EPM May/June 23

FIBRE-BASED PACKAGING TO THE RESCUE? INDUSTRY 4.0 FOR CELL AND GENE THERAPIES

ENHANCING BIOTHERAPEUTIC PROPERTIES

May/June 2023

3D PRINTED PHARMACEUTICALS FINALLY LEVELLING UP

REGULARS

5.EDITOR’S DESK: Going the distance.

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

12. FRONT COVER: Could the 3D printing pharmaceutical revolution finally be upon us?

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

FEATURES

8: DIGITAL HEALTH: Applying Industry 4.0 digital solutions to improve access to cell and gene therapies.

10: PACKAGING & SUSTAINABILITY: GPI on fibre-based packaging and its potential impact on pharma

15: DRUG DELIVERY: Looking at Broughton’s new inhaled pharmaceuticals testing facilities.

16: BIOPROCESSING: Eight pages covering the latest developments and thought leadership from the likes of Revvity, BioRad and more.

24: INNOVATIONS IN MANUFACTURING: Purolite on improved access to pioneering purification materials.

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EDITORIAL

editor rebekah jordan rebekah.jordan@rapidnews.com

publisher duncan wood

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GOING THE DISTANCE

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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 3 May/June 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.

Looking back over the past year, pharma has been focusing heavily on what’s working well and what problematic areas still need addressing. From the advancements in cell and gene therapies to developments in digital health, the industry has made impressive strides forward.

In 2022, the news headlines saw a prevalence of drug shortages across Europe, driven by surging energy costs and distant suppliers. Although not as common throughout this half

of 2023, the issue at hand has yet to find a sustainable solution. The pharma industry needs to come together in hopes to create stronger and more resilient supply chains to bridge the communication gaps between suppliers and manufacturers, all the way to the end consumer. Rare disease drug trials also still pose many problems – from financial constraints to small enrolment rates – opportunities for innovation are encouraged. The decentralised trials model could mitigate these

EDITOR’S DESK

issues and make the patient experience more flexible, integrating a small population that is spread globally and creating a remote engagement experience. From a data perspective, decentralised trials would combine and connect multiple data components and allow insights into trends and patterns. In trials that focus on rare diseases, every

Though it would be naïve to view this as a solution that fits all, especially in trials were on-site and face-toface experience is essential. Perhaps the focus should shift from a fully remote experience to improving the current sitepatient relationship. Creating more flexible trial protocols could see less of a patient burden in terms of travel to sites, financial strain and more.

All of these could encourage stronger recruitment e orts, greater engagement, and lower attrition rates - ultimately providing answers and potential options for those patients seeking them.

With all that said, a reflection piece when we’re only in May, you might ask? It felt like a good opportunity to focus on my year in pharma as this will be my last time sitting at the editor’s desk for European Pharmaceutical Manufacturer. In a short time, I’ve quickly learned that pharma is an innovative, resilient, and ever-evolving industry that constantly presents its own unique challenges and ovpportunities. It’s been a pleasure and an honour to report the latest trends, breakthroughs and emerging innovations that create easier processes, more seamless communications and overall, benefit the patients.

Whilst I’ve not only been privileged to capture the perspectives of leading pharma experts and highlight the stories of the industry’s resiliency, I’ve also had the pleasure to attend reputable trade shows internationally and meet the experts myself. Thank you and farewell.

REBEKAH JORDAN

A small dose

NEW ‘STEALTH’ POLYMER SHOWS PROMISING ALTERNATIVE FOR DELIVERING DRUGS AROUND THE BODY

Researchers have developed a novel synthetic substance with the potential to deliver drugs around the body more e ectively and safely.

Polyethylene glycol (PEG) is the most commonly used polymer for biomedical applications due to its non-toxicity and high solubility. However, researchers have expressed concerns over PEG’s immunogenicity. Its widespread use in Covid-19 vaccines and boosters has led to significantly higher levels of PEG-antibodies in vaccinated individuals.

A team of scientists has created a new ‘active stealth’ polymer, Polythio Glycidyl glycerol (PTGG), which initial data suggests may be safer and more e ective in drug delivery than PEG.

The study, published in the Journal of the

Insulin spray could herald end to insulin needles

Max Bio+ has developed a novel insulin spray that has the potential to eliminate the use of needles - an advancement for patients who require frequent insulin injections. This non-invasive insulin delivery system utilises buccal methods, which have several benefits over current invasive systems of insulin delivery.

