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REGULARS

5: EDITOR’S DESK: With great power comes great responsibility.

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

8: PERSPECTIVE ON PHARMA: Synkrato examines how Industry 4.0 is driving pharma manufacturing.

12. FRONT COVER:

Fette Compacting shares its efforts in continuous direct compression through a Quality-by-Design approach.

28: OPINION:

Avantor shares insights on how to solve scale-up and manufacturing challenges in C&GT.

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

FEATURES

14: LYOPHILISATION: World Courier and Alloga Europe discuss the growing trends for cold chain and cryogenic storage.

16: CONTRACT SERVICES: Wellma explains the winning recipe for successful co-manufacturers.

20: INDUSTRY 4.0: Q&A with Thermo Fisher Scientific on leveraging the power of Pharma 4.0 in biopharma.

32: CLINICAL TRIALS: EPM spoke exclusively to Phesi to learn about the power of AI in navigating big data.

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WITH GREAT POWER COMES GREAT RESPONSIBILITY

manufacturers to maintain focus on product quality, whilst optimising their production processes and minimising the risk of costly breakdowns.

On the clinical side of things, investing in digital solutions could see rising recruitment rates and declining attrition rates. More on this in an interesting interview I had with clinical data company, Phesi, (pg. 32) discussing clinical trial metrics over the past year.

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European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals.

Volume 23 Issue 2 Mar/Apr 2023

While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

Pharma is evolving every year, but a big topic that is sticking around is digitalisation. Recently, LogiPharma reported that 86% of pharma and biotech companies planned to be more ‘digitally agile’ over the next 12 months. The main underlying reasons were to develop closer relationships with their suppliers to improve end-to-end visibility, as well as create a more operationally resilient supply chain.

Although on a larger scale, it so happens that some pharma companies are still asking the question: why go digital?

The pharmaceutical industry is often characterised as conservative and slow to adopt new technologies, including digital innovations. Additionally, the complex and highly regulated nature of the industry makes it difficult for companies to quickly implement digital solutions without compromising safety or compliance.

However, the pandemic and ongoing geo-political situations have only exacerbated the need for a more resilient supply chain. It’s shown us that the conventional way of

EDITOR’S DESK

REBEKAH JORDAN

pharma isn’t sustainable. Long distances between suppliers and manufacturers mean the risk of problems remains high; shortages aren’t timely communicated, and backup measures are absent.

A digital supply chain - one that is supported by real-time monitoring and predictive measures – can enable the preparation of plan Bs. Furthermore, it would allow

But, with all this digital power comes great responsibility - the risks need to be properly considered and evaluated.

Pharma’s shift to Industry 4.0 means an uptick in AI, the Internet of Things, and big data analytics, but it also means an increase in cybersecurity risk and the counterfeit drug market. We’re already seeing evidence of these fake online pharmacies headlining the news; a shortage of drugs means patients are turning to fake alternatives on the internet.

In saying that, it’s hopeful to see pharma already investing in technologies to mitigate these concerns - up to the point now where it has almost become an arms race between the two. Blockchain technology, for one, is making it easier to identify counterfeit products, with serialisation and QR codes to recognise and weed out the anomalies.

Regulatory agencies and pharma manufacturers will need to work closely together to ensure pharma’s digital transformation is a safe one. With data privacy and cybersecurity guidelines in place to ensure patient safety, any reservations that companies may still have about pursuing the change can be reassured and have their minds put at ease.

A small dose

BUILD-TO-RENT OPERATOR LAUNCHES SECTORFIRST PRESCRIPTION SERVICE WITH NATIONAL PHARMACY CHAIN

Moda Living, the UK’s developer and operator of rental communities, announced a partnership with VideoGP by LloydsPharmacy, via the launch of a ‘Health Concierge Service’ enabling residents to book free virtual GP appointments and have prescriptions delivered directly to their door.

The ‘Health Concierge Service’ is being rolled out free of charge to all Moda Living residents living at Angel Gardens in Manchester, The Lexington in Liverpool, The Mercian in Birmingham, New York Square in Leeds, and The McEwan in Edinburgh, plus future residents in Moda’s pipeline of more than 20,000 homes across the UK.

In as little as 30 minutes, residents will be able to claim a usage

code for the VideoGP service via their MyModa app, and speak to a GP on their mobile devices any time from 8am-8pm, wherever they are. Prescriptions can be delivered to the residents the next day, or collected the same day at their nearest LloydsPharmacy of choice, at no additional cost.

The partnership is the latest announcement in a wellbeing strategy to create the healthiest and happiest communities in the UK, all included in a Moda Living residents’ rent.

Speaking on the Health Concierge Service launch, Oscar Brooks, director at Moda Living, said: “Building strong communities is at the centre of the Moda Living brand, and we’re continuously looking for new ways to help support the health and wellbeing of our residents. We are proud to be pioneering this new service with LloydsPharmacy for our residents across the UK, and hope the launch of the Health Concierge Service with VideoGP for free virtual GP appointments and on-demand prescriptions helps take the pressure off residents who may need these services the most.”

SiSaf and University of Leipzig develop BioCourier targeted miRNA for pancreatic cancer

RNA delivery and therapeutics company, SiSaf, announced its collaboration with the University of Leipzig, Germany, to develop Bio-Courier targeted micro interfering RNAs (miRNA) for the treatment of cancer, with an initial focus on pancreatic cancer.

The collaboration will combine SiSaf’s expertise in RNA delivery using its Bio-Courier silicon-stabilised hybrid lipid nanoparticles (sshLNPs) and the University of Leipzig’s expertise in miRNA targeting and therapeutic approaches in cancer, led by Professor Achim Aigner.

SiSaf will develop miRNA Bio-Courier formulations that will be tested in pancreatic cancer models. Under the terms of the agreement, SiSaf has an exclusive option to acquire a worldwide license to a patent by the university.

A major bottleneck in miRNA replacement is their

AION Labs, an innovation lab spearheading the adoption of AI technologies and computational science to solve therapeutic challenges, announced the formation of DenovAI, the lab’s second startup approved by the Israel Innovation Authority. The new company will develop an AI-powered biophysics solution that can discover potential antibodies completely de novo (from scratch), and then suggest candidates likely to make effective drugs.

DenovAI aims to build a next-generation

computational platform for the de novo design of strongly binding antibodies directed towards epitopes of choice. In addition to funding, support and mentorship, AION Labs and its pharma partners will provide DenovAI with pharmaceutical data for model training and advanced machine learning development. Therapeutic antibodies are wellestablished life-saving drugs. Discovery of existing therapeutic antibodies relies on immunisation or invitro selection from large, pre-defined libraries with limited

AI STARTUP TO IMPROVE THE PROBABILITY OF SUCCESSFUL DRUG CANDIDATES WITH DE NOVO ANTIBODIES

e service enables residents to book ee virtual GP appointments and have prescriptions delivered directly to their door.

sequence space coverage. Selecting a drug candidate from billions of potential antibody sequences is laborious, expensive and, in many cases, fails to identify functional antibodies.

DenovAI aims to build on recent advances in protein structure prediction, AI algorithms, computational molecular biophysics techniques

and increased availability of experimentally determined antigenantibody structures to create a new paradigm for AI-driven antibody discovery.

“We are developing an end-to-end AI framework that can predict antibody sequences and structures that bind with high affinity and selectivity to any given epitope. And with

efficient delivery. The aim of the collaboration is to develop a replacement therapy combining both miR506-3p and miR24-3p for a more powerful effect, using SiSaf’s Bio-Courier drug delivery platform that leverages the unique properties of elemental silicon to optimise lipid nanoparticle technology for RNA therapeutics.

“Pancreatic cancer is an area of high unmet need, and we are encouraged by Professor Aigner’s research and the potential to develop miRNA-based replacement therapies to improve outcomes for patients,” said Dr. SaffieSiebert.

unlimited coverage of sequence space. This has never been done before,” said Dr. Kashif Sadiq, founder and CEO of DenovAI.

DenovAI is the second startup to be formed by AION Labs, which creates early-stage startup teams that harness the power of artificial intelligence to transform the process of drug discovery and development for the betterment of human health. The new company has been created through the investment of leading pharmaceutical companies Pfizer, AstraZeneca, Merck, and Teva and with close support from Amazon Web Services (AWS) and additional financial backing from the Israel Innovation Authority and the Israel Biotech Fund.

Applied Nanolayers and SoundCell awarded grant to develop graphene-based antibiotic sensitivity test

SoundCell BV have received €275,000 R&D funding from Provincie Zuid-Holland to develop a prototype for SoundCell’s high throughput single-cell graphene antibiotic sensitivity test.

The announcement follows research undertaken at TU Delft and published in Nature Nanotechnology last year where ultrathin bilayer graphene was used to detect nanoscale forces – at least 1000 times smaller than a mosquito bite – generated by single bacteria.

By tracking the changes in the bacteria’s nanomotion when different types of antibiotics are administered, the team were able to demonstrate that graphene drums can effectively perform antibiotic susceptibility testing with single-cell sensitivity.

This breakthrough

in measuring antibiotic efficacy has major implications for public health worldwide. The technology has the potential to enable very fast antibiotic testing in healthcare settings, giving physicians a much more effective diagnostic toolkit for fast detection of antibiotic resistance in clinical practice, leading to more effective treatment, and acting as an invaluable tool in the fight against antibiotic resistance.

