic development programs.

Traditionally, bioanalysis for cell & gene therapy at the pre-clinical level is performed through in vivo studies that test biologically relevant dose levels, safety in relation to said dose levels, and full characterisation of potential adverse effects including onset and duration. qPCR analysis is also performed on tissue to assess distribution, persistence, and any presence of the therapy throughout the body. These in vivo model tests are significantly more complex in cell & gene therapies than traditional therapies and often extend for more than a year to cover 28-day, 6-month, and 9-month timepoints for toxicology studies. These animal-based bioassays are often the most relevant to clinical response, but cell-based bioassays are generally regarded as most suitable for potency determination due to their lower variability. Further, ethical concerns may lead manufacturers to limit in vivo studies where possible.

or retroviral vector demand. Single-cell “-omics” testing has grown in importance, as researchers are starting to see no two cells are exactly alike.

Traditional “bulk” assays of multi-cell populations provide the average of the population but miss evaluating the features of individual cells as seen in single-cell RNA-seq studies.

Further, more advanced cell therapies, especially for geneediting based cell therapies, may require next-generation sequencing approaches.

For these and other assays, predevelopment preparation, method development, optimisation, and method transfer all add to the timeline for bringing a therapy to market. While Contract Testing Organisations and Contract Research Organisations can be leveraged, the explosive growth of cell & gene therapies in development has created a strain on these services –which were further burdened during the COVID-19 pandemic. Therapy developers with their own internal analytics capabilities can save time by working with starting material suppliers who can isolate purified populations of immune cells to custom specifications to maximise laboratory time dedicated to assay development.

Author: TREVOR SMITH, MS, MBA, product manager, immune cells, BioIVT

In vitro bioanalysis studies characterise the therapy at a more granular level. Tests range from standard cell viability and count vial flow cytometry to functional assays such as cytotoxicity or cell killing evaluation of a therapeutic product against target cells. Cytokine release of cell therapies via ELISA can also be used to ensure the correct response is being had to the target and for what duration that response persists. For cell therapies, transduction efficiency via qPCR and expression of the surface molecules (e.g. CARs) via flow cytometry give insights into the requirements for lentiviral and/

Europe’s role in advancing the cell & gene therapy industry cannot be overstated. While pharmaceutical companies work to strike the right balance with European authorities on pricing, advancements in cost-saving innovations such as allogeneic therapies or significantly reduced manufacturing timelines continue to progress through to the clinic. It is therefore in every developer’s best interest to carefully plan ahead – from starting materials to safety endpoints – to keep up.

A ROBUST, RELIABLE AND REUSABLE PHARMA SUPPLY CHAIN –WHATEVER THE SHIPMENT SIZE

It goes without saying that the pharmaceutical industry has some of the most stringent supply chain requirements of any market. Not only do many biopharmaceuticals require temperature-controlled preservation throughout their journey from manufacturer to patient, but there is growing demand for tangible sustainability, traceability and digitalisation, and mounting regulation to provide a clear, consistent framework for excellence.

Add to this the need to maintain these standards when customers require cold chain solutions ranging from mass shipments to small batches – for example, for clinical trials – and the challenge becomes considerably harder. Manufacturers need partners they can trust, whatever the shipment size.

At the core of any pharmaceutical cold chain solution, sit three key factors. Containers must be able to withstand the rigours of international travel, across land, sea and air. They must prove a consistent internal environment with no temperature excursions. And, increasingly, they need to demonstrate their sustainability credentials to minimise environmental impact.

ROBUST, RELIABLE AND REUSABLE

In light of these challenges, pharmaceutical manufacturers are compelled to seek out packaging solutions which fundamentally meet a core criterion: they are robust, reliable and reusable. And the three are increasingly entwined. Clever product design not only ensures the protective strength to achieve robustness; it also helps to achieve consistent (often sub-zero) temperatures; and optimises the usage of internal space for greater volumetric efficiency.

Likewise, passive temperaturecontrolled containers are becoming a strategic choice for organisations, achieving consistent temperatures, without excursion, for up to 120 hours – without requiring an active energy source. That’s one of the ways in which sustainability takes centre stage. Just as important, is what happens to that container at the end of its journey. A single-use solution obviously offers a poor return against the resources used to create it. As such, reusable cold storage containers are growing in prominence, simply by the fact that they stay in market circulation for a long time. And clearly, a truly reusable

container must be robust and reliable to fulfil its function of protecting pharmaceutical shipments.

SIZE MATTERS

With a global footprint comprising two-dozen hubs at major airports, Tower’s focus has been on bringing the ‘robust, reliable, reusable’ ethos to larger, pallet sizes – to give the pharmaceutical industry the top-class product protection and repeatable performance it needs.

More recently, we’ve also developed a solution to suit the growing demand for personalised medicines, small batch shipments and last-mile delivery. It was clear from talking to customers that the market would benefit from a solution that delivered the same standards of cold chain excellence in a small box.

The result is the KTEvolution, a manually handleable container (in either 26L or 57L sizes) which offers the same protection, security, and visibility as our existing containers. Even in the most challenging and remote environments, it is designed to withstand shock, vibration and climate risk, and prequalification testing confirms it meets 120+ hour protection for < -60°C (ultracold), -20°C (frozen), +5°C (refrigerated), and +20°C (controlled room temperature) shipments.

Whether big or small, an effective pharmaceutical cold chain must always be robust, reliable and – increasingly important – reusable. With these things in place, clinicians and patients alike can be sure the pharmaceuticals they use have been well looked after on their journey.

Niall Balfour, CEO, Tower Cold Chain, discusses the current challenges in the pharmaceutical cold chain and highlights how pharmaceutical manufacturers can ensure safe delivery of shipments, from mass-market to clinical trials.

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Two key trends can currently be identified in the pharmaceutical market: innovative drugs are strongly on the rise, and the oral solid dosage form will continue to be the preferred dosage form on the global market.

On the one hand, innovative active pharmaceutical ingredients are designed to be highly specific to their biomedical targets, which enables therapeutic breakthrough and lowered side effects. On the other hand, these substances have specific challenges, especially when formulation as oral solid dosage form is targeted. Such challenges are poor solubility and oral bioavailability, as well as the highly potent nature of active

INNOVATIONS IN

ORAL SOLID DOSAGE FORMS

ingredients (up to OEB 5). Consequently, developers and manufacturers must leverage innovative technologies and offer solutions to handle highly potent APIs (HPAPIs).

Di erentiated technologies for complex therapeutic systems and better bioavailability

Most of the drug substances in research and development belong to biopharmaceutical classification system (BCS) class II (low solubility / high permeability) and IV (low solubility / low permeability). To formulate these substances as solid dosage forms, three key technology solutions have been successfully applied:

• Amorphous solid dispersion

• Particle design

• Lipid-based formulations

The formation of amorphous solid dispersions has been gaining increasing attention in the last decade. Key technologies to generate amorphous solid dispersions are Hot Melt Extrusion, spray drying or co-precipitation. Particle design is often considered as micronisation of APIs, however, innovative technologies leading to nanocrystals have been successfully applied for several marketed medicines. With soft capsules as dosage form of choice, lipid-based formulations make use of the advantage to keep the API in a lipophilic environment.

In the field of complex solid dosage forms, intelligently encapsulated mini tablet systems (EMTS, see photo 1) or multi-unit pellet systems

(MUPS) can control the release of the active ingredient(s). This can increase the bioavailability of the active ingredient, but it also enables the combination of different active ingredients to improve the therapeutic effect of different molecules. Additionally, the drug release can be designed in a way that is optimising therapeutic effects and therapy adherence. Such innovations also include projects in the field of highly potent drugs, particularly in oncology, to offer patients a simplified and less burdensome form of therapy. This is especially relevant to overcome exhausting therapy cycles by applying oral solid dosage forms, which can improve patient acceptance level and consequently therapy success.

Every drug substance is unique in its physicochemical properties and its pharmacokinetics. Consequently, a CDMO must provide all of the above-named technologies paired with the respective formulation and process know-how. This is key to be in the position to select and apply the most suitable technology and formulation and deliver rapid and riskmitigated development and launch.

[ABOVE] Encapsulated mini tablet systems (EMTS can control the release of the active ingredient(s) (Photo: Aenova)

Authors:

Dr. Klaus Pollinger and Dr. Martina Breuer, Aenova Group, explore the challenges of development and commercial manufacturing of oral solid dosage forms, from a CDMO perspective.

Challenges in the development and production of HPAPIs

Oncology and hormone therapy have become increasingly important in the past decade, as innovation in drug research allowed to develop more and more target specific substances. These active substances exhibit an improved risk-benefit profile. Consequently, HPAPIs are on the rise and will play an important role in drug therapy in the future.

Market demands for cancer therapies is also growing rapidly. As a result, the targeted patient group is becoming smaller, as are the SKUs produced. However, the development and production of drugs with HPAPIs in the field of oncology is highly complex and often must be achieved under time pressure, as many of these new molecular entities (NMEs) are approved as “breakthrough therapy” in a fast-track process to quickly meet the high medical demand. This makes it all the more important to have a competent CDMO partner for a fast time to market, from development to commercial production.