American Chemical Society (JACS), found that PTGG was less likely to be detected by immune systems and enhanced physical stability while protecting tissue from oxidative and inflammatory damage.

Lead author Dr. Farah El Mohtadi, from the University of Portsmouth’s School of Pharmacy & Biomedical Sciences, said: “PTGG’s ‘activestealth’ character makes it a highly promising alternative to PEG for delivering drugs and therapeutic proteins.

“Not only can it e ectively avoid detection in the bloodstream, but the polymer’s advantageous properties can significantly reduce the need for expensive substances to prevent freeze damage during storage.”

The study’s findings have significant implications for the

development of more e ective and safer drugs and nanocarriers. Further research will be conducted to explore the potential applications of PTGG in clinical settings.

“Beyond its medical application, we also want to explore PTGG’s potential use in other areas. These include temporarily bonding the polymer to enzymes and investigating whether they are more e ective at breaking down manmade materials, including plastics,” added Dr. El Mohtadi.

Scientists at CEI have already developed enzyme technology to reduce single-use plastics, including PET, to their chemical building blocks, promoting safe and energy-e cient recycling. They now aim to create a similar process for polyester textiles, targeting nylon for this particular project.

With the incidence of diabetes increasing rapidly, there is a pressing need for alternative insulin delivery methods. Max Bio+ has conducted all its research and development in

the UK, where it has been investigating the use of water-soluble nanoparticles to improve drug absorption. This technology has been applied to the development of an insulin spray for buccal/ sublingual administration, which has shown promising results as a controllable, portable and pain-free insulin delivery system.

The team at Max Bio+ has been researching and developing novel delivery systems for a variety of beneficial drugs and supplements, with diabetes a priority.

FOR NEW TB DRUGS

Rising Tuberculosis (TB) cases and growing resistance to key TB drugs, Isoniazid and Rifampin, necessitate improved early-stage diagnostic tests to predict treatment success and curb resistance. Actiphage, a phage-based test, o ers a possible ‘test of cure’ for TB by confirming its eradication from the bloodstream.

“When added to a blood sample, Actiphage finds and infiltrates the mycobacteria, overtakes their replication system to produce more phages

and enzymes. These enzymes break down the bacterial cell walls and release the DNA for PCR analysis,” explains Jane Theaker.

Initially, Actiphage was intended for screening latent TB to find the ‘missing three million’ undiagnosed and untreated active cases. However, its use may be wider. “A new opportunity is emerging to monitor the response to treatment,” Theaker continues.

Actiphage is unique because it selects only live, actively replicating

POTENTIAL FOR ACTIPHAGE TO PROVIDE ‘TEST OF CURE’

One of the innovations is a technology that can create water-soluble composite nanoparticles that improve how medicines are absorbed by the body. Combining this research with the challenges in diabetes management, MaxBio+ prioritised investigating the development of an bacteria, indicating the patient’s disease state. This is a shift from traditional tests like IGRA that focus on the immune response, which can remain heightened even during recovery.

Typical drug regimens for drug-sensitive TB require patients to take multiple drugs for up to

injection-free insulin delivery device.

Because the MaxBio+ technique uses water as a carrier for beneficial drugs, the team looked at ways to deliver the drug without needles. Insulin being delivered orally has numerous challenges. It therefore became clear that a spray, which could be used for buccal administration, was the ideal solution.

The simplicity, portability, and noninvasiveness of an insulin spray mean it has less chance of creating adverse health e ects.

The buccal method of insulin delivery eliminates the need for needles, which can be a significant source of pain, discomfort and anxiety for patients. It also makes it easier for patients to

six months, monitored regularly. Those with drug-resistant TB often face longer, complex treatments with significant side e ects and costs. Thus, quick and precise drug resistance testing is crucial for both drugsensitive and resistant TB, but access can be restricted due to high

adhere to their insulin regimen, which in turn, leads to better overall health outcomes.

In addition to being non-invasive, the insulin spray is also controllable. Patients can adjust their dosage as needed to achieve optimal blood sugar control. The spray can be used discreetly and quickly, making it a more convenient option for patients who are constantly on the go. Since the insulin spray is a discreet and pain-free option, it could reduce the stigma associated with diabetes management. This benefit is particularly important for children with diabetes, who may feel embarrassed or stigmatised when they need to administer insulin in public.

costs and technical hurdles.

“Actiphage has the potential to allow for genotyping of the MTB strain. It releases M.tuberculosis DNA from mycobacteria in a blood sample for downstream amplification and sequencing,” Theaker explains.