The 18-month project will optimise the antibiotic sensitivity platform, bringing it closer to market. Enhancing the throughput of the platform, developing faster read-out schemes, and validating it against a variety of pathogenic samples, the funding will accelerate development of a clinical-grade graphenebased antibiotic screening device that is manufacturable in high volumes.

Conversations around the fourth industrial revolution, commonly known as “smart factory” or “industry 4.0,” have been sweeping the globe, and manufacturing processes powered by artificial intelligence (AI), augmented reality (AR), robotics, internet of things (IoT), and the metaverse are now a reality for the pharma industry.

In 2022, a large pharmaceutical company announced a new smart manufacturing site in the UK, and multiple pharmaceutical companies already leverage IoT devices to ensure that medication is transported and stored under safe ambient conditions.

WHAT PHARMA CAN EXPECT FROM INDUSTRY 4.0

The fourth industrial revolution focuses on connecting all business details through digitalisation using cloud or on-prem solutions. In a smart factory, all functions and processes are connected, providing transparency across teams and processes,

Amin Sikander, Synkrato co-founder & president, examines the trends within pharmaceutical manufacturing that will incur as the processes become smarter, more data-driven and transparent.

PERSPECTIVE ON PHARMA

e ture of pharma: How Industry 4.0 is driving pharmaceutical manufacturing

including sales forecasts, ordering raw materials, machine maintenance, floor plan operations, reporting, and last-mile delivery. The team ordering raw materials can access AI sales forecasts and adjust orders accordingly. Operators can access the same sales forecasts and adjust production line speed to avoid client stockouts. Likewise, when forecasts predict fewer incoming orders, maintenance can seize the opportunity to run machine maintenance.

Creating smart manufacturing starts by identifying which areas in the manufacturing process should be digitised first; not all pharmaceutical companies have the same digital maturity and needs. New pharma trends are emerging as processes and functions become interconnected, we review some of these trends below.

INCREASED PATIENT SAFETY

Patient safety has always been a focus for the pharma industry, so any technology

that can reduce patient risks is important. Patient safety continues to be an industry 4.0 technology driver. Drugs must be stored and transported under certain conditions to ensure product quality. Changing ambient temperature, humidity, light, or air can contaminate raw materials and the final product. IoT sensorsan Industry 4.0 solution - were designed to track small ambient variations and have become a key player in patient safety. They can aggregate real-

time data and transfer it to a centralised data hub, usually accessed by a group of users to monitor and take action to protect patients.

END-TO-END PRODUCT TRACEABILITY

Product traceability goes from ordering raw materials to lastmile delivery. New track-andtrace systems and serialisation solutions introduced in Industry 4.0 create additional transparency for pharma manufacturers, suppliers, and last-mile players to track every stage of the supply chain.

Product traceability has also been supported by the new DSCSA regulation that goes into effect by the end of 2023 and by new technologies like cloud labelling solutions and blockchain technology.

Pharmaceutical companies can leverage label management solutions to adhere to new label requirements. These solutions allowed working in a central platform to review, approve, and track labels across the supply chain. In a product recall, for example, pharmaceuticals know when and where a label was printed and can quickly locate the product batch. Blockchain will also be a key player in keeping drug batch records as specified in the DSCSA for at least six years.

PREDICTABLE PHARMA MANUFACTURING ISSUES

Predicting what could go wrong, when, and perhaps most importantly, how to avoid things going wrong, is the desired outcome for any manufacturing floor. Industry 4.0 provides pharma with new ways to analyse previous, current, and future production conditions to predict outcomes using AI. Companies can run what-if scenarios to reduce downtime, streamline production lines with new operations, and test new facility layouts, for example.

RESHAPED WORKFORCE

As manufacturing facilities become more autonomous, human involvement will be reshaped. AI can be used to predict machine failure points before failures occur and trigger maintenance processes to reduce risk, removing the need for an operator to check on equipment. Instead, an

operator’s new role will be to connect all the technical processes and ensure data is transferred correctly. Humans won’t be replaced by technology, but roles will evolve as technology use is widely adopted.

PROTECTED MANUFACTURER REPUTATION

One of the challenges pharma has faced is counterfeit medicine, which affects patient safety and the manufacturer’s reputation. Using blockchain, another technology that is part of the fourth industrial revolution, manufacturers can add a new level of transparency to avoid being impersonated.

For example, perhaps Company X has manufactured a new drug. During the manufacturing process, a QR code to combine all the product properties is created and securely stored using blockchain. As the drug moves down the supply chain with its QR, parties add information, origin, destination, method of transportation, and so on. When the product reaches the consumer, he or she can use a QR enabler to access this information to confirm that the product is legitimate.

A late or poorly managed product recall is another item

that can damage a pharma manufacturer’s reputation. In the last ten years in the US alone, more than 15,000 products have been recalled. Costs vary depending on the complexity of the recall, but according to Mc Kinsey, the average in 2010 was $600m per recall.

In the pharma industry, drugs go through multiple trials and tests, the results of which must be shared and approved. Blockchain provides secure sharing of highly sensitive information. If a product anomaly is detected, like a counterfeit drug, a recall can be done even before the counterfeit enters the supply chain, thereby protecting the brand’s reputation and patient safety.

A HOLISTIC VIEW OF PHARMA MANUFACTURING OPERATIONS

The items discussed above create a holistic view of pharma manufacturing. Pharma’s highly regulated environment requires a high level of expertise and oversight at every production stage. In the past, these processes created data silos, scaling difficulties, and inefficient operations.

Industry 4.0 connects all stakeholders to create new levels of transparency, operations control, quick, informed decision-making, and an autonomous floor plan. Removing data silos reinforces data-driven decisions across an organisation, giving everyone access to the same validated data. Smart factories will allow pharma manufacturers to adapt to market and regulatory changes without putting patients at risk, while they become flexible and competitive by sending information to the right person at the right time.

Smart manufacturing starts by identi ing which areas in the manufacturing process should be digitised rst.

Technical process advantages mean that continuous manufacturing could soon assert itself as an alternative to the batch-tobatch process. Market research institutes are forecasting high growth of around 10% for the years to come. Regulatory authorities such as the Food and Drug Administration (FDA) consider the process to be an innovative, quality-driven tool for modernising the pharmaceutical industry.

Continuous manufacturing is a central development area at Fette Compacting – with a focus on continuous direct compression. In particular, this can be attributed to a wide range of applications which can be combined with plant design optimised in terms of space and resources as well as precise process analysis. Direct pressing entails feeding the powder from the dosing and mixing module into the tablet press without any additional granulation.

Compared to granulationbased production, several production steps are no longer required, which is why spatial requirements are reduced and the process is leaner overall.

FURTHER DEVELOPMENT VIA QUALITY BY DESIGN

In an effort to further develop the continuous direct pressing process, Fette Compacting has been pursuing a Quality-byDesign approach for some years now which has also contributed toward a versatile process design. Ultimately, culminating in the FE CPS dosing and mixing unit. In combination with a rotary tablet press and a central operating panel, it forms a comprehensive continuous direct pressing line. The entire plant can be integrated on a single level in existing production rooms.

On its way to becoming a finished tablet, the powder (or premixture) goes through several flexibly adjustable

The technology used in continuous pharmaceutical manufacturing has matured even further in recent years. Within the scope of tablet production, one major focus is on direct compression, which combines a particularly lean plant design with process analysis technology. The FE CPS dosing and mixing unit sets new standards in the continuous direct compression process.

CONTINUOUS TABLET MANUFACTURING:

HOW THE POWDER STARTS TO FLOW

process steps: from the inlet ports for the materials to the outlet port for the mixture, which is in turn connected to the inlet of the downstream tablet press. The continuous product flow can be summarised and described in the following steps:

1. MATERIAL FEED

The dosing and mixing unit features up to six inlets for the material feed. Each inlet can be used for an individual ingredient or a premixture of several ingredients. A premixture is used when the total number of ingredients exceeds six or the concentration of an ingredient in the formula is particularly low. Each feeder is equipped with an automatic refill system (ARS) which feeds the material reliably and at consistent intervals to the next process step. As this first step is decisive for the correct operation of the line as a whole, Fette Compacting has developed its own refill system with special screws. These can convey very complex raw materials into the dosing process, both reliably and consistently.

2.

DOSING

Dosing is at the heart of the new technology, so to speak. Up to six gravimetric (loss-in-weight, LIW) powder dosing units are used here. For each feeder, the concentration of the respective material in the formula is stored in the cross-plant product

recipe. Combined with the required plant throughput, the control system automatically calculates the requisite flow rate. The LIW feeders use twin screws to feed material to the next process step with the required feed rate and minimal feed variability.

3. MIXING PROCESS

In the next step, a specially developed horizontal powder mixer is used. It has two successive but independent mixing zones – without a dead zone in between. This allows mixing processes with high and low shear energy to be combined in a single mixer and to achieve the best mixing results depending on formulation requirements. The mixer is equipped with four inlet ports: two in the first mixing zone and two in the second. The various ingredients are directed from the LIW feeders to the mixer inlets using a combination of downpipes and transfer hoppers. Each specific hopper configuration determines which outlet of the feeder is connected to which mixer inlet. The mixing duration for the respective ingredient is thereby specified. Various hopper configurations are available as format parts, offering a great deal of flexibility. This enables users to achieve the optimal process setting of shear intensity and mixing duration for a wide range of recipes.