Three pillars for safe and e cient handling of HPAPIs

Dealing with HPAPIs and the manufacturing of high potent medicinal products is challenging. The regulatory requirements to produce high potent drugs, which are laid down in various international guidelines, are consequently high and strict. This refers not only to the quality of the product, but also to the safety within production (see figure 1).

In a risk assessment developed by Aenova, the potency of the active ingredient, the physio-chemical properties, the quantity, and the duration are set in relation to each other to achieve the best possible risk minimisation in development and production (see figure 2).

Figure 1: Risk assessment in the manufacturing of oral solid dosage form per process step (Graphic: Aenova)

sieving, tableting and tablet coating are executed in a closed containment environment. This equipment train ensures safe and efficient handling of HP products from powder handling to finished dosage form (see figure 2).

In terms of optimal use of rooms and facilities, workflows and handling, there must be a deep understanding of efficiency and optimal use of all resources, e.g. implementation of lean and scalable processes, suitable room concepts, proper pressure concept, fitting supporting processes.

In addition to equipment and well-designed processes, there is a third, particularly important pillar: the highly qualified, experienced and well-trained employees with the appropriate awareness and the right mindset for handling highly potent active substances.

Outsourcing can speed up time to market Contract manufacturers play a key role in the supply of medicines worldwide, and the trend towards outsourcing continues unabated. It is crucial for CDMOs to offer their pharma customers technology solutions, production concepts, regulatory support and knowhow to serve the requirements of innovative and novel drug.

Figure 2: Closed containment concept for the manufacturing of high potent drug products (Graphic: Aenova)

To ensure safe and efficient handling of high potent products, it is key to master a holistic production concept as a basis for the three pillars - production equipment, processes and people.

Production equipment, processes, people

It is important to provide a closed containment of the various equipment and production lines in combination with a clear flow of material. For example: starting with API dispensing in an isolator and all subsequent process steps, i.e. blending, granulation,

For the development and manufacture of highly potent products, pharmaceutical companies are turning to specialised service providers often. A CDMO specialised in a holistic HPAPI handling with decades of experience and readily available expert knowledge like the Aenova Group, offers its customers significant competitive advantages and enables them to bring innovative technologies and products to market quickly.

[BELOW] Flexible commercial production of high potent APIs (Photo: Aenova)

Author: Russel Green, director product growth for Drug Discovery and Synthetic Biology, Automata

As vaccine development continues to advance and innovative techniques such as mRNA sequencing are being successfully used to deliver results, scientists must focus on fast-tracking progress, reducing the risk of errors and ensuring vaccines are accessible to as many people as possible.

But the complexity of the process – with common barriers being long antigen discovery times, regulatory disputes and lack of knowledge of the human immune system – means vaccines can often take 10-15 years or more to come to market.

Such elongated timelines put the lives of immunocompromised and vulnerable individuals at risk every day. Speeding up this process while keeping accuracy at its highest will be essential to eradicating diseases and keeping the global population healthy.

When the stakes are high, as we saw with the urgent need for COVID-19 vaccines, being able to improve all processesfrom data collection to scaling production – while maintaining accuracy, becomes critical. And automation underpins all of this. Here are three reasons why automation should become an integral part of the vaccine development process.

1. INCREASING THE ACCURACY OF VACCINE DEVELOPMENT

During vaccine research and development, tracking every step of the process is vital. However, many labs still track progress and results on paper, which is susceptible to manual error, especially when tens or hundreds of samples are

WAYS

AUTOMATION CAN SPEED-UP AND SCALE VACCINE DEVELOPMENT

managed per hour. At a time when a single mistake can cause a U-turn in development, precision is crucial.

By automating data collection and producing digital batch reports, it’s possible for scientists to accurately analyse the results of early drug candidate research, without the risk of error. This ensures a high level of repeatability and traceability, empowering technicians to process much higher volumes of data samples with greater precision and record them for future use. As seen with how SARS research was used to speed up the development of the COVID-19 vaccine, access to previous research is invaluable.

2. AUTOMATING ENTIRE WORKFLOWS

Vaccine development is a long and complex process, with some projects – notably the BioNTech COVID-19 vaccine – having around 50,000 steps required from beginning to end. To ramp up this process, labs often invest in automated tools for specific steps in the workflow, such as bioanalysers to conduct DNA quality control before sequencing. While these tools are excellent solutions for single tasks, they are often bulky and require manual loading and unloading – taking up lab space and elongating development time.

Making the most out of automation in vaccine development will require labs to think about enabling end-to-end workflows. By using robotics and automation to link each step of the process,

lab technicians can transform previously clunky, step-by-step systems into one continuous flow that increases both the scale and precision of vaccine research and development.

3. CREATING AGILE WAYS OF WORKING

The unprecedented nature of the COVID-19 pandemic highlighted the importance of being prepared to deal with the unexpected. When creating vaccines for brand new strains of a disease, or finding the right treatment for a rare condition, scientists need flexibility.

When needs change, or demand increases, scientists should be able to change their workflows to meet new requirements – and quickly. To do this, they should approach automation with a capability first mindset. By adopting this model, it’s possible for single automation tools in the lab to perform multiple processes – such as liquid handing or thermocycling – efficiently. With the same piece of automation technology being optimised to carry out new tasks when needed, labs can meet demand in times of crisis.

CONCLUSION

With the possibility of more global disease outbreaks in the future, the demand for vaccines to keep populations safe is only set to increase. This means that now more than ever are labs under pressure to scale, and reducing manual processes is critical. While automation can’t solve all obstacles around vaccine development, it can help to significantly reduce time by optimising process, thus helping scientists to produce better results faster.

MAVIS Platform is our latest innovative suite for best-in-class inspection results. Developed to match every drug perfectly, it guarantees easy and accessible operations for maintenance and control. It also combines advanced inspection performances with a small footprint.

THE ADVANTAGES OF SINGLE-USE IN CELL AND GENE THERAPY MANUFACTURING PLATFORMS.

Authors: Dr. Alex Van Hagen, Life Sciences Sector specialist, Watson-Marlow Fluid Technology Solutions; James Drinkwater, head of GMP Compliance, Franz Ziel GmbH and Dr. John Milne, director of Training and Education, National Institute for Bioprocessing Research and Training (NIBRT).

Cell and gene therapies (CGTs) present huge promise in the fight against a range of previously untreatable diseases. However, investment in this sector is not taken lightly. Typically, developers must invest billions of dollars in therapies that might take ten years to reach the market as they battle the odds against high failure rates.

Many more advanced therapy medicinal products (ATMPs), such as CGTs, are now entering the commercialisation stage. Finally, they are set to bring a return on investment and deliver their promises to the patients who need them. As developers embark on this next phase, new pressures emerge. Organisations must meet ever more stringent compliance standards and ensure the very highest quality and safety levels, while consistently driving down costs through efficiency.

CGT commercialisation is on a firm and fast trajectory, yet many challenges remain in the manufacturing stages. ATMP platform technologies

are providing solutions for some of the most demanding manufacturing challenges the industry has ever had to face. Hand in hand with singleuse technologies, platform technologies are delivering efficient manufacturing solutions through flexibility, modularisation, intensification, automation and digitalisation.

RECOUPING DEVELOPMENT COSTS

The average cost to develop a new therapy stands at $1.3 billion. When a CGT gets to the commercialisation stage, there is enormous pressure to recoup this cost. Manufacturing efficiencies are critical here to provide the cost savings that deliver payback without

transferring unnecessary cost burdens to payers or patients.

For highly targeted CGTs, reducing manufacturing costs is challenging. Very small batches require single-use fermenters; in the case of autologous treatments like CAR-T cell therapy, this might be one fermenter per patient and a complete upstream single-use fluid pathway. This costly but robust approach is necessary because every wasted millilitre could lose thousands of dollars.

THE ADVANTAGES OF SINGLE-USE ENSURING SAFETY

Contamination is a huge risk in the production of CGTs, and the very highest standard of aseptic processing is needed to mitigate this. CGTs are often injected straight into extremely vulnerable patients, and sterility must be ensured.

The latest revision of the GMP Annex 1, the European Union’s requirements for the manufacture of sterile medicinal products, addresses these issues in a standardised, mandated way. It requires manufacturers to increase contamination control measures, barrier technology and automation to reduce risk to patients and operators. Requirements, such as pre-use post sterilisation filter integrity testing (PUPSIT) that use sterile filter testing within single-use fluid paths, will increase the focus on ensuring each element of the manufacturing process accommodates the nuances of CGT

manufacturing.

ATMP manufacturing platforms, utilising single-use components and drawing on the latest technology and industry experience, are ideally placed to fulfil these goals.

TRIED, TESTED AND PREVALIDATED TECHNOLOGY

It is already known how to safely transfer cells in the biologics sector, using peristaltic pumps with fast, non-shearing processes, and we already use reliable bioreactors and suspensionbased culture systems in biologics manufacturing. Where tried and tested equipment is fit for purpose, it can easily be incorporated into new CGT workflows.

Single-use technology is an obvious choice, giving the option to remove every pathway associated with a batch and replace it with a new prevalidated system. Without cleanin-place (CIP) or sterilise-in-place (SIP) requirements, single-use systems can guarantee sterility and meet small-batch and bespoke needs.