She concludes: “Collaborations are vital for developing pan-TB treatments requiring multiple drugs. With Actiphage, there’s potential to identify antimicrobial resistance mutations, which would give doctors insights into which drug combinations to use, increasing the e cacy of these new regimens.”

Panasonic Connect Europe introduced a circular transportation system for temperature-controlled pharmaceuticals connecting the EU, US, and Japan. This service employs VIXELL, Panasonic’s unique vacuum-insulated box, in partnership with Nissin Corporation, a pharmaceutical transport expert. Customers will enjoy cost-saving and sustainable transfer of sensitive pharmaceuticals internationally. The VIXELL system will be reused after each trip, promoting a circular system.

Edin Osmanovic, Panasonic Connect Europe’s Business & Industry Solutions, said: “This sustainable industry deposit system service could only be delivered using the unique technology of the VIXELL system. Panasonic and Nissin provide a turnkey solution dramatically reducing the cost of

temperature-controlled transportation and waste.”

VIXELL’s robust design, thermal insulation, and cold storage performance enable reuse after transportation –impossible with singleuse boxes. It features a wireless vacuum sensor and a contactless power supply technology for easy pre-shipping performance checks. Moreover, VIXELL’s temperature logger transmits real-time radio signals, allowing real-time tracking of the box’s temperature and location. Unlike traditional metal boxes, VIXELL’s resin housing doesn’t block radio signals.

Osmanovic added: “Panasonic VIXELL is an ideal solution for pharmaceutical cold chain logistics companies. Its groundbreaking design, reliability, e ciency, and ease of use look set to elevate the transportation of pharmaceutical goods.”

Vixell: E cient and waste-free international transportation service for pharma

APPLYING INDUSTRY 4.0 DIGITAL SOLUTIONS TO IMPROVE ACCESS TO CELL AND GENE THERAPIES

Ori Biotech’s Chief Digital O cer Kevin Gordon, who leads digital strategy for the company’s automated cell and gene therapy manufacturing platform, discusses the key pain points that are preventing patients from accessing this new generation of curative therapies.

New therapeutic modalities are challenging the biopharma industry as never before. The curative impact of first-wave chimeric antigen receptor (CAR)-T cell therapies in blood cancers, for example, has spurred dozens of companies to launch hundreds of clinical trials for next-generation advanced therapies.

However, a digital sea change is needed if we are to rapidly master the unique complexities for producing cell therapies at scale.

KEY INSIGHTS:

● The industry is not currently meeting the needs of the majority of patients who most need access to advanced therapies

● Centralised and paper-based processes are hampering manufacturing throughput and limiting scalability

● Digital-first solutions o er a route towards smart, scalable, (where applicable) decentralised manufacturing

LOGISTICAL CHALLENGES BAKED INTO CAR-T

Cell-based therapies have generated more excitement than perhaps any new modality since the start of the biotech revolution, demonstrating robust and durable cures for patients with fatal diseases who have often failed all other treatment options. Paving the way for this new era of personalised medicines are autologous CAR-T cell therapies. However, the clinical success of these therapies, coupled with expansion to earlier lines of treatment, has unfortunately left cell therapy makers as victims of their own scientific success – unable to produce enough therapeutic doses, with devastating consequences for untreated patients.

Established biopharmaceutical manufacturing methods do not scale for cell-based therapies. As a result, the industry has had to invest heavily in large manufacturing facilities and human operators in order to manufacture even a small number of products, bringing its own set of problems and bottlenecks.

Digital- rst solutions o er a route towards smart, scalable, decentralized manufacturing

CENTRALISED MANUFACTURING APPROACHES

Strictly centralised manufacturing approaches that make sense for large-batch small molecule or antibody production add complexity to personalised therapies derived from patient cells. Manufacturing advanced therapies in large facilities, often far away from hospitals, means that therapies often have to be shipped back and forth between the apheresis site and the manufacturing facility – regularly across countries or continents.

Such centralised approaches will never be scalable and contribute to higher cost of goods and longer vein-to-vein times.

PAPER-BASED PROCESSES

Cell therapy manufacturing is intricately tied to the existing paper-based manufacturing paradigm originally designed for large-batch antibody and small molecule manufacturing. For example, quality control for a single clinical dose of a cell therapy can require a 1,000-page paper batch record, a highly ine cient and costly method for

tracking (and storing) data that does not let developers easily learn from or adapt processes.