4. INLINE QUALITY CONTROL

Embedded process analytical technology (ePAT) can be used at the output of the mixer. A near-infrared spectroscopic sensor checks, among other things, the homogeneity of the mixed powder and the concentration of the active ingredient. In this way, the system can be permanently monitored, and quality deviations can be discovered without delay. Especially in process development, it is important to continuously record and optimise the mixing process. Further ePAT sensors are located at the tablet press, which enables continuous in-process monitoring at high speed.

5. CONVEYING

In the last step before tableting, the powder mixture is conveyed evenly and without the risk of segregation to the inlet of the tablet press. For this purpose, a powder transport system was developed, which conveys

the product by dense phase conveying over a distance of up to ten meters without the risk of segregation. Via a conveying hose, it reaches the conveying arm of the FE CPS, which can be flexibly aligned with the inlet of the tablet press. This ensures that the thoroughly mixed powder reaches the tablet press without interference and is compressed in the usual quality. The mixing conveyor system also allows a two-room set-up of the direct pressing line: the FE CPS can be set up in one room while the tablet press is in an adjacent room. This can be interesting if the system is to be installed in an existing tablet production line.

In this combination, these process steps open up new perspectives for efficiency and product quality in tableting. Thanks to its lean plant design and a process analysis technology adapted to it, the FE CPS offers a compact yet reliable solution for continuous manufacturing.

ABOVE: FE CPS dosing and mixing unit from Fette Compacting.

ABOVE LEFT: Various sets of twin screws are available for feeding.

ABOVE RIGHT: A special mixer combines mixing processes with high and low shear, as well as di erent mixing durations.

LEFT: The starting materials are prepared for tableting in five process steps.

The European Commission in December issued the first approval of an allogeneic T-cell therapy in the world, a significant milestone for the cell and gene therapy sector. The landmark approval reflects the potential promise of pharmaceutical products currently in development and also highlights a broader industry trend: a growing percentage of products – from vaccines to cell and gene therapies – require cold chain storage and handling.

The global market for cold chain products (e.g. temperatures ranging from 2 to 8 °C or lower) is expected to increase from $366 billion in 2021 to $480 billion in 2027, driven in part by the projected influx of biopharmaceutical products. Recent reports suggest cold chain products will continue to grow at twice the rate of non-cold chain products through 2024, creating a heightened demand for cold chain logistics, including temperaturecontrolled distribution and storage. While these products offer tremendous promise for patients worldwide, they rely on a secure cold chain – any exposure to temperatures outside the specified range can threaten a product’s viability, resulting in product wastage, lost revenue and, most importantly, delayed patient access.

As significant R&D investments and scientific advances power breakthroughs in medicine, biopharma companies and their logistics partners need to build end-to-end strategies to ensure the products can reach patients who need them – no matter where they

Nick Porter, president of World Courier, and Chris Williams, senior vice president and international managing director of Alloga Europe and ICS (all a part of AmerisourceBergen), discuss the growing trends for cold chain and cryogenic storage in transporting ATMPs, and the technology investments needed to safeguard the supply chain.

throughout Europe, with recent investments in France, the Netherlands and the United Kingdom to meet the heightened demand.

Advances in packaging solutions, tracking technology

THE LOGISTICS BLUEPRINT:

Pharma cold chain in Europe

Logistics providers today are delivering more complex and sensitive products over longer distances and, in some cases, across multiple countries. As a result, there is a heightened demand for tracking technology and cold chain packaging solutions that can protect product integrity and quality throughout deliveries. In 2020, live. Successful cold chain logistics requires highly choreographed shipping schedules, cold storage infrastructure, temperaturecontrolled packaging, tracking technology and adherence to strict regulatory guidelines.

Expanding cold chain and cryogenic storage capacity

Strategies need to be tailored to the unique product requirements. While many cold chain products require storage at refrigerated (2 to 8 °C) or frozen (-15 to -25°C), a growing number of advanced therapy medicinal products (ATMPs) require ultra-frozen (as low as -80°C) or cryogenic (as low as -196°C) storage. Cell therapies, for example, are highly labile, remaining viable only within narrow ranges of temperature and time—fresh cells have a shelf life of between 12 and 96 hours before degrading. Freezing cells below -150°C using cryogenic storage techniques can be a viable solution to enable long-term storage.

The rapidly growing pipeline of ATMPs, coupled with the increasing number of

allogeneic cell therapies – often referred to as “offthe-shelf” – in clinical development, underscores the need for expanded cryogenic storage globally. By 2026, the UK, Switzerland and Germany will experience a more than 20% growth in cryogenic transportation and storage needs related to in-country clinical trials.

Robust cryogenic infrastructure in strategic locations across the world – ideally close to processing facilities and healthcare providers – is critical to enable timely and reliable access to ATMPs and to accelerate time to treatment. World Courier, for example, has doubled its cryogenic storage capacity across its global network of clinical and commercial depots since 2021 and expanded its network of liquid nitrogen (LN2) charging centres and stations to help ATMP developers build logistics platforms that support the clinical development and commercialisation of the therapies. Alloga also continues to expand its cold chain storage capacity across its network of facilities

nearly 30% of the $17.5 billion spent on pharmaceutical cold chain logistics went toward packaging costs, as well as tracking technology and monitoring solutions, like data loggers.

Technological advances and innovation in design have led to the emergence of packaging solutions that offer extended temperature stability, enabling reliable deliveries over longer distances and protection against potential challenges, such as airport customs delays or extreme weather. Biopharma companies and logistics providers can deploy a wide range of temperature-

controlled solutions to protect products throughout transit, such as dry shippers to support cryogenic shipments, and passive solutions, like Cocoon, that leverage various insulators and a variety of coolants. By engaging with logistics providers early in the clinical or commercialisation process, biopharma companies and their partners can identify the right packaging for their product as well as the most efficient transport route – helping them save time, reduce costs and ensure optimal security.

Real-time tracking of cold chain shipments has become increasingly important.

Technology that provides reliable, real-time monitoring data enables teams to proactively monitor shipments and identify potential risks. Logistics providers with an expansive global footprint are well-positioned to respond quickly, if needed, to take corrective measures to prevent any impact to the product. At World Courier, we are deploying a real-time location monitoring solution on all of our multi-use packages, providing our team members with enhanced visibility into the precise location of shipments in transit globally. Continued investments in tracking technology and monitoring tools are critical to increase end-to-end visibility and maintain a secure and reliable supply chain.

Maximising commercial success, patient access

The approval of the first allogeneic cell therapy offers a glimpse into what is on the horizon, particularly as biopharma companies continue to develop novel therapies to treat conditions with unmet needs. Over the last three years, the European Medicines Agency (EMA) has recommended for authorisation more than 130 new active substances, including ATMPs and orphan medicines.

As the pace of innovation continues to accelerate across healthcare, logistics providers that continue to invest in cold chain storage infrastructure, packaging solutions and advanced technology capabilities will be well-positioned to support the evolving needs of their customers and ensure their products are delivered on time and in the right condition.

The current role of the CDMO (or comanufacturer as we call it) is critical and we expect its importance to continue to grow over the coming decade. We see that there are various factors behind this trend, with different sub-sectors being affected in unique ways.

Capacity constraints and capital expenditure are overall strong driving forces, whilst in some sectors, technological advancements have increased the demand for outsourcing. Shifts in the regulatory environment have also been a material contributing factor, with new requirements demanding deeper expertise from the internal organisation. Although not new; these developments have become even more relevant over the past few years, offering an explanation as to why the overall percentage of development and manufacturing outsourced to co-manufacturers has increased.

What has then been the winning recipe for successful co-manufacturers? We believe strong regulatory and quality track records, sustained operational excellence, and leading R&D capabilities have been foundational drivers of success.

SCALING TOGETHER A WINNING RECIPE FOR FUTURE CDMOS

In addition to consistent high performance on the critical factors above, we see some other common threads underlying the success of leading co-manufacturers:

Focus: Leaders within specific sub-segments that focus on depth and excellence within a narrower field rather than a thinner, broader base have experienced high, profitable growth.

Flexibility: Co-manufacturers being able to manage peaks in demand and working closely with their clients to smooth out variations in business activity are performing well. This facilitates not only efficiency, but also their focus on excellence within niche areas.

IP: Another winning recipe has been those co-manufacturers developing their own IP with high product complexity. This has allowed successful co-manufacturers to create a solid differentiating factor and demonstrate their previous success.

Having said this, not all is rosy in the CDMO market. Supply chains have been disrupted, first by COVID-19 and then by Russia’s fullscale invasion of Ukraine, causing production inefficiencies and raw material price spikes. Furthermore, cost inflation and volatile energy prices have put further pressure on margins, especially for the players unable to transfer such cost increases to their customers.