Single-use pathways often come pre-validated for regulatory compliance and this is extended into some automated, modular equipment too. Prevalidated, standardised systems bypass bespoke validation and design processes, provide a key part of a robust contamination control strategy and can lead to faster regulatory signoff. These are all important aspects of an efficient manufacturing process that is designed to get CGTs to commercialisation faster.

FLEXIBILITY

CGTs are a broad and diverse range of therapeutics, so manufacturing platforms need to reflect this. There is strength in standardisation from modular equipment and single-use

pathways, but this shouldn’t come at the expense of flexibility, which is the only way to ensure the most efficient and effective production.

Platforms need to accommodate different batch sizes, from clinical production to small batch processes. They also need to be suitable for scale-up to meet increasing market demands. Ideally, this scaling potential needs to be incorporated in the research and development (R&D) stages. By using systems in R&D that have manufacturing-scale counterparts, small batch production can be easily and predictably upsized for larger allogeneic production.

Flexibility also needs to extend to the future. Given the fast-paced environment CMOs and CDMOs find themselves in, manufacturing systems need to offer the ability to be adapted for future requirements. More static equipment with stainless steel components is very hard to adapt without relative difficulty. Single-use technologies provide the solution; as long as the

MODULARITY

Modular systems that are pre-validated, enclosed and automated address many of the pain points of regulatory compliance, safety, waste reduction and changeover between products. Far from restricting flexibility, these systems are often fully configurable. ATMP filling platforms, for example, can now be configured to process a range of different products, with or without containment.

BRINGING LIFE-CHANGING THERAPIES TO MARKET WITH SINGLE-USE

CGT manufacturing requires an evolution of existing methods, rather than a revolution. The advantages of single-use components are well established and their incorporation into CGT manufacturing platforms is already transforming the industry.

at’s the beauty of single use. It’s an ever-evolving, iteration a er iteration, sort of product, instead of a more in place and dramatically changing later in the ture approach that we’ve seen in the past.

processing equipment can facilitate the required action, any component can be included within an assembly.

speedsolutions

- Accelerating your product through development to commercialisation and beyond

PCI continues to grow and evolve and as a fully integrated global CDMO, we are truly spanning the cycle, connecting development and commercialisation, de-risking the supply chain and delivering true speed to market on behalf of our clients. PCI is a strategic partner and an integral part of the supply chain as the bridge between life-changing therapies and patients. Our expertise combined with innovative technologies means we deliver more than just a service, we are a trusted partner sharing an industry depth and breadth of knowledge.

As part of the ongoing evolution of PCI and by listening to our clients, we are proud to introduce speedsolutions Speedsolutions combine valueadded services and expertise, delivering an integrated approach to every client project, de-risking the supply chain by eliminating the need to transfer to alternative suppliers. Irrespective of where you enter the PCI world, you will be supported with the option of an end-to-end solution both within specific phases of the product lifecycle and across your development to commercialisation journey.

PCI speedsolutions

speedtostudy – entering the PCI world during Phase I, speed-to-study offers services from the earliest stages of development including manufacturing, primary and secondary packaging, storage and distribution, supporting all your proof of concept and Phase I requirements with:

• Expert guidance understanding early phase safety and efficacy

• Financial benefits accelerating your Phase I timelines

• Risk mitigation - managing strategy, inventory and destruction

• Faster First-In-Human – Xcelodose microdosing and sterile robotic technologies

• Scalable manufacturing utilising geometric scale-up for reproducibility

speedtopatient – entering the PCI world during Phase II of the clinical lifecycle, speed-to-patient continues your clinical program and delivery of pivotal Phase II data, while achieving faster completion times and more reliable study results by:

• Enhancing retention, decentralised footprint accelerating recruitment

• Simplifying supply reaching patients wherever they are

• Risk mitigation - managing strategy, inventory and destruction

• Reducing launch timelines proactively managing commercial considerations early

• Scalable manufacturing utilising geometric scale-up for reproducibility

speedtoapproval – entering the PCI world during Phase III, speed-to-approval offers acceleration through this critical stage of the product lifecycle ahead of commercial launch with:

• Advanced technology and focus on commercial packaging design

• Seamless transition by identifying and eliminating hurdles

• Reducing overheads by addressing every commercial consideration

• Scalable manufacturing utilising geometric scale-up for reproducibility

speedtolaunch – entering the PCI world ahead of commercialisation, speed-to-launch offers acceleration to commercial success by identifying and eliminating potential hurdles with:

• Real-time data effortlessly coordinating and forecasting inventory

• Launch efficiency providing a seamless transition through commercial launch

• Packaging excellence by considering every design and engineering process

• Scalable manufacturing utilising geometric scale-up for reproducibility

ABOUT PCI PHARMA SERVICES

PCI is a global CDMO, providing integrated end-to-end drug development, manufacturing and packaging solutions to increase product speed to market and opportunities for commercial success. PCI brings the proven experience that comes with more than 90 successful product launches each year and over five decades in the healthcare services business. We currently have 30 sites across Australia, Canada, U.S., UK and Europe, with over 4,300 employees that work to bring life-changing therapies to patients. Leading technology and continued investment enable us to address global drug development needs throughout the product lifecycle, collaborating with our clients to improve patients’ lives.

RECOMBINANT FACTOR C: A STRAIGHTFORWARD

SWITCH TO VALID, SUSTAINABLE

QC TESTING

Author: Allen Burgenson, associate director, Global Subject Matter (SME) Testing, Lonza, discusses a more sustainable route to future-proof testing and quality control in pharma.

TRADITIONAL LAL-BASED TESTING — RISKS FOR THE MODERN QC LAB

Testing injectables and parenteral pharmaceuticals for bacterial endotoxins is critical for their safe release to the market. Traditionally, the test of choice for bacterial endotoxin testing (BET) has been the limulus amebocyte lysate (LAL) test, which requires the blood of the horseshoe crab (HSC). However, rapid expansion of the pharma market is driving an increased need for BET, and the finite resources critical for LAL. Estimates suggest the global LAL testing market will grow by 9% per year between 2022 and 2029.

As such, the industry is increasingly seeking more sustainable BET methods — to minimise supply chain risk and future-proof pharmaceutical quality control (QC) testing operations.

RECOMBINANT FACTOR C: THE ROUTE TO MORE SUSTAINABLE QC OPERATIONS

Recombinant Factor C (rFC) is one sustainable method. First developed and commercialised in 2003, rFC was a critical development in the biomedical industry’s continued commitment to reduce reliance on HSCs in the face of growing BET demand. The rFC assay uses a recombinant form of Factor C, the first protein of the HSC blood coagulation cascade that reacts with endotoxins. In the rFC assay, endotoxins activate the recombinant factor C protein, which then cleaves

a fluorogenic substrate to produce a fluorescent signal (figure 1).

The rFC assay offers many advantages over traditional LALbased assays. As recombinant Factor C is manufactured in a lab and not derived from HSCs, it is more sustainable. rFC assays can therefore better accommodate growing testing demand, imparting greater supply chain security. Additionally, as the rFC assay works via a single enzymatic step, it is less susceptible to interference. Conversely, the traditional multi-step LAL cascade is activated by glucans and endotoxins, which can lead to false positive BET results (figure 2).

Finally, while HSC blood contains myriad factors that vary between animals, the rFC assay contains only Factor C. rFC assays therefore retain all the endotoxin reactivity of LAL-based tests, but none of the biological variability, leading to greater lot-to-lot consistency.

Nevertheless, like LAL tests, rFC must be tested with each pharma product to confirm its suitability, as no single BET method works for all products.

AN ESTABLISHED, EQUIVALENT METHOD FOR BET

Despite the benefits, some organisations have hesitated to adopt rFC methods, owing to concerns around the method being too new or lacking equivalency to LAL tests. However, the rFC assay is already a well-established alternative. The test has been

Figure 1: Illustration of the rFC assay reaction. rFC assays work via a single enzymatic step.

Figure 2: Illustration of the LAL assay reaction. Unlike the rFC assay, the traditional multi-step LAL clotting cascade is susceptible to interference by glucans.

commercially available for almost two decades, and, in that time, a wealth of peer-reviewed studies have demonstrated the assay’s feasibility, specificity, and comparability to traditional LALbased tests.

A multi-site study, published in Pharmacopeial Forum in early 2010, was the first comparison of the rFC assay with traditional LAL tests and followed the requirements of the United States Pharmacopeia (USP) chapter <1225>. Researchers compared the rFC assay to Kinetic-QCL Kinetic Chromogenic LAL (KQCL) across 10 different pharmaceutical products.

As per USP chapter <1225>, researchers evaluated specificity, precision, accuracy, linearity, quantitation limit, and range. In all cases, results showed rFC to be comparable to the LAL-based method when using reference standard endotoxin (figure 3). The study thus concluded that the rFC method is a suitable BET assay for the products tested, providing a sustainable alternative BET method. In 2021, researchers conducted another comparative study (expected to be published in Pharmacopeial Forum in Q1 2023), this time looking at natural endotoxin contamination. Researchers spiked four parenteral products

with natural water to simulate a purification system breach, and then tested the products using LAL and rFC methods. Results demonstrated that rFC assays can be comparable to LALbased methods across various product matrices.

Global regulations also support rFC assays, with the rFC assay being either a compendial or alternative method as per several pharmacopeias (Table 1).