Today, the same rigorous release process we apply to batches of small molecules or antibodies –which each produce thousands or millions of doses – must be applied to every single individual dose of an autologous cell therapy. The requirement for the quality team to manually review each individual paper batch record before a dose can be released to a patient adds huge amounts of time to the manufacturing process, a daunting bottleneck to producing cell therapies at scale.

DIGITAL SOLUTIONS CAN HELP SOLVE THESE CHALLENGES AT SCALE

Industry 4.0 o ers a potential roadmap for improving advanced therapy manufacturing and alleviating the key obstacles that are holding back access to cell therapies.

1. SMART FACTORIES

A first step would be making the manufacturing technologies themselves smarter. Fully connected digital devices would also allow developers to capture information at every stage of manufacturing. This would help structure and aggregate data in a way that it is easily accessible for analysis, power faster optimisation, identify process e ciencies and eventually adapt mid-process to the needs of an individual patient’s cells. In cell and gene therapy manufacturing, a move towards smart factories – as used in other industries like automotive manufacturing – would implement IoT interconnectivity, helping detect instrumentation problems in real time, and preventing unnecessary batch failures.

DISTRIBUTED MANUFACTURING

Instead of cell and gene therapies being manufactured in one large central facility, production could take place in several smaller facilities located closer to treatment centres and their patients. This would reduce the logistical burden of shipping therapies backand-forth and would reduce patient vein-to-vein waiting time. As manufacturing scales up, a digital-first approach would allow for a centralised quality control team to monitor all manufacturing processes taking place globally, in real time, via cloud computing, improving safety and e ciencies.

Across the industry, there is momentum building towards digitally native, decentralised processes. This urgency is based on more than just e ciency: in a time where demand for advanced therapies is only growing, digitalisation will give us a better understanding of the impact of individual manufacturing steps on therapeutic response, will open the door to more flexibility in tailoring therapies to individual patient needs, and will increase throughput to enhance accessibility for patients globally.

Digital approaches alone will not solve all the manufacturing challenges faced by advanced therapeutics manufacturers, but they will undoubtedly play a critical role as the industry strives to make these life-changing therapies available to all patients in need.

DOES FIBRE-BASED PACKAGING HOLD THE KEY TO A SUSTAINABLE FUTURE FOR PHARMA?

Author: ERWIN KLÜNDER, Head of sales, Healthcare at Graphic Packaging International

The global drive for sustainability is impossible to ignore. It plays an increasingly noticeable role in the way each of us lives our lives, from the cars we drive to the food we eat. And, while the health of patients is still the number one priority for the industry, now is the time for pharma companies to seize this vital moment and prioritise the health of the planet, too.

The Packaging and Packaging Waste Regulation (PPWR) proposal published by the EC on 30th November last year is set to shake up pharma packaging and once approved in its final version will be phased in from 2025. While there will likely be some

amendments as the proposal makes its way into the statute books, the substance of the proposals is expected to remain the same. This means many core aspects of pharmaceutical packaging will fall within the scope of sustainability legislation for the first time.

PPWR AND PPWD –WHAT’S THE DIFFERENCE?

PPWR is the EU’s attempt to overcome two key challenges. The first is the amount of packaging waste produced across Europe, which is high and growing. The second is the number of barriers to packaging

circularity, meaning much of that waste ends up incinerated or landfilled.

It follows the previous Packaging and Packaging Waste Directive (PPWD), the EU’s flagship packaging waste statute that first came into force in 1994. However, its e ectiveness has proven to be limited. Eurostat figures highlight the wide disparities in recycling rates between Member States, which mean the EU as

a whole is struggling to meet its current recycling targets –particularly in terms of plastic recycling, which lags well behind its target of a 50 percent recycling rate before 2025.

To achieve its new goals, the EU has set new targets for both member states and businesses to aim for while expanding the scope of the regulations to consider healthcare products. PPWR also considers all types of packaging; primary, secondary, and tertiary. Member States must aim for incremental reductions in all packaging waste generated, cutting waste by 5 percent per capita before 2030, 10 percent before 2035, and 15 percent before 2040.

To help achieve this, several regulatory measures will be put in place to enforce compliance, giving PPWR more teeth than its predecessor.

WHAT PPWR MEANS FOR HEALTHCARE PACKAGING

One is a ban on excessive packaging, which will mandate solutions that are scaled

down to a minimum size or weight. This will promote a more utilitarian approach to packaging design, where no space is wasted. It means product protection features like double-walled packaging or false bottoms will become less viable and should be phased out unless absolutely necessary to protect the product. While it may require some creative rethinking of certain packaging designs and downgauging of plastic or board materials, this legislation should drive the development of innovative pharma packaging that is more cost-e ective without compromising performance but also bearing in mind the recyclability of chosen materials.