LOOKING AHEAD

We see more and more challenges of being an independent, smaller co-manufacturer and believe their role will be challenged going forward (especially if you are not IP-protected as presented above). Why is this so? Smaller actors will always be disadvantaged by lack of scale, whilst larger co-manufacturers have a unique position to affect purchasing prices and reinforce their scale advantage. Moreover, when outsourcing continues to grow, regulatory investment requirements will likely increase, leading to sub-optimal use of existing capital. It is also riskier to make

necessary investments in physical infrastructure to improve scale, and returns on digital investments are lower. Add to this the inherent customer concentration risk of smaller co-manufacturers and the challenges ahead are clear to see.

Having said that, many of these companies have amazing people and capabilities, with a strong entrepreneurial mindset, flexibility and niche offering that is much harder – if not impossible - for larger companies to attain. Therefore, we believe a new winning model will grow out of this segment in the coming years, and that it will combine the benefits of being a large co-manufacturer (and thus eliminating the small company risks above) with the entrepreneurial power of a smaller co-manufacturer.

HOW CAN THIS BE ACHIEVED?

A strategy we believe will succeed in the future European CDMO market will combine several of these smaller comanufacturers with unique capabilities to a synergetic complementing team, maintaining their deep expertise and entrepreneurial flexibility, whilst also exploiting scale advantages.

Moreover, commitment to high regulatory standards and quality controls, along with investments in digital infrastructure to simplify collaborations and interactions between the entrepreneurs, are all essential to enable this model to reach its full potential. The group that can find this deep expertise and flexibility, and bring it together in a scalable and collaborative way, will have a formula for success at the front of the European comanufacturing market.

We certainly think this is a winning model of the future, and those that succeed will be difficult to compete with.

Author: Christian Merup, CEO of Wellma.

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CLINICAL TRIALS

As evidenced by the COVID-19 pandemic, it is essential to bring new life-saving vaccines and antivirals to the market quickly. To support pharma and biotech companies in developing drugs and vaccines for serious diseases and unmet medical needs, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have set up different expedited review programs.

Human Challenge Trials (HCT) or Controlled Human Infection Models (CHIM) are trials in which healthy volunteers are administered a pathogenic or virulent strain of a challenge agent - which can be a virus, bacteria, or parasite - together with a vaccine or antiviral.

In current drug development, Human Challenge Trials can be used in a variety of ways, like dose-finding studies, in preparation for field trials, but the most common use is that HCTs are used as phase 2 proof-of-concept (PoC) trials.

These Human Challenge proof-of-concept trials are designed to provide early evidence about efficacy and determine if a drug is likely to be successful in later clinical trial phases. Hence, PoC studies can guide drug developers to make smarter “go or no-go” decisions about whether to proceed with larger, more expensive studies in the next stage of drug development. The results of PoC studies are pivotal for strategic decisions in early drug clinical trial development.

The main advantage of Human Challenge Trials compared to ‘classic’ field trials is two-fold. On one side, they require fewer subjects

compared to field studies (approx. 40-60 vs 120-240) and they can be completed in a shorter timeframe (approx. 3-4 months vs 12-16 months) compared to field trials. Challenge trials for respiratory diseases are also not seasonally dependent, therefore giving an additional advantage that they can be performed any time of the year. This also allows obtaining proof of concept data in years with a ‘low circulation’ season.

Expedited review programs in the US

The FDA has several programs to support the expedited development of new drugs and vaccines for the treatment and prevention of a potentially life-threatening condition and unmet medical needs.

Fast Track Designation

Fast Track was introduced in 1992 by the FDA to support the development of drugs for serious conditions. To be eligible for Fast Track designation, the drug should be developed to treat a serious condition or must demonstrate the potential to address unmet medical needs.

To be successful with a request for Fast Track designation in a condition where there are already available therapies, the new treatment should fulfil at least one of the following criteria:

• Show superior efficacy or improvement compared to the existing therapy

• Improved safety profile compared to existing therapy

• Provide an alternative to patients that are not eligible for the existing therapy

• Improve patient compliance, in such a way it is expected to lead to a better outcome

• Address an emerging or anticipated public health need

Fast Track designation can be obtained based on non-clinical efficacy data and can be submitted at the time of IND submission or later, but ideally as early as data are available that indicate the drug’s potential to address an unmet medical need.

Obtaining a Fast Track designation offers multiple advantages to pharma companies:

• More frequent meetings and interactions with FDA to discuss the drug’s development plan

• Eligibility for Rolling Review (if relevant criteria are met)

• Eligibility for Accelerated Approval and Priority Review (if relevant criteria are met)

Breakthrough designation

Breakthrough Therapy designation was introduced under the FDA Safety and Innovation Act in 2012.

To be eligible for a Breakthrough Therapy designation, the drug should be intended to treat a serious condition. Preliminary clinical evidence should demonstrate the new drug showing a substantial and clinically meaningful effect on an important outcome over a placebo (or a well-documented historical control where applicable).

When there is already a therapy available, the clinical evidence

should indicate that the drug may demonstrate a substantial improvement on a clinically significant endpoint(s) over available therapies.

Breakthrough Therapy products are entitled to the below advantages:

All Fast Track designation program features:

• Intensive guidance on an efficient drug development program, beginning as early as Phase 1

• Organisational commitment involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review

• Eligibility for Rolling Review and Priority Review if relevant criteria are met

UTILISING HUMAN CHALLENGE TRIALS

AS A TOOL IN EXPEDITED REVIEW PROGRAMS FOR INFECTIOUS DISEASES

Expedited review programs in Europe

In 2016, PRIME (PRIority Medicines) was launched by the EMA, with the objective to strengthen support for medicines that target an unmet medical need.

The scheme focuses on medicines that may offer a major therapeutic advantage over existing treatments, or benefit patients with no treatment options.

The PRIME scheme offers the below advantages:

• Appointed rapporteur from the Committee for Medicinal Products for Human Use (CHMP) / Committee for Advanced Therapies (CAT)

• Organise a kick-off meeting with the rapporteur and a multidisciplinary group of experts, so that they provide guidance on the overall development plan and regulatory strategy

• Assign a dedicated contact point

• Provide scientific advice at key development milestones, involving additional stakeholders such as health-technologyassessment bodies, to facilitate quicker access for patients to the new medicine

• Confirm potential for accelerated assessment

What is the added value of Human Challenge Trials?

In each of the expedited pathways listed above, the key element is the availability of early clinical efficacy data.

HCTs are an ideal tool to collect these data on infectious diseases. They allow the collection of efficacy data to support the evidence that the medicine shows promise in serious conditions and, where applicable, show superiority over existing treatments.

The efficacy data is collected in a well-defined model, without the ‘noise’ of a field trial. This allows the collection of ‘crisp’ data while being able to focus on the required clinical outcomes.

A number of RSV vaccines currently under development, including the J&J, Pfizer and Bavarian Nordic vaccines, received breakthrough and/or PRIME designation based on preliminary clinical evidence collected in a Human Challenge Trial.

An additional advantage is that the data is collected quicker than if they would have been collected in a field trial, allowing drug developers and regulators to make faster decisions on candidates and progress those that have a greater chance of improving public health.

Conclusion

A designation in an expedited review program gives a strong advantage in your development pathway. For infectious disease medicines, a Human Challenge Trial can provide the needed early efficacy data which grants the required designation, both in the United States and Europe.

BRUNO SPEDER, VP of regulatory affairs & consultancy services, hVIVO, discusses how Human Challenge Trials can be used in the framework of expedited review programs as part of drug and vaccine development.

Kimberly Remillard, RAC, senior regulatory affairs manager at Thermo Fisher Scientific, examines how leveraging the power of Pharma 4.0 can ensure data integrity within biopharma.

PHARMA 4.0: BUILDING AN AGILE CONTINUOUS MANUFACTURING SYSTEM

Q. What is Pharma 4.0 and how can digital maturity and data integrity drive it?

A. The term Pharma 4.0 is a pharma industry-focused interpretation of Industry 4.0 –focused on adopting innovative methods to deliver higher quality treatments to patients. There is an intrinsic link between Pharma 4.0 and data integrity –and therefore the systems and technologies which organisations can use to drive these strategies. The Pharma 4.0 concept builds on Quality by Design and process analytical technology. Instead of waiting to check the product only at the end of the manufacturing process, Pharma 4.0 moves to real-time monitoring, using connected systems to enable a truly agile continuous manufacturing system where processes selfadjust based on the data being collected.

Since data is at the heart of this system, it’s important to apply the latest data analysis

techniques such as artificial intelligence (AI), machine learning (ML) and deep learning (DL) to enable simulations through which the system can learn and optimise product quality. Finally, Pharma 4.0 looks to automate and eliminate any human or manual intervention by leveraging software to make decisions based on information collected from the connected systems, and where possible automatically drive any actions, such as changes to the manufacturing process. This complete system creates a far more intelligent scenario, where pharma products are manufactured in a process which is constantly learning and proposing solutions to any issues that arise to enable optimum product quality.

Q. What challenges does pharma manufacturing face today and how would Pharma 4.0 combat these?

A. Now more than ever, there is an increased sense of urgency to deliver high-quality drug products in as short a timeframe as possible. More tests are required but with the same number of analysts. This drives a real need to decrease the level of manual intervention that scientists are required to make throughout all processes, and to move toward modular manufacturing where continuous adjustments and improvements can be made based on in-line sensors and process monitoring. Ever-increasing compliance and validation requirements across various global markets lead to more processes and documentation to provide evidence of the who, what, where and when of each action.