Besides being supported by many studies and regulations, rFC tests have been — and continue to be — widely used. Eli Lilly’s Emgality was the first FDA-approved drug released using rFC, back in 2018. Since then, regulatory bodies around the world have approved many other drugs tested using rFC. Our latest market data indicates hundreds of organisations, spanning more than thirty countries and an array of pharma industry segments, currently use rFC for BET.

STRAIGHTFORWARD VALIDATION

The rFC assay’s status as a non-pharmacopeial assay in the US and Japan means laboratories must validate it for use with products destined for global distribution. The added validation process has prevented some manufacturers from using rFC. However, the validation process is significantly easier than

Table 1: rFC assay status according to the European, Chinese, United States, and Japanese pharmacopeias.

Pharmacopeia rFC assay status

European Pharmacopeia Compendial (Chapter dedicated to rFC

Chinese Pharmacopeia Compendial

United States Pharmacopeia Alternative (rFC chapter currently in draft)

Japanese Pharmacopeia Alternative (rFC chapters currently in draft)

laboratories presume. Assuming a laboratory has already validated a quantitative LAL-based method for its product, QC personnel can validate rFC within five days. The validation process is identical to that used for LALbased methods, with just one added step — “validation of alternative method” (figure 3).

While the validation procedure is straightforward enough, BET product vendors offer solutions that further streamline the process. For example, some vendors provide a full, easy-to-follow validation protocol with rFC products. The latter means lab personnel can directly compare results when evaluating traditional and alternative methods, saving time and space. Endotoxin detection and analysis software is available that can accommodate multiple BET methods, including rFC, regardless of

hardware platform, with the most advanced solutions also supporting rFC assay automation. Lab personnel don’t therefore require any additional software training for adopting rFC assays, and rFC testing post-validation can be as efficient as automated LALbased testing.

FUTURE-PROOFED QC OPERATIONS

BET is critical for the safe release of injectables and parenteral pharmaceuticals. But demand for LAL-based assays is projected to grow rapidly in coming years. The rFC assay is a sustainable alternative option, boasting many advantages for QC labs. Most importantly, making the transition from LALbased methods to rFC is easier than QC personnel commonly perceive, and BET vendors are stepping up to help make the process even simpler.

but for one step: “validation of

Figure 3: Product validation of rFC assays is a simple 5-step process, identical to LAL method validation

alternative method”.

ADAPT AND OVERCOME

PROACTIVELY ADAPTING COLD CHAIN AND FILL-FINISH CAPABILITIES FOR NEW DRUG MODALITIES

Woocheol Chae, director of Drug Product Support at Samsung Biologics, examines the lessons learned following the onset of COVID-19 and highlights how CDMO flexibility is helping to hail in an era of new therapeutic modalities.

In rapid reaction to the COVID-19 pandemic, pioneering drug developers introduced a novel drug modality worldwide in the form of mRNA vaccines. The success of the global vaccine roll-out was facilitated in part through the efforts of contract development and manufacturing organisations (CDMOs) that quickly adapted their capabilities to support mass production.

REVOLUTIONARY TECHNOLOGIES

From the onset of the COVID-19 pandemic, drug developers reacted quickly to produce essential treatments and vaccines. This global health crisis set the stage for the introduction of a groundbreaking drug modality: mRNA vaccines. Although this technology had been used in treatments for a variety of infectious agents, including influenza, Zika virus, and cytomegalovirus, the pandemic highlighted its potential for worldwide vaccination programs.

Owing to the relatively simple editing involved in adapting mRNA, this technology offers “plug-and-play” applications, opening the door to its use in a wide number of different therapeutic areas. mRNA drugs have now entered the development pipeline targeting even more infectious diseases, from HIV to malaria, as well as autoimmune disorders, rare diseases, and a range of cancers.

The global mRNA therapeutics market reflects this growing potential and rising interest from the biopharma industry, as the market is forecasted to grow from $46.7 billion in 2021 to $101.3 billion by 2026.

Author:

Shortened timelines were essential to bring vaccines to clinical trials on time when vaccines were in an urgent demand.

SUPPORTING CONTINUED MRNA PRODUCTION

For the biopharma industry to meet the rising demand for new mRNA drugs, it will need unending support from CDMOs with expertise and experience. Anticipating this growing requirement, many CDMOs have shifted and adapted their services to expand their cold chain and fill-finish capabilities.

With increasing pressures to accelerate project delivery times, cold chain capabilities are relied upon heavily for mRNA drug development. Rather than spending considerable time ensuring product stability at room temperature in formulation development, shortened timelines can be achieved using cold storage. Shortened timelines were essential to bring vaccines to Phase I and Phase II clinical trials on time when vaccines were in an urgent demand.

ADAPTING TO MEET MRNA PRODUCTION DEMANDS

To meet the growing needs of mRNA projects on the horizon, development and manufacturing facilities and capabilities must be reassessed with mRNA at the heart. Manufacturers must face the challenges that surround implementing or expanding both their cold chain and fill-finish capabilities, as well as understanding this novel and often unfamiliar technology.

COLD CHAIN CAPABILITIES

In biologics production, manufacturers will have common cold chain processes already in place, but there are additional considerations they will need to consider when working with new drug modalities like mRNA.

1) Freezing and storage

Temperature ranges used for freezing biologic products are generally standard, but to provide flexibility, especially

for new drug modalities, manufacturers should offer access to multiple types of storage capabilities and have the appropriate standard operating procedures (SOPs) in place. For example, having blast freezers whose storage temperature can be adjusted anywhere from -20C to -70C can help CDMOs support a wider variety of projects.

For some biologics, slower freezing rates can cause cryoconcentration, where freezing from the outside-in causes compression of the bulk material and ultimately damages the molecular structure of the drug. Although this can be a common problem with blast-rate freezers, control-rate freezers can minimise potential damage by controlling the cooling rate at specific points of freezing. In DP production, manufacturers will need to consider the thawing process, for which control-rate freezers can also be used. Control-rate freezers require careful management and operational resources to be effective.

2) Primary packaging

Various types of containers are used throughout biologic cold chain processes and the choice of which will primarily be dependent on the platform used by the product owner. Manufacturers must therefore offer flexibility to mRNA product developers while remaining conscious of how the container materials could impact the product in terms of extractables and leachables.

Manufacturers will also need check for any damage to containers like glass vials during the handling/shipment processes that could lead to product loss as well as deteriorate product quality.

VALIDATION

Both static and dynamic handling validations of cold

chain capabilities during storage and transport. Static validations will be needed for the on-site handling of drug products (DP), where variations in temperature are unlikely to occur and can be more easily controlled. Contrastingly. dynamic validations are associated with off-site DP handling (e.g. during transport), where greater variation can be anticipated.

Appropriate controls and monitoring of temperature and humidity should be in place for manufacturing, storage, and transportation. In the event of deviation and control failures, there must also be risk management systems and continuity plans.

FILL-FINISH CAPABILITIES

As most vaccines are in parenteral format, manufacturers will need to ensure that these types of mRNA therapeutics are sterile to minimise the risk of exposing patients to contaminants.

Sterile filtration is the only method that can suitably sterilise vaccine products without impacting stability, a challenge that is also seen in general protein product manufacturing. This is usually conducted in grade A environments using two inline filters during fill-finish as close as possible to the filling points. Consequently, as the product flows through the lines to the container, the product is sterilised. A thorough control will be required to prevent changes in mRNA concentration that could arise due to filtration clogging.

FAMILIARISATION WITH THE TECHNOLOGY

In the early days of the COVID-19 pandemic, manufacturers were faced with a common problem: unfamiliarity with a relatively new drug modality. Most of

those with a background in supporting the production of biologics had predominantly worked with water-soluble drugs, in comparison to mRNA products encapsulated with lipid nanoparticles.

The unpredictable nature of mRNA drugs meant that these manufacturers had to quickly familiarise themselves with the new technology to determine how fill-finish and cold storage conditions could impact the product characteristics.

In part, manufacturers relied upon transparent and strong communication between the CDMO and the mRNA drug sponsor to form a clear understanding of the technology. By having a trusting relationship, efficient and effective transfer of important information can be achieved, with critical process parameters shared between both parties rapidly. In a public health emergency, this approach can minimise delays, ensuring patients receive critical vaccines in shorter timeframes. With new mRNA products entering the development pipeline, it will be increasingly important to build this trust and transparency between the parties involved in manufacturing.

LOOKING AHEAD

The COVID-19 pandemic highlighted three key areas that manufacturers must carefully consider when working with a relatively new technology: fill-finish capabilities, cold chain capabilities, and building a familiarisation with the product. The need for CDMOs that can proactively anticipate these needs and continue to offer flexibility will remain essential. This support will be further necessary for areas set to see rising expansion in the future, including the cell and gene therapy space.

Over the past decade, there has been an explosion of research in the field of artificial intelligence (AI)-enabled drug discovery. Both the number of AI-native companies and the size of their pipelines have increased significantly. According to the 2022 State of AI Report, there are now 18 investigational drugs in clinical studies from AI-native companies. Two years ago, there were none.