Perhaps the most headlinegrabbing aim of PPWR is its goal of decoupling growth from the consumption of resources – in other words, the pharma industry will need to more closely align with the principles of the circular economy. To accomplish this, PPWR calls for 100 percent of pharma packaging to be designed for recycling (DfR Grade D or higher) by 2035 (for other sectors, the date is earlier: 2030) and able to demonstrate recyclability at scale.

This means pharma packaging must be designed to facilitate e cient recycling and be easy to collect and sort into separate waste streams. It must also result in secondary material that is of su cient quality to substitute for primary material.

Paper-based materials, used in cartons and corrugate, are the obvious choice to help the industry rethink its secondary and tertiary packaging. They are already capable of being recycled at scale – figures show 82 percent of fibre-based packaging is recycled already –and can easily meet DfR criteria.

The issue of creating sustainable primary pharma packaging is more complex. PVC, PVDC, PS, multi-material multilayers, aluminium blister packs, and other common materials traditionally o er very poor recyclability but possess the barrier and hygiene attributes that many healthcare products demand. This creates a problem for the industry to solve – and to find a solution, pharmaceutical businesses must take notes from other industries which embraced this journey earlier.

FINDING INSPIRATION WITH FIBRE-BASED SOLUTIONS

The food industry has been under pressure to become more sustainable for some time and especially to focus on the circularity of used packaging. While there is still much work to be done in the sector, this pressure has nonetheless driven many innovations that could be transferred to the healthcare industry.

The food packaging sector has been focused on developing innovative new fibre-based solutions that can o er equivalent performance to plastic. These materials can be used alone or combined with barrier coatings or mono-polymer films – to create hybrid solutions.

Should PPWR permit the inclusion of food-grade PE – which is chemically recycled to prevent contamination – following the requirements for including recycled content in the plastic parts in packaging, the food and pharma industry alike may also be able to consider post-consumer recycled content in the used flexible and barrier materials, which opens up more circular design possibilities.

At Graphic Packaging International, our experience in the global food industry alongside our pharma packaging expertise means we have seen – and been involved in – the development of many of these innovations that could be adapted to provide a more sustainable future for pharmaceutical products.

It is true that DfR alone is not enough. Waste collection and recycling infrastructures across Europe must become more sophisticated and able to accept more materials that may be contaminated by active substances – currently only collected in residual streams – by engaging in cross-industry collaboration. But these are unprecedented times, and they call for unprecedented action to secure a healthier future for our planet.

By embracing fibre-based innovations that have been successfully rolled out in other sectors, the pharmaceutical sector can navigate these uncharted waters while protecting its patients – and the planet that we all share.

By embracing bre-based innovations that have been success lly rolled out in other sectors, the pharmaceutical sector can navigate these uncharted waters while protecting its patients –and the planet that we all share.

In the bustling world of pharmaceutical manufacturing, whispers of a game-changer are getting louder. Triastek, Inc., is the trailblazer behind an innovative 3D printing technology that’s causing a stir within the industry. The implications of Triastek’s technology, laced with the company’s ambitious vision, could potentially bring to light a technological shift that has been promised for a number of years. This shift promises not just enhancements to production e ciency, but also provides fresh solutions to complex drug delivery conundrums.

Nestled in Nanjing, China, Triastek is already turning heads on the international stage, bagging recognition from heavyweights like J.P. Morgan, which included the company in its illustrious list of Top 100 Women-Powered, High-Growth Businesses in the Asia Pacific.

Recently the organisation announced a collaboration with Siemens Ltd., China, which brings together a pioneering 3D printing technology and a wealth of automation and digitisation expertise. This partnership is a calculated attempt to accelerate the digital transformation of the pharmaceutical industry. While the concept of digital transformation is not new, the full extent of its impact on the pharmaceutical industry is yet to be realised. As Mr. Jinsong Zhang, Senior Vice President and General Manager of sales region east of digital industries of Siemens Ltd., China, acknowledged in the accompanying press release, “Siemens’ strategic cooperation with Triastek builds a win-win cooperation of a digital solution provider leader and a 3D printing pharmaceutical leader.”

EPM TAKES A LOOK AT A TECHNOLOGY COMING OUT OF CHINA RECEIVING INTERNATIONAL ACCLAIM AND REGULATORY APPROVAL AND PONDERS IF 3D PRINTING CAN FINALLY LEVEL UP.