Currently, pharma and biopharma organisations use a plethora of systems to manage their labs, production environments, and their data. Enterprise connectivity is essential to bring together all the pieces of relevant data and information that could be helpful in successfully and safely bringing a drug product to market. The

production and lab systems both hold critical data which are far more valuable as a complete piece – providing all the relevant people in the organisation with access to that data ensures they can make fast, informed decisions.

Where innovative technologies are adopted, they require new methods and increased regulatory checks – there is a need to ensure manufacturing organisations remain agile and can adopt new capabilities to optimise manufacturing and deliver high-quality products. By adopting Pharma 4.0, organisations can not only connect their data to provide them with holistic information, but they are also able to quickly act upon that to make essential improvements to production.

Q. What state is data compliance and integrity at today - and what else is needed to ensure overall integrity?

A. The digitalisation of data is an ongoing transition for many organisations. As systems become more automated and digitalised, the data is often in repositories which are not centralised and created using systems which are not able to speak to one another. This often results in a dependency on a strong culture of quality, as well as manual processes and SOPs to ensure compliance and integrity. With separated systems and manual processes, the challenge to meet the data integrity levels expected with ALCOA+ relies heavily on human elements to monitor data across systems, ensure procedures and processes are followed, and identify and correct issues in a timely and effective way. This is inefficient and leaves room for errors. The more organisations that can centralise their data, the better they can enable control over the integrity of data throughout the data lifecycle.

In place of the data lifecycle being scattered across various platforms, systems, and sites, a centralised data system allows the users to view data as a whole and identify trends and inefficiencies, whilst correcting issues in a more effective way. Security of these systems is critical to maintaining data integrity so ensuring the systems being used are designed, managed, and qualified properly is an essential step to safeguard the overall integrity of the associated data.

Q. What is still to be done for businesses to reach Industry/ Pharma 4.0?

A. Considering the resources required to achieve Pharma 4.0, we are looking at a culture of digitalisation to enable such an intelligent system. The workforce too must be ready to accept this way of working, with an openness to change. Organisations

need to have qualified experts ready to drive science forward. The tools, devices, and IT systems need to be on an open platform to connect the necessary instruments and equipment, with common data standards and likely cloud-based to enable data sharing. The information systems are the basis of integration and traceability as well as automation, eliminating unnecessary manual or human intervention and reducing regulatory oversight. A culture of strong communication, with a leadership keen to drive positive experiences through technology, is also key. Above all, data integrity is the common theme throughout Pharma 4.0, so organisations need to look at how this can be driven using the technologies and processes available.

Q. How will Industry 4.0 impact the maturity of quality management systems?

A. As Pharma 4.0 continues to mature we expect to see this digitalisation harmonisation expand to allow pharma and biopharma organisations to manage control of their processes and materials throughout the whole supply chain. When organisations automate and integrate processes, workflows, and data collection, they allow for the ability to reduce errors and improve data integrity.

In addition to improving the quality and efficiency within pharma and biopharma organisations, one of the objectives of moving towards Pharma 4.0 is to help make compliance an automated and integrated part of the quality system. By moving toward this approach of enterprise connectivity, organisations enable a higher level of efficiency and control of the data.

By using a centralised and secure system that follows the FAIR principles (Findable, Accessible, Interoperable, Reusable), data can be evaluated and monitored in real-time. This can be especially beneficial to the quality management system processes as it provides the opportunity to monitor process effectiveness and efficiency for quality data-driven decisions. Early awareness provides the opportunity for more valuable root cause analysis of potential issues and inefficiencies, which can result in improved processes and workflows. Improving the capabilities to automate systems and reduce manual operations to build compliance into the process can improve efficiency, reduce time and effort, and allow for a more effective quality system.

IMPROVED FILL-AND-FINISH PROCESSES REDUCE THE TOTAL COST OF OWNERSHIP

Pharmaceutical companies are continuously assessing the productiveness of their filling lines to achieve higher yields with less resources, thereby ensuring high quality standards and maintaining flexibility in the fill-and-finish process. Lower cost, better quality and higher flexibility might appear to be contradictory goals.

This article focuses on possible fill-and-finish solutions based on an increased usage of pre-washed and pre-sterilised drug containers compared with traditional filling concepts that work with purchasing non-sterile, so-called ‘bulk’ containers from primary packaging suppliers.

The challenges facing pharmaceutical companies today require a fundamental rethinking of manufacturing processes. Pharma companies are increasingly outsourcing value chain steps to simplify their manufacturing processes and streamline their production footprint by forming mutually beneficial strategic partnerships with CDMOs. Multi-sourcing is becoming the new normal for key products, not only to reduce the risk of supply-chain interruptions, but also because collaboration spreads the costs and risks of developing and producing new treatments.

There are three main challenges affecting drug manufacturing and filling operations. First, reducing value chain complexity by outsourcing production steps allows pharma companies to focus on their core business. Second, detecting and eliminating areas of risk along the value chain ensures patient safety. And third, speeding up time to market maximises patent lifetimes.

When deciding on a filling strategy, all costs must be factored in and carefully

balanced against each other. Profitability is best assessed by looking at the total costs of ownership, including all incurring and recurring costs, across the whole project lifetime. Deciding on a fill-andfinish concept that needs to be economical for several yearsor even decades - is becoming more challenging with new container options entering the market and the increased need for flexibility.

For fill-and-finish operations in the pharmaceutical industry, the total costs of ownership (TCO) can be calculated for RTU containers in different scenarios to help pharmaceutical companies choose the right packaging configuration for their business case. Taking into account capital expenditure and operational costs, the TCO must also incorporate a number of other important factors, such as the geographical location of the factory, the duration of the project, the types of different containers to be filled, the equipment to be used, the shift pattern and whether it will be small batch or campaign production.

There are several ways in which RTU packaging can reduce TCO, including more flexible operation, faster time to market and lower costs of non-quality (CONQ). As a supplier of pharmaceutical

drug containment and delivery solutions, SCHOTT Pharma’s extensive industry knowhow can help pharma manufacturers get a clear picture of which machine and container combination enables a feasible operation throughout the project lifetime, and thereby reach a sound business decision.

In the value stream for bulk pharmaceutical containers, glass containers are produced and transported to the pharmaceutical manufacturing facility, where they are fed into the filling line, washed, dried and depyrogenated, to provide a safe and sterile container for the fill-and-finish process. This translates into a significantly higher initial capital investment when installing the filling lines and a greater cleanroom footprint requirement.

With RTU systems, the value stream is forward integrated. The glass containers are washed, dried and depyrogenated, before being nested and sterilised and supplied to the pharma facility ready to feed directly into the fill-and-finish operation. Besides the smaller area of cleanroom space required, there is no need for a washing station, a depyrogenation oven, a range of filling and capping machinery, transport belts or format parts.

A key feature, e.g. as builtinto the SCHOTT iQ platform, is the compatibility of different RTU container types with a wide range of new and existing filling equipment. The different container formats can be filled on a single line, minimising capital investment, reducing complexity and greatly increasing flexibility. The ability to switch easily between different vial formats and types is especially relevant for sequential small batch production, while for large scale production it allows the manufacturer to choose the optimum combination of vial, secondary packaging and filling line to suit the product and processes.

But capital expenditure savings are only part of the story. Although filling traditional containers is associated with lower expenses for primary packaging, RTU filling offers advantages when it comes to recurring operational expenses. Using an RTU system means there are no direct costs for washing and sterilisation, greatly reducing the inputs, such as the energy required for depyrogenation and the need for a WFI loop. The higher degree of automation of RTU fillings lines also requires fewer personnel, thus also reducing labour costs.

IMPROVED FILL-AND-FINISH PROCESSES ENSURE PATIENT SAFETY

The cost of non-quality is another factor that needs to be considered. Switching to an RTU system reduces the amount of glass-to-glass contact to which the containers are subjected during fill-andfinish operations. In traditional filling operations using bulk containers, vial transport in the depyrogenation tunnel or on turning plates causes the containers to bump into and rub up against each other, resulting in a deterioration in the cosmetic quality of the glass.

As RTU vials are nested in a tub, they can be processed without glass-to-glass contact, without any deterioration in their cosmetic quality. This not only minimises rejects arising from cosmetic defects but also significantly reduces the generation of particles and cuts the risk of breakages on the filling line.

IMPROVED FILL-AND-FINISH PROCESSES REDUCE TIME TO MARKET

Switching from bulk to RTU containers can also significantly speed up the time to market for new products thanks to the reduction in qualification and validation resources required. Traditional bulk container operations use bespoke packaging, which multiplies the qualification steps. But a standardised RTU platform, such as adaptiQ vials from SCHOTT Pharma, unifies the transfer steps to get the

containers into the aseptic core (debagging, decontamination, delidding) and these need to be qualified only once. This allows the qualification effort to be refocused around the aseptic filling and closure steps. And with the adaptiQ documentation built into the DMF, less paperwork is needed for the FDA.

SCHOTT Pharma uses trusted partners to carry out efficient and highly standardised sterilisation procedures to the industry standard of EtO sterilisation. Sterilisation cycles are optimised to have minimal environmental impact, and residuals in the final RTU container are below detection limit and thus significantly lower than industry-wide accepted ISO standards.