This wave of new therapeutics is just the beginning of the digital transformation of drug discovery, powered by a new data-driven approach. Similar transformations in biotech have occurred in the past; in the 1990s, multiple new tools like DNA sequencing, genotyping and high throughput automation converged to fuel a genomic revolution in medicine. Today, AI and new computational tools are allowing us to create and analyse broad, high-dimensional datasets that can dramatically accelerate the pace and scale at which we understand and control biology and chemistry. This is important because biology is extraordinarily complex. Despite scientific progress, we still see an abysmal 90% failure rate across all clinical trials, driving the total cost to bring each new approved medicine to approximately $2 billion. If we can uncover novel insights about the way biological systems and chemistry interact, we’ll create better medicines.

Here are two recent examples coming out of our labs at Recursion: our investigational program for familial adenomatous polyposis (FAP) and a potential therapeutic agent for the treatment of clostridium difficile (C.diff ) infection, both for which we initiated new clinical studies in September of this year. Biologically, these diseases

Opinion POWERING DIGITAL TRANSFORMATION IN DRUG DISCOVERY

are very different – one is a rare tumour syndrome, while the other is a common bacterial disease. But together they represent the power of our AI-enabled platform to discover novel insights across diverse therapeutic areas.

UNCOVERING NOVEL BIOLOGY FOR FAP

Author:

SHAFIQUE VIRANI,

chief corporate development officer and interim chief medical officer, Recursion, delves into digital transformation within drug discovery and the power of AI-enabled platforms in the future of therapeutics.

FAP is a rare hereditary cancer syndrome affecting 50,000 people in the US and EU. Patients develop hundreds or even thousands of polyps along their gastrointestinal tract throughout their lives, which have a high risk of becoming invasive cancers of the colon, stomach and other tissues. Many patients eventually undergo a colectomy to avoid the disease progressing into colorectal cancer, but the predisposition to tumours remains a major cause of death following surgery. There are no approved drug therapies to treat FAP.

While the downstream biology of FAP can be varied and complex, the cause of the disease is well understood: mutations in a gene called APC cause FAP. This provides a unique opportunity for Recursion’s phenomics platform because we have an anchoring point from which to start our search. We can model and manipulate the disease in a cellular context and use machine learning algorithms to uncover relationships between the disease model and a library of compounds, unconstrained by the bias of any existing target hypothesis.

We initiated a screen using cellular models of loss-offunction of the APC gene. This led us to identify a known chemical entity that had a very strong and specific effect in the context of APC mutants, but not in the context of other kinds of oncogenes or

tumour suppressor diseases. This particular molecule was originally studied by another pharmaceutical company to potentially treat colorectal cancer, but it had failed to meet its endpoints in clinical trials.

There was, however, a small subset of patients who had responded in the trial, but the company couldn’t explain why. The data we gathered from our platform and subsequent validation studies led us to believe that those were patients whose cancer was driven by APC mutations.

Today, this molecule is known as REC-4881, and it’s being studied in a clinical trial that is actively enrolling patients with FAP who have previously undergone a colectomy/ proctocolectomy. It has been granted Fast Track and Orphan Drug designations by the U.S. Food and Drug Administration,

as well as Orphan Drug designation by the European Commission. If successful, it could be the first drug therapy to treat FAP.

UNCOVERING NOVEL CHEMISTRY FOR THE POTENTIAL TREATMENT OF C.DIFF INFECTION

Clostridium difficile (C. diff ) is a common bacterial disease that impacts more than 730,000 people in the US and EU every year. The current standard of care to treat C.diff infection relies on the use of antibiotics, which can negatively impact the gut microbiome and even lead to recurrence of inflection, which happens in 20-30% of all patients, or more severe forms of the disease (i.e. Toxic Megacolon). These patients who experience recurrent infections represent an opportunity for new treatment options that may provide benefit beyond standard antibiotic regimens.

We began by exploring relationships across cellular models of C. diff infection, which we created using different toxins produced by the C. diff bacteria, and our compound library. Following an initial ‘hit’ in our platform, we launched a comprehensive medicinal chemistry effort to optimise the compound properties to be suitable for the intended use. We created a series of new chemical entities (NCEs) that we fed back into our platform to drive structure-activity relationship (SAR) testing and optimisation. This process allowed us to gain a more complete understanding of the molecule’s interactions with the target and other biological systems, helping us reduce off-target activity and drug-drug interactions.

As a result, our lead candidate, REC-3964, is a completely novel non-antibiotic, small molecule approach designed to selectively inhibit the toxin effects produced by C. diff in the gastrointestinal tract. It’s the first NCE discovered by our platform to enter clinical trials. We believe this molecule has the potential, when used as part of a treatment regimen, to prevent recurrent disease and/or other forms of C. diff infection.

THIS IS JUST THE BEGINNING. FAP and C. diff infection are just two of many examples in which big data and AI are being used to power a digital transformation in drug discovery. The beauty of AI-enabled platforms and the fitfor-purpose datasets that fuel them is the relatability of data across disease models, experiment types and therapeutic areas, revealing the interconnectedness of human biology. As our dataset grows with more experiments and inputs, the number of insights we can generate expands exponentially. This allows us to explore biology and chemistry at an unprecedented scale, and ultimately, to power the future of medicine.

We can use machine learning algorithms to uncover relationships between the disease model and a library of compounds, unconstrained by the bias of any exisiting target hypothesis.

NEXT LEVEL VITAMIN D SUPPLEMENTS WITH GALENIQ

EXCIPIENT OFFERS MORE EFFICIENT PRODUCTION PROCESSES AND IMPROVES TASTE OF TABLETS

Although previously seen as a “winter time” supplement when shorter days mean that exposure to natural sunlight is limited, vitamin D is rapidly becoming a year-round topic for many people as consumers are increasingly aware of its role in supporting the immune system. As vitamin D can activate the innate and inhibit

the adaptive immune systems with antibacterial, antiviral and anti-inflammatory effects, its deficiency is known to increase the risk or severity of viral infections. For example, recent research has shown that supplementing people with a vitamin D deficiency reduces the likelihood of developing acute respiratory viral infections by 42%. A recent study highlighted that, among hospitalised COVID-19 patients, preinfection

deficiency of vitamin D was associated with increased disease severity and mortality.

ENSURING SUFFICIENT INTAKE OF THE “SUN VITAMIN”

EFSA has defined an adequate intake of vitamin D to be 15 µg per day for healthy individuals older than one year of age. The lack of direct sunlight causes vitamin D levels to decrease. Therefore, consumers are looking for

dietary supplements to prevent vitamin D deficiencies. As vitamin D supports the uptake of calcium in the gut, many nutritional supplements contain both calcium and vitamin D.

When it comes to producing vitamin D supplements in tablet form, BENEO’s sweet tasting filler-binder galenIQ is the excipient of choice. This multifunctional excipient ensures both better

compliance and more efficient production processes for tablet manufacturers.

SUPPLEMENTS: IMPROVING TASTE AND FORMULATION

Vitamin D supplements are important for all consumer groups and all life stages, irrespective of factors such as lifestyle. “If we want to support people and help them to boost their immune system and their overall health with nutritional supplements, we need to take a closer look at the dosage forms we use,” says Dr. Maj-Britt Cepok, head of Business Development, Pharma at BENEO. Are products easy to swallow, do they taste good, are they easy to take on the go, does every age group accept them? After all, nutraceutical supplements should ideally be taken for a longer duration to see effects.

“When developing vitamin D and calcium tablets, it’s important that the bulk excipient in the formulation

MAIN IMAGE: galenIQ enables to create tablets which ensure a convenient and pleasant intake.

Credit: fizkes/shutterstock

BELOW: BENEO’s multifunctional excipient ensures both better compliance and more efficient production processes for tablet manufacturers. Credit: BENEO

fulfils certain functions, such as providing excellent flowability, low hygroscopicity, physical stability during mixing, chemical inertness and a high content uniformity. Ideally, the end product tastes good as well. Vitamin D is one of the most recommended nutritional supplements and, with galenIQ as an excipient, we enable consumers to make their intake convenient and pleasant”, says Dr. Cepok.

GALENIQ: HIGHLY

VERSATILE EXCIPIENT galenIQ is the pharmaceutical grade of isomalt, BENEO’s disaccharide alcohol derived from beet sugar. This excipient range is available in a wide array of particle size distributions, morphologies and levels of solubility. There are specific grades for direct compression, wet granulation, roller compaction, hot melt extrusion, syrups and pan coating. This makes it an allrounder for oral solid and even liquid dosage forms. In fact, the agglomerate morphology of galenIQ 721 ensures that both a high

ABOVE:

Winter time is the traditional season for Vitamin D supplementation as shorter days mean that exposure to natural sunlight is limited.

Credit: Evgeny Atamanenko/shutterstock

concentration of calcium and a comparatively low amount of vitamin D can be evenly distributed within a powder mixture and that there is high content uniformity in the finished dosage form.

PUSH FOR DIETARY SUPPLEMENTS

As consumers have been increasingly reflecting on their health and lifestyles in recent times, the nutraceutical industry has experienced a surge in demand. For example, a survey from the Council for Responsible Nutrition (CRN) in 2020 found that vitamins and minerals continue to be the

most frequently mentioned supplement category, with nearly all supplement users reporting usage in the past year (98%).