As new drugs are commercialised, adopting RTU packaging based on fewer process steps requiring development and validation can contribute to easier scale-up and scaleout. Internationalisation of production can also be accelerated as tech transfer is made easier and expansion of the manufacturing footprint is more flexible. In cases where manufacturing is taking place in parallel across a number of facilities to supply local markets, installation of new filling lines can be accelerated, reducing the time to market.

Rather than custom designing a filling line around a specific drug prior to its launch, the pharma manufacturing company can install flexible filling capacity

that can process different vial formats on the same line, allowing batch size variations to meet the changing market demand or manage a multiproduct portfolio.

This strategy can also simplify and derisk the supply chain by reducing reliance on a single large production line at one central location, while also facilitating partnerships with CMOs and CDMOs.

The SCHOTT iQ platform is available across the globe and can be used with more than 50 machine types from a broad range of global machine vendors. The online shop and stocks of Fast Track Kits for quick shipping can offer immediate supplies of

small quantities direct to the customer’s door, enabling pharma companies to focus on developing best-in-class drugs and worry less about packaging components.

The key to leveraging the advantages of RTU packaging is standardisation. The customer receives high-quality, washed and sterilised containers in an industry-standard 3-inch tub, allowing them to reduce the complexity of the fill-and-finish operation and ensure that each filling line functions at optimum overall equipment effectiveness (OEE) by maximising uptime and minimising changeover times.

The adaptiQ RTU vial platform from SCHOTT Pharma enables flexibility while simplifying and speeding up processes, and thus saving costs. Implementation, validation, and ramp-up of new filling lines can be carried out in shorter time scales while enhancing the quality of the containers. When choosing the primary packaging and the corresponding fill-and-finish concept, medical safety and economic viability must be considered in parallel, and the benefits arising from wellthought decisions cannot be overstated.

MATTHEW LOWRIE, QUALITY ASSURANCE MANAGER, ALMAC CLINICAL TECHNOLOGIES, EXPLORES HOW THE EVOLVING REGULATORY GUIDANCE AROUND DATA INTEGRITY IS IMPACTING CLINICAL TRIAL APPLICATIONS AND DATA.

EU Regulation 536/2014 came into effect for new trials in January 2023, impacting supply management practices for clinical trials conducted in the EU, replacing Directive 2001/20/EC. With an aim to simplify trials and enforce consistent rules throughout Europe, these changes have a definitive impact on clinical trial planning activities.

The regulation enhances patient protections and adds increased requirements for trial oversight and data integrity. Some examples are heightened GMP standards for investigational medicines, stricter oversight of auxiliary medicines, and consistent expectations for safety reporting.

There are significant changes that require attention and consideration in how you are using, and will use, established systems for supply chain management, which is the focus of this article.

A key change raising much concern is the restrictive labelling requirements inclusive of investigational and auxiliary medicinal products, laid out in Annex 6 of the regulation. One being the expectation that the expiry date must be printed on all primary and secondary container labels. The revision allows the expiry

date to be omitted from the immediate container only when the immediate container will remain with the outer container, or when the immediate container is small and has limited space for label text. In both cases, the immediate container must be provided with an outer container that has the expiry date printed on the label.

Annex VI also allows for the information on the label to be managed through alternative means, such as a central IXRS system, however some particulars cannot be omitted from labels. It never allows for the expiry date to be omitted from the outer container label. Allowances to exclude the expiry date from the immediate container label of IMP or Auxiliary MP are aligned with the specific circumstances detailed above.

This revision will make management of expiry updates significantly easier – whenever the immediate container is packaged and supplied with a labelled outer container, it will likely be possible for the sponsor to justify the omission of the expiry date from

the immediate container. However, this has the potential to make expiry updates more complex because if there is outer packaging, it will need to be opened to expiry update the label on the immediate packaging.

Another requirement details that tracing, storage, return, accountability and destruction arrangements must be in place and detailed in the clinical trial application. Destructions and returns haven’t historically been an area of focus during the trial set-up phase but will now be required to be established and described upfront. What this means is you need a system or process that can address these arrangements while also maintaining the integrity and chain of custody. Your eClinical systems can be utilised to link and manage electronically these actions, often with greater accuracy and efficiency than performing the tasks manually on paper.

It is very common that IXRS includes features that facilitate and automate the accountability, reconciliation, returns and destruction processes. The benefit of including this functionality in the IRT is that the data already known about the medicinal products can be used to fuel these subsequent steps of the process. This streamlines the process, reducing data entry activities, helping to avoid mistakes, and reducing overall efforts. The technology also provides reporting and alert mechanisms to ensure the trial is on track, avoiding any end-ofstudy push to catch up on tasks and data reconciliation that should be done throughout.

Another important aspect, which should not be minimised, is the overall traceability of

Labeling (Annex VI) GMP Requirements Trail Conduct CT Application Process

• Specific requirements for all EU Coutries

• Expiry date must be printed on all primary containers

• Auxiliary Medicinal product laneling requirements

• Specific GMP Regulation and new Detailed Guidelines for IMP (replaces Annex 13)

• Emphasis on GMP of IMP

• Return / accountability and destruction arrangements- at start

• Stricter control of Auxiliary Medicies (formerly NIMPs)

the supply. IXRS is commonly managing the trial supply activities electronically: drug release, supply transfers and shipments, patient assignments, accountability and returns/ destruction, amongst others. Being able to track activities, but just as critical as the view of the data. Data must be presented in a way that allows easy review at both summary and detailed levels providing endto-end traceability. This enables oversight of the data, providing assurances to the viewer that processes are occurring as expected. This is key to the prevention of large reconciliation efforts at the end of the trial and questions around why the data is being updated sometimes years after its initial entry. An electronic chain of custody solution that incorporates all IP events in a single system is the best way to comply thoroughly with GCPs and GMPs and to gain maximum efficiencies in the accountability process.

In line with these regulations, data integrity guidance from MHRA, FDA and EMA is evolving

• Emphasis on safety reporting and building

• Incorporation of GDPR into CT Regulation

• 25 year retentionn of Trial Matser File

Single application and single approval

• Substantial modification process

around sponsors’ responsibilities with respect to trial data oversight. As stated in ICH E6(R2), inspectors expect to see documented evidence on how the sponsor performed oversight of the study data.  We are seeing a rise in the number of findings where there was a lack of real-time data monitoring and/or data monitoring was not done in a contemporaneous manner to show continuous oversight of the trial.  Inspectors are expecting to see established data monitoring processes. Planning the study’s approach to proactive data reviews and knowing what tools are available from your technology partners and how they will be used is key.

In summary, with EU Regulation 536/2014 now in force, modifications to practices around supply chain management are a necessity for clinical trials running in the EU. With upfront planning, leveraging eClinical solutions such as Almac’s IXRS, challenges can be overcome. A comprehensive end-to-end approach to clinical supply chain planning will ensure clinical trial integrity ensuring regulatory compliance.

An electronic chain of custody solution that incorporates all IP events in a single system is the best way to comply thoroughly with GCPs and GMPs.

ANSWERING PHARMA’S CALL FOR SMARTER SOLUTIONS TO ASEPTIC MANUFACTURING CHALLENGES WITH READY-TO-USE VIALS

Innovation and continuous improvement have always been cornerstones of the pharmaceutical industry. Supply chain partners who are invested in the research and delivery of innovative solutions, those that never stand still and are committed to support the success of their customers, tend to witness long term, sustainable growth.

Right now, much innovation comes in the form of smarter solutions for aseptic manufacturing. The evolution in regulatory

requirements is always constant in our sector, with increased regulation creating ever greater demands in quality; specifically in terms of protecting the integrity of medication and reducing contamination via particulates.

The market growth in more complex, and therefore more expensive, biologics and biosimilars is placing a real focus on high performance primary packaging and process performance to mitigate against waste. There is also an emphasis

on enabling small batch production with rapid changeover to support low volume and personalised medicines. Indeed, according to recent market intelligence data, the growth in premium Ready-to-Use (RTU) vials is significant, with a Compound Annual Growth rate (CAGR) of 14.5% in the period 2021–20301.

Alongside the trends in quality, come requirements in terms of reduced time to market, reduced complexity of operations and rationalised space

and resources available for pharma companies and CMOs to achieve lower total costs of ownership. This is manifested in several ways, but most notably the push is on investment optimisation, flexible cost configurations, scalable processes and a refocus on core pipeline activities.

As usual, the supply chain has responded; developing technologies in Ready-toUse (RTU) vials that deliver increased quality, reduced complexity, and higher levels of sustainability in equal

measure.

Despite RTU vials meeting all the requirements mentioned above, it can still be argued that there are some hurdles in their adoption, mainly related to costs. But when looking into detail, the advantages of adopting this option become crystal clear.

When it comes to the impact on customer’s TCO, there are de-facto real savings to be realised in every aspect of the aseptic manufacturing process. RTU components enable total cost savings of up to 45% versus the conventional packaging containers2 over a period of 8-10 years.

One such example is EZ-fill: a fully integrated pre-sterilised containment solution from Stevanato Group. An easy, flexible and streamlined production process means pharmaceutical and biotech companies can immediately fill their pre-sterilised vials containment solution, consistently shortening their time-to-market. But there is more to this, leveraging this technology, Stevanato Group recently developed EZ-fill Smart: a further enhanced version of its pre-sterilised platform, focusing initially on vials.

EZ-fill Smart grants the same top-notch features as EZ-fill in terms of flexibility and streamlined pharma operations whilst providing extra benefits. The platform commits to improving pharmaceutical manufacturing quality standards while reducing the Total Cost of Ownership (TCO) by mitigating the cost of upstream operations such as utilities and equipment as well as reducing the costs and issues associated with lower quality solutions. These

gamechanger savings can be realised, thanks largely to improvements in product quality, and by process optimisation.

Because the platform features no-glass-to-glass and no-glass-to-metal end to end, the integrity of pre-sterilised containers can be maximised throughout the manufacturing process, while reducing costly rejects and breakages which have serious impacts on productivity. In addition, the Tyvek lid has been replaced by a transparent polymer film featuring a reduction of >90%3 in particles by comparison to older technologies. Moreover, it can grant a clean peeling without residuals of adhesive due to a different sealing material than Tyvek.

Improving operational efficiency via high levels of automation is another key feature of the platform. As well as increasing productivity, a reduction in production risks and human error can be realised. From a sustainability perspective, the sterilisation method integrates a safer and more environmentally friendly

method in the process, with the use of biopolymers, re-usable materials and weight reduction also leading to improved sustainability standards.

Critically, the EZ-fill Smart platform was developed in close collaboration with major machine vendors, testing the processability, and can be seamlessly configured with current fill and finish processes and production

lines.

It is often said that there must always be a compromise in the cost, time, quality triangle. In an industry with innovation at its core and safety/efficacy guiding principles, there can be little room for compromise. The EZ-fill Smart pre-sterilised platform has been realised through innovation but is deeply rooted in quality and efficiency.

1. https://www.psmarketresearch.com/market-analysis/rtf-rtu-vialsmarket-trends.

2. 2018 Roots Analysis Research Report.

3. Reduction verified by external certified laboratory.

One of the most exciting and revolutionary trends driving biopharmaceutical growth and innovation is cell and gene therapy. It is exciting not only because of the growth of successful trials and approved therapies, but also for the technology’s ability to impact patients’ lives.

Initially, these therapies targeted diseases with small defined patient populations, including paediatric diseases with very limited treatment options. Many of the first patients treated for acute lymphoblastic leukaemia are thriving, four to six years later. Recently (November 2022, FDA-2021-D-0776), the FDA issued a guidance document entitled: “Studying Multiple Versions of a Cellular or Gene Therapy Product in an EarlyPhase Clinical Trial”; this is indicative of significant industry developments. We are seeing leading research institutions, biotech and major biopharma companies moving onto larger populations — starting with leukaemia, lymphomas, multiple myeloma and autoimmune and inflammatory diseases.

CRITICAL CHALLENGE: SCALING-UP MANUFACTURING

We are currently setting a new, historic pace at which new therapies are being taken from research to fullscale manufacturing. Therein lies a major challenge: To take advantage of these opportunities to advance these therapies requires that

Author: DR. NANDU DEORKAR, senior vice president, research & development at Avantor.

Opinion

SOLVING SCALE-UP AND MANUFACTURING CHALLENGES IN CELL AND GENE THERAPIES

we address the challenges in manufacturing processes that remain.

The industry needs to continue to find efficiencies and optimise manufacturing to deploy cell and gene therapies economically and at a scale that can make a difference for patients globally. Across the

board, we need to implement improvements in raw material inputs and drive innovations in manufacturing technology to deploy gene therapies economically and at scale.

For example, adherent cell culture systems are inefficient. Given the magnitude of the therapy being delivered

to the patient, it is clear the industry does not have the ability to produce enough to satisfy growing demand.

Either something must change with the process itself or massive manufacturing capacity will need to be built to sustain current production methods, which will make it difficult to make these therapies more affordable for wider patient populations.

IMPORTANCE OF PROCESS STANDARDISATION

Equally important is the need for process standardisation to improve scalability. Variables and failure modes must be taken out of the process — this is where innovations in process technology can make a real difference.

Production systems can be standardised and closed so they are less exposed to failure modes. Processes can be minimised to drive cost efficiencies and, perhaps, better clinical outcomes.

We can employ better workflow technologies, such as single-use sterile fluid transfer. It is also probable that fill/finish requirements will be different for cell and viral products, so improved excipient technologies will play a large part in better patient experience and response.

WHAT ARE SOME APPROACHES THE INDUSTRY CAN PURSUE TO ADVANCE OPTIMISATION?

There are two major pathways to process optimisation: First, we must anticipate innovation and optimisation coming from advances in academia. Second, we expect step changes in process improvements from contract development and manufacturing organisations (CDMOs) and other producers. This can be done with close monitoring and, where relevant, partnering with these organisations early on.

Developing partnerships with providers as soon as possible should increase process efficiency and minimise later missteps, even on joint approaches to regulators. In raw materials, specifically,

manufacturers are receiving more requests for cGMP grades of materials that have never needed to be made at scale or to cGMP specifications before. Even if these are available at the correct analytical grade, there is considerable raw material expense associated with components such as plasmid DNA. The requirement for biological activity to be retained limits the use of harsh purification methods and adds a special sensitivity, so that potentially harmful or adventitious agents cannot be introduced through the raw material supply chain.

This is an area that greatly benefits from close partnerships between manufacturers and their raw material suppliers, to better understand the requirements for cGMP materials and use them early in the therapy development and manufacturing process. Additionally, partnering helps with tracking and measuring a raw material supplier’s quality system, to ensure consistency over time. The importance of collaborations and quality agreements with raw materials suppliers cannot be understated.

NEW SOLUTIONS TO IMPROVE MANUFACTURABILITY

In areas such as cell culture components, production chemicals, single-use technologies, sterile fluid transfer, excipients and the technology surrounding those process components, there is value in trying new solutions to address improving the manufacturability of cell and gene therapies.

Even at the early stages of trials, we can better understand the variability that comes from research data and use it

to correlate with clinical and process outcomes. Taking out manual steps as early as possible is important, as well as creating closed systems using sterile fluid transfer technologies to eliminate process risk.

Hopefully, one outcome of these efforts will be to find scalable ways to address costs for cell and gene therapies, which are still exorbitant. Ultimately, these drugs must be developed in a more cost-effective manner. That is an area where technology providers and suppliers can play a significant role by closing and automating systems and by understanding the contribution of labour, overhead and possible economies of scale from reducing processes.

With the amount of strong research into developing, understanding and characterising drug targets, and figuring out how to make these in production-level volumes, this will be a constantly changing landscape. And there will be many parts to patient treatment options going forward.

Cell and gene therapy has the potential to change patient outcomes for the better as treatments and therapies evolve, adding one more healing tool to monoclonals and biologics. As with other treatments that moved from theoretical possibilities to real results, the industry is developing a clearer and more complete understanding of the issues that need to be addressed to drive better patient outcomes. Through collaborative partnerships among researchers, manufacturers and suppliers, the industry as a whole has the opportunity to move science forward.

Throughout the drug authorisation process and right across the marketing authorisation lifecycle, licence holders are responsible for ensuring the continuous monitoring of the safety profile of a medicinal product. This includes accountability for all third parties and contractors with a potential impact on that safety profile. Relevant suppliers could include anyone from local distributors or qualified persons to IT system partners, security providers and even auditors themselves.

Disruption and turbulence in the global life sciences market are adding to that complexity, with changes to the line-up of suppliers and service providers, all of which affect the vendor records and controls that companies must maintain to ensure end-to-end quality. Where control slips, there is a real risk of problems and if these are exposed during inspections, this could lead to fines or even product withdrawal from affected markets.

So how can marketing license holders take back control?

IDENTIFY THE IMPACT THAT THIRD PARTIES HAVE ON THE CURRENT SAFETY SYSTEM

It’s important to start by identifying ALL suppliers with a potential bearing on a product’s safety profile, however tenuous. Once a definitive list has been compiled, each supplier can be reviewed for potential risk/ safety impact and appropriate due diligence.

Each third party can then be assessed for potential safety profile impact, the current supply/contract status and any monitoring, and required next steps.

THIRD-PARTY VARIABLES:

MAINTAINING A ROBUST SAFETY PROFILE THROUGH TIGHTER SUPPLIER CONTROLS

how much impact that vendor will have on the safety profile based on the services it is going to provide.

Once the new partner has been classified, the associated risk level must be assessed through a process of due diligence. The objective here is to gather and review all relevant information to facilitate an informed, riskbased decision as to whether your organisation should enter into a contractual relationship. Performing an audit or riskbased questionnaire on all critical and significant third parties is the suggested best practice.

EXTEND THE SAME VIGILANCE THROUGHOUT THE LIFECYCLE OF THE AGREEMENT

Arriello’s director of auditing and quality assurance, Helen Lowe, considers how drug companies can ensure quality without boundaries and build new confidence in their end-to-end safety profile.