Particularly in light of the ongoing COVID-19 pandemic, concepts that support a quick and full recovery from virus infections will be a great help for consumers. Owing to its sweet taste and excellent technical properties, galenIQ is ideally suited for manufacturers of nutritional supplements containing vitamins and minerals in tablet or stickpack form who are looking to make the most of this trend.

Contact: BENEO GmbH galenIQ@beneo.com galenIQ.com

Quick questions with Juan Guerra, president of International Business Group at AmerisourceBergen, to learn about the increasing market for cold chain products and the future of the biopharma supply chain.

Q. How has the market for cold chain products changed in recent years and how have the needs of biopharma companies evolved?

A. The cold chain pharmaceutical market has experienced tremendous growth due, in part, to the increasing number of biopharmaceuticals and vaccines entering the pipeline. Over the next five years, the global market for cold chain products is expected to jump from $366 billion to $480 billion.

The influx of specialty pharmaceutical products, such as cell and gene therapies, offers tremendous promise for patients worldwide. However, these products also introduce unique logistical challenges and considerations. For example, temperature-sensitive biological products require storage within a narrow temperature range, such as refrigerated or frozen, throughout warehouse storage and transport. Any deviations in temperature could affect the safety and efficacy of the

product, resulting in significant financial losses and, more importantly, delaying patient access to the treatment they need.

Biopharma companies increasingly seek partners that can offer validated storage across a global network, cold chain packaging solutions and monitoring capabilities that provide enhanced endto-end visibility across the supply chain. Innovation in packaging design, in particular, has introduced new cold chain packaging solutions that provide extended temperature stability, enabling reliable deliveries over longer distances and protection against potential challenges, such as airport custom delays or shipments through extreme climates.

As more high-value products are being delivered over longer distances, biopharma companies want to work with partners that can also provide them with more data and information on the shipment’s temperature and status. Partners that can deploy tracking technology and advanced monitoring tools are able to provide biopharma companies with increased visibility across the supply chain, including real-time updates on precise location and internal temperature. Although their specific needs have evolved, biopharma

companies’ ultimately want to work with a partner they trust to protect their products and deliver them on time and in the right condition.

Q. How is AmerisourceBergen expanding its global cold chain logistics capabilities to meet its partners’ evolving needs?

A. While the COVID-19 pandemic shined a spotlight on cold chain logistics, the demand for temperaturecontrolled solutions has grown steadily over the last decade. During that timeframe, Alliance Healthcare, World Courier and ICS (all a part of AmerisourceBergen) have made significant investments to build out our cold chain capabilities— from expanding our cryogenic storage capacity around the world to developing new solutions, like World Courier’s Cocoon, a passive solution which uses a combination of honeycomb, vacuum-insulated panels and advanced phase change materials to provide stable thermal protection for more than 120 hours across the main temperature ranges, including ambient, refrigerated and frozen.

Through the continued investments in infrastructure and temperature-controlled solutions, our collective teams were well-positioned to work with various government agencies and supply chain

partners to support the delivery of millions of COVID-19 vaccine doses around the world—from islands off of Norway and remote regions in Africa to communities across England.

As more innovative products enter the pipeline, we continue to elevate our capabilities to ensure we’re well-positioned to meet our partners’ needs – whether it’s cold chain storage to support a clinical trial or transporting an oncology product across multiple countries within a very narrow timeframe. As more allogeneic cell therapies enter the pipeline, World Courier has doubled its cryogenic storage capacity across its global network of clinical and commercial depots. Alliance Healthcare and Alloga, Alliance Healthcare’s healthcare logistics provider, continue to expand their presence and cold capabilities in key markets across Europe. These continued investments, coupled with our operational expertise and presence in markets worldwide, enable us to deliver unmatched logistics and distribution support around the world.

Q. What do you think the future holds for the pharma supply chain in Europe?

A. The European Commission in 2020 outlined a pharmaceutical strategy for Europe that aims to advance patient access to innovative medicines and bolster the competitiveness and sustainability of the industry. A core pillar of the strategy focuses on secure supply chains.

Robust and well-functioning international supply chains are essential to ensure pharmaceutical products can safely and reliably reach patients across Europe—whether it’s an investigational medical product (IMP) for a clinical trial or a potentially life-saving treatment that requires urgent transport. Through our panEuropean distribution capabilities and presence in countries across Europe, we play a vital role in safeguarding the pharmaceutical supply chain. Over the last couple of years, the pharmaceutical supply chain proved to be resilient, in part, because of effective public-private partnerships and robust infrastructure, such as strategically located warehouse facilities, that enabled teams to be agile and respond quickly at the regional and local levels to avoid interruptions. We continue to expand our distribution capabilities and presence across Europe to meet the evolving needs of our partners and maintain an efficient and reliable pharmaceutical supply chain.

As we look ahead, one priority will be the continued focus on establishing more sustainable and responsible operations across the supply chain. There is a significant opportunity to

deploy practices that increase efficiency, product safety and quality, while also reducing greenhouse gas emissions and minimising waste. For example, the Alliance Healthcare team in the Netherlands recently introduced hybrid vans to its fleet and many of our sites in Romania are sourcing almost 50% of all electricity needs from solar energy. It’s imperative that we, as an industry, continue to maintain this momentum in order to create meaningful change.

Q. It has been a little over a year since AmerisourceBergen acquired Alliance Healthcare. What are some of the positives you’ve seen since the acquisition?

A. Through our joint capabilities, we’re able to provide biopharma companies looking to launch products in Europe with enhanced and differentiated support across the product lifecycle.

In addition to its best-in-class distribution capabilities, AmerisourceBergen offers a portfolio of commercialisation solutions to help our manufacturer partners navigate challenges at each stage of the process and maximise commercial success and patient access.

Our Global Pharma Services team includes an experienced group of consultants across Europe who are experts in real-world evidence and health economics and outcomes research and can provide valuable market access support. The market expertise and consulting capabilities is particularly valuable as biopharma companies must navigate varying regulations and requirements across the different countries in Europe. We’re now able to pair those consulting services with Alliance Healthcare’s manufacturer solutions and pan-European distribution capabilities to deliver unmatched end-to-end support that can be tailored to our partners’ specific needs.

CUSTOMISED EXCIPIENT BLENDS FOR CAPSULE TO TABLET FORMULATIONS

Dr. Sandeep Kumar, Formulation Development manager, Colorcon, sheds light on how selecting an excipient in early formulation development is critical to developing a robust scalable SOD formulation and can help the transition from capsule to tablet formulations.

Solid oral dosage forms still represent 50% of all new drug applications over the last three-year period, with 49% of applications submitted in a tablet format, of which 84% were coated, and 24% as capsules. While new dosage form technologies are coming to the market, such as 3D printing or “gummies”, most drug product manufacturers and patients consider tablets to be the preferred dosage format. However, for early safety and dose ranging studies, dose flexibility in the formulation is key and therefore capsule drug product formulations are considered the most convenient.

In order to reformulate from a capsule to a tablet dosage form, the formulator would need to re-assess the capsule powder blend for flow and tabletability. Sometimes this requires both qualitative and quantitative changes to the excipients used, to enable a robust scalable tablet dosage form. Colorcon propose a pragmatic approach to early formulation development, where multifunctional excipients like Starch 1500, StarCap and StarTab can be incorporated into formulated excipient blends that help to speed up formulation development; and not only provide excellent encapsulation performance, but also enable essentially the same qualitative

Table 1. Compositions of the formulation blends

composition to be utilised for both encapsulation and tablet manufacture.

Developing a scalable tablet formulation requires the same attributes as a capsule dosage form. You need to ensure the drug substance properties such as flow and compressibility are robust and do not change over the drug development cycle. However, drug substance manufacturers often make changes to optimise the manufacturing process, which can lead to changes in the drug substance physical attributes and ultimately result in drug product manufacturing challenges.

DESIGN-SPACE FOR TABLET TO CAPSULE DEVELOPMENT

One of the strategies to help de-risk drug product development and the subsequent transition from capsule to tablet formulations, is to ensure reliable, established suppliers are used that provide high-quality, consistent excipients. Excipients with multiple functionalities, for example Starch 1500 are preferred, which can act as a diluent, binder and disintegrant with moisture scavenging functionality.

At Colorcon we are exploring the concept of using excipient blends with multifunctional

ingredients to help customers with early formulation screening and to develop individualised drug products with flexible and scalable manufacturing capability built in.

Typically, starting excipients are selected based on physical attributes for the concept design, and often include 3 parts:

a. Plastically deforming multifunctional materialStarTab (disintegrant/filler/ flow aid/binder)

b. Plastically deforming compression enhancerMicrocrystalline Cellulose (filler/dry binder)

c. Brittle deforming material -

mannitol (soluble filler). A matrix of starting compositions with these model excipients has been explored in an experimental design with range 10 to 80%w/w. The inclusion of StarTab in these concepts provides disintegration, flow aid and optional binder functionality, while microcrystalline supports additional tablet tensile strength and mannitol helps mitigate tablet delamination and strain rate sensitivities sometimes associated with plastically deforming materials at high compression speeds.

Figure 1. shows the tabletability profiles of three excipient blends from the experimental design, with StarTab, microcrystalline cellulose and mannitol in various combination. StarTab when mixed with these excipients produces tablets of tensile strength >1.8 MPa and ≤25% strain rate sensitivity (SRS); indicating robust tablets that would be suitable for scale-up manufacture. The strain rate sensitivity (SRS) of these formulations for compression was determined at low speed (2 mm/sec) and high speed (300 mm/sec) and the composition, SRS values and disintegration times are given in Table 1.

Figure 2. shows the compressibility profiles (compaction pressure vs solid fraction) of three excipient blends of StarTab with microcrystalline cellulose and mannitol. The data demonstrates that all these combinations have solid fraction of ≤0.9, at nominal compression pressure of 200 MPa, indicating negligible risk of over compression.

Figure 3. shows the compactability profiles (solid fraction vs tensile strength) of three excipient blends of

StarTab with microcrystalline cellulose and mannitol. The data demonstrates that for formulation A and B, the tensile strength is higher than formulation C at same solid fraction levels, this is likely due to higher levels of mannitol in the formulation C leading to reduced tensile strength.

Overall we see from this work that a balanced formula with a 2:1:1 ratio of MCC : StarTab : mannitol provides a good combination of high tablet strength at low compaction pressures, low strain rate sensitivity and rapid tablet disintegration time.

A TOOL FOR RAPID DRUG FORMULATION SCREENING

Excipient choice for early formulation development is critical to develop a robust scalable SOD formulation and formulators often assess a combination of excipients to achieve the desired quality target product profile. This is often a trial-and-error process involving iterative testing. It is also not uncommon in drug development to need to reduce or increase the dose following clinical study outcomes, and this sometimes requires changes to the manufacturing process. Using excipient blends with multifunctional excipients like StarTab could offer several advantages to the formulator, as a qualitatively equivalent formula could be used in both wet or dry processes without concern about drug substance compatibility, thus offering added benefits for manufacturing flexibility.

Contact Colorcon about our multifunctional excipients and complimentary prototype formulation development lab to assist in developing flexible formulations for tablets and capsules.

Figure 1. Tabletability profile of various blend ratio of StarTab with MCC and mannitol

Figure 2. Compressibility profile of various blend ratio of StarTab with MCC and mannitol

Figure 3. Compactability profile of various blend ratio of StarTab with MCC and mannitol

ENABLING FAILURE PREDICTION IN THE PHARMA INDUSTRY AS TIME TO MARKET DEMANDS GROW

from 7.8 billion in 2020 to 9.9 billion in 2050, the demand for consistent access to vital drugs and vaccines will continue to increase.

to the War in Ukraine continues apace. Over the past 2-3 years, pharmaceuticals businesses have become increasingly used to expecting the unexpected.

With AI becoming more prevalent in the pharma space, RAMAN BHATNAGAR, Pharmaceuticals lead, Aspen Technology, explores the power of machine learning and analytics, and how this helps anticipate failure prediction in pharma manufacturing..

One of the biggest challenges the pharmaceuticals industry is facing is to ensure fast time to market. The speed at which companies developed and brought new Covid-19 vaccines on stream during the pandemic was widely celebrated. The fastest any vaccine had previously been developed – from viral sampling to approval – was four years – for mumps in the 1960s. Yet the Pfizer-BioNTech COVID vaccine was approved for use on 2 December 2020, just seven months after the start of clinical trials, with other vaccines following close behind.

That has set a precedent that the industry needs to live up to. Currently, half the world lacks access to essential health services, and with the global population expected to grow

Moving forwards, manufacturers will focus on developing a more efficient production cycle to support accelerating the industry’s time to market for all medicines. But achieving this will not be easy. Macro-economic disruption from China’s Zero COVID policy

The notion of volatility, uncertainty, complexity and ambiguity (VUCA) best explains this growing trend. While all four individually are reflective of distinct elements that can cause businesses to lose control of their wider environment, they also come together to prove

that with increasing volatility and complexity in an industry, the harder it will be to predict future events. This is pushing agility to the forefront for organisations.

PINPOINTING THE FACTORS THAT MATTER

At a more granular level, factors impacting a pharmaceutical company’s ability to ensure supply of end products include equipment failures but also

continually-changing operating conditions and the associated impact on process health. Both factors need to be addressed enterprise-wide in a timely, scalable fashion. Both can cause batch quality failures, resulting in costly production losses and disruptions to supply. With single batch values for some drugs surpassing running into the millions of pounds even one lost batch can deliver a serious blow to profits and supply.

FINDING A WAY FORWARD

Digital solutions, particularly advanced analytics, can help pharma manufacturers prevent equipment breakdowns and ensure process consistency, optimising production and protecting the supply of product to customers. The good news is that pharma manufacturers increasingly understand the value of these kinds of tools.

These advanced technologies are increasingly prevalent in the pharmaceuticals space. The global AI in pharma market reached a value of nearly $699.3 million in 2020, having increased at a compound annual growth rate (CAGR) of 31.8 % since 2015. The market is expected to grow from $699.3 million in 2020 to $2,895.5 million in 2025 at a rate of 32.9%, according to “AI In Pharma Global Market Opportunities and Strategies to 2030: COVID-19 Growth and Change.”

Predictive maintenance solutions use advanced analytics to identify the signs of pending equipment failure and warn maintenance teams in advance, allowing drug makers to plan repairs, adjust production and avoid unplanned failures that would result in lost product.

Process multivariate analytics solutions further evaluate the complex variables in batch production and determine which are critical to quality, helping pharma producers keep batches on course and driving greater consistency and yields. With these tools in place, pharmaceutical makers position themselves to safeguard security of supply, optimise production and control costs.

ANALYSING PRECISE FAILURE PATTERNS

Predictive maintenance solutions analyse precise failure patterns to provide anomaly alerts and advance warnings of pending equipment failures. With weeks or even months to plan for repairs, drug manufacturers can avoid unexpected shutdowns, reducing maintenance costs and preventing production losses.

GlaxoSmithKline (GSK) is a science-led global healthcare company that researches and develops a broad range of innovative medicines and brands. Today, it is creating a future-ready supply chain with predictive and prescriptive maintenance using Aspen Mtell. With Aspen Mtell, GSK receives up to 35 days’ advance warning of potential issues.

The manufacturer estimates that Mtell has also enabled it to save tens of millions of US dollars in lost batches avoided and achieve a 50% reduction in lifecycle maintenance costs. As Kevin O’Keeffe, head Engineering Primary & Antibiotics Manufacturing, GSK, stated: “Early and accurate warnings, speed and scalability of deployment, and ease of use were key drivers in choosing Aspen Mtell for predictive maintenance. Aspen Mtell

effectively predicts factors causing pharma process disruptions, improving production uptime and avoiding plant deviations.”

HOW PREDICTIVE MAINTENANCE HELPS PREVENT FAILURES

Predictive maintenance tools also offer faster implementation and shorter time to value than many other digitalisation investments, making them a strong choice for pilot projects in what Deloitte calls “digital incubators.”

Easy-to-use predictive maintenance software captures and analyses data quickly, making best use of all knowledge and skillsets within an organisation. Drawing on data history, past work orders and known failure modes, plant staff can develop Agents that identify anomalies and signs of pending failure. The Agents provide alerts that allow operators to investigate anomalies to determine whether they indicate a potential problem or schedule maintenance before a breakdown occurs.

Multivariate analytics software analyses and continually monitors for how discrepancies in material properties, variations in procedures and process anomalies such as sensor drift and changing environmental conditions impact the final product. These tools can help identify and troubleshoot process and product quality issues, increase yields and reduce off-spec product. Multivariate analytics monitoring can be especially valuable when applied to the complex chemical and biological processes prevalent in many pharmaceutical manufacturing processes; not reacting to small variations can steer a high-value batch off course.

The latest sophisticated tools support data scientists executing deep analysis while also being accessible to the operational teams most familiar with the process and helping them make sense of the available data. Without creating a need for dedicated staff, software that quickly diagnoses batch deviation to enable informed and timely action pays for itself many times over. Moreover, because these solutions can draw conclusions from sparse data, additional sensors or physical inspection rounds are not required to reap the benefits of reduced downtime.

ACCELERATING DIGITALISATION WITH ADVANCED ANALYTICS

Pharmaceutical companies that embrace the power of advanced analytics solutions gain a significant competitive advantage by reducing maintenance costs and eliminating production losses to ensure security of supply. Tools that can easily scale create greater agility, and deliver greater value, while leveraging all existing process and data science talent effectively.

Predictive maintenance and multivariate analytics tools offer fast return on investment and quick wins for pharmaceutical companies at all stages of the digitalisation journey. Deloitte estimates that these tools can improve overall equipment effectiveness (OEE) by up to 20% and deliver as much as a 5% increase in yield. These benefits add up over time, especially as organisations scale across multiple products, assets and sites.

As the pharmaceuticals market becomes ever more complex and competitive, security of supply and fast time to market will become ever more important. Rapidly identifying ways to increase OEE, reliability and throughput, while maintaining product quality offers pharmaceutical companies a formula for success – and predictive maintenance and multivariate analytics are the tools that make that formula happen.

THE SUPPLY OF MEDICINES IN EUROPE IS IN DANGER

Alexander Krujatz, chief commercial officer at Centrient Pharmaceuticals, explains the instability of the European supply chain of medicines, and what can be done to safeguard the essential medicines for patients in Europe.