CONSIDER THE AUTHORITIES’ PERSPECTIVE & HOW IT’S EVOLVING

As the life sciences ecosystem continues to change in shape and makeup, and as globalisation is counterbalanced by supplier consolidation and supply chain restructuring, regulators are expected to issue firmer guidance on vendor management controls sooner rather than later.

In the meantime, robust vendor management is an expectation under EU GxP requirements. So if drug developers or license holders fall short, they could risk their reputations as well as significant fines and ultimately

product withdrawals.

IDENTIFY & ADOPT BEST PRACTICE

A robust vendor management system (VMS) is every bit as important as a robust quality management system (QMS). Ultimately, it should form an integral part of the QMS, and awareness, training and buy-in to vendor management practices should be formalised with appropriate communication and training.

PERFORM INITIAL DUE DILIGENCE

When considering new third parties, it’s important that the R&D, MAH, CRO or service provider organisation assesses

From a post-marketing perspective, under GVP Module IV.B.1. (Pharmacovigilance audit and its objective), there must be ongoing due diligence and assessment, alongside an audit program based on risk. This should reflect evolving factors such as changes to legislation and guidance, or a major restructuring of the PV system (e.g. following an acquisition).

All license holders should have all responsibilities clearly documented in an appropriate agreement, to avoid misunderstandings around relative responsibilities. Across the lifetime of the contract, it will be important to review any contractual changes made. Regular testing of the contact details to ensure they are still valid and correct offers one simple way to uncover changes that may not have been identified otherwise through a routine process.

NAVIGATING

EPM editor, Rebekah Jordan, sat down with Dr. Gen Li, president and co-founder of Phesi, to learn more about how the company’s AI-driven clinical database is allowing insights and observations to be drawn from big clinical trial data. T H E D A T A O C E A N

Q. Could you tell us about the kind of work Phesi does?

A. Let me start by saying there is nothing more objective than data. The industry has many mechanisms to collect large amounts of data, but they have shown little value to us.

The way in which Phesi works is that we have huge mechanisms for collecting, structuring and interpreting data. Using different types of big data technology and artificial intelligence (AI), we have been able to assemble a huge database, from patients to clinical trials.

The history of Phesi over the past 15 years has always been about innovation. We are innovative and intuitive in the ways we collect, process, and interpret data.

We can identify the most important investigative sites around the world in a way that creates a much more detailed, quantifiable profile, through an evidence-supported process.

Q. How does the AI work to gather and analyse the data?

A. Our method of interpreting the data is patented and protected, but we can share that we gather the data with our AI mechanism.

The AI gathers data by using a formula that is much faster than human processing. It also has a kind of self-improving processjust like a human being - minimising the need for manual input and handling.

By interpreting the data and looking at the patterns, we started building algorithms. These algorithms are then fed into AI to interpret the data. The results feed back to the mechanism, encouraging a self-enhancing, self-improving process – achieving better and more accurate results each time.

Q. Breast cancer was highlighted as the most studied area of 2022, does Phesi research the reasons behind such data?

A. We found that breast cancer was the most studied area in 2022, even though in the same year, the entire clinical trial development activity was declining.

One of the factors at play here, not surprisingly, is that breast cancer is the most profound cancer type impacting women around the world, at almost all ages. It affects a large amount of the global population, which could explain why it came out on top.

The second is the complexity of the disease. Over time, our understanding of breast cancer has been improving and getting more sophisticated. Previously, we were treating breast cancer as though it was one disease. Now, we know there are many different subtypes and each of them becomes one of its own kind of disease. I think we have identified around 20 different diseases all under the umbrella of breast cancer.

Although we can treat some of these subtypes, other aggressive subtypes prove more difficult to treat, which is why we are intensely working on them to understand how they work and act, to develop

better treatments. I have no doubt we’ll achieve those things in the coming years.

Q. What reasons do you think are behind the increasing clinical trial attrition rate?

A. Oddly, it’s been anticipated. With physical restrictions preventing national and international travel, the interaction between physicians and patients became very limited. Even so, it became much more difficult to recruit patients for clinical trials.

A recently published article in Applied Clinical Trials showed that the number of sites only able to recruit a single patient for a particular trial is increasing.

Even in a normal situation, recruiting cancer patients is a difficult process – and 40% of the trials being conducted now are cancer trials. With the factors derived from Covid-19,

the Ukraine invasion, there were physical restrictions on certain populations that we could reach. As a result, the recruitment figures certainly declined – which affects the reliability of the data that is being gathered.

In terms of the causal analysis behind the high attrition rate, we know Covid-19 had an impact – we can see that from the timing of the increase. But what is more interesting is whether this impact is going to be temporary or have a lasting effect. At this point, we don’t have a clear answer yet.

Q. What effect could decentralised trials have on the current attrition rate?

A. The decentralised trials concept has been here before the pandemic, but what the pandemic forced us to do was to find solutions in a situation

they are here to stay. Even with Covid-19 behind us, the effects of applying these trials will make the resources for pharma companies more productive, and it may also encourage more patients to participate in clinical trials.

However, it would be naive to think decentralised trials are going to solve all our problems. There are certain situations, and certainly many diseases, where you simply cannot apply decentralised trials. For example, the patientdoctor relationship could be negatively impacted which affects the success of the trial. It’s a similar situation to working from home; although it opened new opportunities, it didn’t come without difficulties.

Additionally, the pharma industry is a conservative one. It is hesitant to adapt to anything new, no matter how

If we can get more people to understand the advantage and efficiency of decentralised trials and AI, and how they can be brought in to help handle big data, we will be able to see the application of these technologies grow within clinical development. AI can ensure that all aspects of a clinical trial are in sync, giving a higher level of assurance for success.

Q. What trends in clinical development do you expect to see this year?

A. I’m hoping we will see the level of clinical activity coming back to the way it was in previous years. As we find better ways to manage and handle certain diseases, the level of impact will continue to be minimised.

What we are going to see, and what we are already seeing since working with our clients, is that more people are understanding the value behind big data, and what data science can bring into this space. In turn, the industry can create smarter clinical trials, bringing faster cures to patients – I hope to see this trend continue.

Generally speaking, chronic challenges within the whole clinical development industry are going to continue. There’s no such thing as a perfectly designed clinical trial, we can categorically say. The difficulty of recruiting patients will take some time to resolve.

Finally, we are swimming in a mass amount of data and trying to understand what data is important to us. We aim to build a good structure which will make it easier to spot certain patterns and trends. With a better understanding, a more data-driven approach, and a collaborative effort, we can address challenges across the industry.

Pistoia publishes free guide to accelerate implementation of FAIR principles in clinical data

The Pistoia Alliance, a global, not-for-profit alliance that advocates for greater collaboration in life sciences R&D, launched its freely accessible FAIR4Clin guide. The guide will help clinical regulators, biopharmaceutical and healthcare organisations to implement the FAIR principles (Findable, Accessible, Interoperable, Reusable) in clinical datasets.

The diversity of data types, standards, and regulatory and privacy requirements, combined with the huge volume of clinical datasets, has presented a particular problem in life sciences R&D. The guide

Talking points

emphasises the value of FAIR to the clinical space, including making data machine-readable to support AI, innovating in clinical trial design, and enabling the transfer of data between sponsors, CROs, and regulatory agencies. FAIR4Clin was co-authored by the Pistoia Alliance and other experts in the field, including AstraZeneca, Bayer, Roche, Genentech, Galapagos, The Hyve, Elixir, The University of Manchester and Oxford University.

“We’ve had huge interest in the FAIR project since its launch, even more so after the Covid-19 pandemic reiterated the importance of being able to reuse and share clinical trial and healthcare data to accelerate drug development timelines. We are now calling on even more organisations to get involved in the next phase of the project, which will examine the business value of FAIR and develop further tangible resources, enabling best practices across industries, increasing more interoperability and effective collaborations,” commented Giovanni Nisato, PhD, project lead at the Pistoia Alliance.

Check out the latest news and insights in the world of medical devices at Med Tech Innovation: www.med-technews.com.

BACHEM PARTNERS WITH SIMPLYNANO PROJECT TO INSPIRE YOUNG PEOPLE WITH NANOTECHNOLOGY

Bachem, a Swiss pharmaceutical company, has partnered with the SimplyNano project, educational experiment kits published by the non-profit foundation SimplyScience. This project aims to get young people excited about science and technology with the help of nano experiments.

The project involves the “SimplyNano 2”, which is a comprehensive nano-experimental kit for schools. Published by the SimplyScience Foundation and developed by Innovationsgesellschaft (a St. Gallen-based start-up), these kits are available free of charge for some secondary schools in northwestern Switzerland. By 2025,

the SimplyNano 2 experiment kits should be available throughout Switzerland.

Nanotechnology deals with substances and materials of less than 100 nanometres, otherwise known as nanoscale. Nanotechnology often manipulates individual atoms and molecules to produce unique properties, making them suitable for a variety of applications.

Bachem focuses on promoting young talent, which is why they are allowing their headquarters training centre to be used by SimplyNano. This helps SimplyNano to achieve its goal of educating young people and inspiring future nanotechnology scientists.

The SimplyNano project is financed by the Basel-Land and Solothurn lottery funds; the Basel-Stadt Department of Education; and sponsorship from companies, associations, and foundations. The high level of support from the 39 project partners highlights the importance of promoting science and technology in schools and fostering young talent.

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