THE DECREASING RESILIENCE OF THE SUPPLY CHAIN OF ESSENTIAL DRUGS TO EUROPEAN PATIENTS

In the last 40 years, a significant share of generic medicine manufacturers, especially those producing active pharmaceutical ingredients (APIs) and intermediates, relocated or outsourced their manufacturing capabilities to Asia driven by comparative cost advantages. The shift is especially true for the European pharmaceutical market. According to a recent study conducted by consultancy MundiCare on behalf of the German industry association of generic and biosimilar companies Pro Generika, the European generics market underwent dynamic

growth and massive shifts in the past 20 years. Two-thirds of the CEPs approved (Certificate of Suitability of Monographs of the European Pharmacopoeia) required to produce active substances are now held in Asia, and more than half of the manufacturers are based there. The number of active ingredient certificates has increased fivefold between 2000 and 2020. Much of the growth is attributable to Asian market participants. Most generic medicines prescribed and dispensed to European patients are produced elsewhere, putting the supply chain of essential medicines

at risk.

Several recent global events further underscored the importance of securing the European supply

of all 2022.

chain of medicines, especially the off-patent types. Offpatent drugs constitute 92% of treatment volume in the European Union. The recent COVID-19 pandemic, the ongoing war in Ukrainian, and the steep increase in energy costs in Europe all disrupted the global supply chains for all goods, including medicines. According to the European Central Bank, inflation continues to surge, and Harmonized Index of Consumer Prices (HICP) inflation rate is expected to stay above 9% for the rest of

Transportation costs are increasing dramatically (up to 500%), and manufacturing input costs have risen by between 50-160%. All these factors keep impacting the production output and may negatively impact the medicine supply across Europe. Examples of recent shortages include breast cancer treatment tamoxifen in Germany and Amoxicillin suspension in Europe and the US.

Today, there are few API manufacturers left in Europe. Centrient Pharmaceuticals’ sites in Spain and the Netherlands are some of the few remaining manufacturing supply networks based in Europe that produce Active Pharmaceutical Ingredients (APIs) and intermediates for first-generation Cephalosporin antibiotics. This type of betalactam antibiotic is included in the WHO’s Essential Medicines List and is generally prescribed to patients allergic to penicillin. The energy bill at Centrient’s production site in the Netherlands grew eightfold in the last 12 months and has become the most significant cost driver in producing high-volume and high-energy consuming yet low-margin generic drugs. The growing pressures on European pharmaceutical producers leave many important considerations for maintaining a European manufacturing base. What can be done to safeguard the essential medicines for patients in Europe?

1. The pressure on global supply chains underlines a growing need for deeper collaboration between the European Union, governments of European member states, the industry, and other

healthcare stakeholders to secure the European supply of such essential medicines as antibiotics. Pricing policy and maintaining a solid European manufacturing footprint for drugs consumed in Europe should be the priority.

2. Creating an environment that fosters innovation — empowering research and development capabilities will make Europeanproduced medicines more competitive globally. European governments need to support innovative, sustainable production that reduces environmental impact and requires less energy, fewer raw materials, chemical solvents and other harmful substances. This can be achieved by including sustainability criteria in procurement processes.

THE URGENT NEED FOR SUSTAINABLE MANUFACTURING

One of the ways to safeguard the supply of essential medicines to patients in Europe is by looking into enhancing sustainable manufacturing capabilities in Europe. Even though antibiotics are classified as essential drugs, the environmental impact of irresponsible antibiotic manufacturing sparks global concerns for the Asian region and the rest of the world.

If factory wastewater is left untreated, remaining high concentrations of antibiotic residue can create hotspots of resistant bacteria which may lead to AMR. 700, 000 people die yearly due to drug-resistant diseases, and the number of AMR-related deaths is forecast to reach 10 million by 2050 unless urgent action is taken. The World Health Organization recently declared antimicrobial

resistance (AMR) as one of humanity’s top global public health threats.

Sustainable manufacturing is the only way to preserve the environment and combat the spread of antimicrobial resistance, keeping the current antibiotic treatments effective. Established in 2017, the AMR Industry Alliance created the Common Antibiotic Manufacturing Framework (CAMF) and set stringent Predicted Non-Effect Concentration (PNEC) targets for use in environmental risk assessments of antibiotics to be self-reported as a part of this framework. The PNEC discharge target is the concentration of an antibiotic in water at which there is unlikely to be a risk of adverse environmental effects or of AMR developing. For the first time, the pharmaceutical industry, as member companies of the Alliance, have released the existing antibiotic data for antimicrobial resistance and eco-toxicity. This year’s Progress Report shows that an impressive 85% of Alliance members involved in manufacturing antibiotics are assessing their sites against the Alliance’s Common Antibiotic Manufacturing Framework (CAMF).

As a founding member of the AMR Industry Alliance, we fully commit to innovative, clean manufacturing. In May 2022, Centrient Pharmaceuticals was the first generics company to publicly announced 100% compliance with the stringent PNEC discharge targets set by the AMR Industry Alliance (AMRIA) for clean manufacturing of its full oral antibiotics product range.

ThePureActives enzymatic platform pioneered by Centrient Pharmaceuticals enables a 63% reduction in carbon footprint compared with the traditional chemical process. It requires fewer raw materials and no hazardous solvents or other chemicals –preserving the environment for generations to come.

The growing pressure on the European supply chains of medicines underlines an urgent need for deeper collaboration between the European Union, the European governments, the pharmaceutical industry, and other healthcare stakeholders to build and maintain a strong manufacturing base in Europe. Developing practical policies paired with incentivising local green production and is vital to safeguard the supply of medicines to European patients. The time to act is now.

Sustainable manufacturing is the only way to preserve the environment and combat the spread of antimicrobial resistance, keeping the current antibiotic treatments e ective.

CEOs from AstraZeneca, GSK, Merck KGaA, Novo Nordisk, Roche, Samsung Biologics and Sanofi announced joint action to achieve near-term emissions reduction targets and accelerate the delivery of net zero health systems.

For the first time, the global health sector has come together to reduce greenhouse gas emissions through the Sustainable Markets Initiative (SMI) Health Systems Task Force, a public-private partnership launched at COP26.

The Task Force is taking scalable action to collectively address emissions across supply chains, patient care pathways, and clinical trials. This includes aligning on a set of common supplier standards to incentivise decarbonisation efforts across the supply chain, and jointly pursuing renewable power purchase agreements and green transportation corridors.

Task Force members will build an end-to-end care pathway emissions calculation standard and tool that allows stakeholders to measure and track emissions across the care pathway and will publish product-level life cycle assessments (LCA) data to increase transparency on treatment emissions.

In addition, a common framework to measure the emissions from clinical trials will be created.

Read the full article at: www. pharmaceuticalmanufacturer. media

Talking points

URINE COULD PLAY KEY PART IN FUTURE BIOTECH SYSTEMS

Acommon chemical found in urine can be used to kick-start large-scale production of proteins such as hormones and antibodies used by biotech companies.

Researchers at the Universities of Birmingham and Aston have developed a system that uses urea to trigger the production of these proteins in the large quantities needed by the biotech industry.

Typically, in this process, small pieces of DNA are introduced into bacteria such as E.coli to persuade them to overproduce certain proteins. It is a well-understood technology that was first developed in the 1970s. Overproduction, however, is typically triggered by ‘inducer’ molecules, which can be costly, and often need careful handling, such as refrigeration.

By using urea instead, the researchers have developed a method that is cheaper, more straightforward, and uses easily accessible materials.

In a new study, published in New Biotechnology, the team investigated both purified urea and the urea contained in common garden fertilisers. They showed that similar results could be

achieved using either source.

Co-author, Professor Steve Busby, in the University of Birmingham’s School of Biosciences, said: “Our aim is to make this technology available to biotech companies who want to explore how to optimise their processes and also keep their costs down.”

The team also showed it was possible to fine-tune the amounts of protein triggered by the urea molecule, by varying the concentrations used. This is important to avoid harming or exhausting the host bacteria. They found it was possible to optimise production to quantities similar to those produced using mediumstrength promoters currently used as standard by the biotech industry.

The research was funded by the Biotechnology and Biological Sciences Research Council, part of UK research and Innovation.

Read the full article at: www. pharmaceuticalmanufacturer. media

OUTSIDE EPM

Check out the latest news and insights from the Med-Tech Innovation magazine at: www.med-technews.com.

BE SURE TO LISTEN TO

The latest episode of The MedTalk Podcast features Alan Foreman, CEO of B-Secur, explaining the potential of biometrics in life sciences.

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Level up to Automatic Capsule Filling IT’S TIME FOR A CHANGE

Introducing the NCF-45

Natoli’s NCF-45 fills up to 45,000 capsules per hour. Using the time-tested tamper dosing method. The NCF-45 can accommodate powder or pellets. Natoli saves time and delivers quality.

Need a custom solution?

Natoli answers the questions no one else can. Our global customer support is ready. Let’s talk!

Complimentary consultation with every quote.

Change Parts

Natoli has the change parts you need to take your operation to the next level. The change parts are in-stock and ready to ship for brands like: ACG, BOSCH and Capsylon.