THE FUTURE OF PHARMACEUTICAL MANUFACTURING?

At the centre of this collaboration is Triastek’s proprietary MED (Melt Extrusion Deposition) 3D printing technology. This technology uses a solvent-free process that eliminates the need for drying, thereby reducing production time and potentially increasing manufacturing e ciencies. It also allows for greater flexibility in the use of excipients, expanding the range of materials that can be used in the 3D printing process. This presents a significant departure from the conventional pharmaceutical manufacturing processes.

Triastek’s MED technology is also allowing the company to create complex drug structures and formulations, overcoming limitations of traditional extended-release product development. This technology could open up new avenues in the development and manufacturing of solid dosage forms.

Triastek has already developed a commercial-scale MED 3D printing system, the world’s first continuous manufacturing line for 3D printing pharmaceuticals. With a production rate of approximately 50 million tablets per year, it marks a significant milestone, testifying to Triastek’s determination to realise its vision.

INTERNATIONAL ACCLAIM

Moreover, Triastek’s 3D printed medicine, T21, represents an exciting potential use of this technology for targeted drug delivery. Designed for the treatment of ulcerative colitis, T21 aims to achieve colontargeted drug delivery. This innovative application of MED technology could allow for lower drug doses compared to reference listed drugs, thereby minimising potential side e ects.

Triastek’s innovative spirit, as embodied in its MED technology, has not gone unnoticed. The company’s nomination as a finalist in the TCT Awards 2023 for Healthcare Applications, hosted by the same company that runs the European Pharmaceutical Manufacturing (EPM) magazine, recognises the potential of Triastek’s technology to disrupt the status quo in pharmaceutical manufacturing. One of the TCT Awards’ expert judging panel noted:

“It is great to see this concept coming to fruition as it has been talked about for many years. The productivity of this process along with the use of FDA-approved materials is very impressive.”

OVERCOMING REGULATORY HURDLES

Despite these promising advancements, the journey towards a digitally transformed future in pharmaceutical manufacturing is a challenging one, fraught with technical and regulatory hurdles.

There’s no question that the regulatory hurdles for any pharmaceutical innovation are colossal, and it’s worth noting that Triastek has already made substantial progress in this area.

In April 2022, Triastek announced that the US Food and Drug Administration (FDA) had granted Triastek permission to begin clinical studies of its Investigational New Drug (IND) 505(b)(2) application for a 3D printed drug product – T20. This approval marks Triastek’s second product to receive IND clearance from the FDA.

The importance of this clearance cannot be overstated. T20 is a once-daily formulation developed using Triastek’s innovative digital formulation development process and programmed drug release technology. Its application is significant; it’s intended for the treatment of cardiovascular and clotting disorders and promises to improve patient adherence by reducing the current twicedaily dosage to just once a day. The potential improvement in patient outcomes is a powerful demonstration of the real-world impact of Triastek’s technology.

Triastek’s Melt Extrusion Deposition (MED) 3D printing technology was instrumental in the development of T20. The company’s 3D printing formulation by design (3DFbD) method begins with the desired extended release pharmacokinetic profile, informing the formulation development with a physiologically-based biopharmaceutical model (PBBM) of gastrointestinal tract (GIT) absorption. This novel process overcomes many limitations of traditional extended release product development and manufacturing, as demonstrated in animal studies using a prototype formulation of T20.

The FDA IND clearance of T20 is more than just a regulatory milestone. As Dr. Senping Cheng, founder and CEO of

Triastek, noted at the time, “The FDA IND clearance of T20 is a significant milestone for Triastek, and demonstrates the significant progress in 3D printing pharmaceuticals.” These are not mere words; they encapsulate the journey of an emerging technology that has been explored for over 26 years, now nearing its maturity with the potential to make a real di erence in the pharmaceutical industry.

Triastek is not just about creating innovative technologies; it’s about applying these technologies to develop its own product pipeline, as well as codeveloping products with multinational and Chinese pharmaceutical companies. The focus is on blockbuster small molecule drugs, demonstrating the utility of Triastek’s novel pharmaceutical product development technology and continuous GMP manufacturing capabilities.

As we look towards the upcoming TCT Awards in June 2023, where Triastek’s innovation in pharmaceutical manufacturing has been recognised with a nomination, it’s evident that the pharmaceutical industry is on the cusp of a digital revolution.

Triastek’s innovative spirit and the potential of its MED technology to disrupt the status quo have certainly caught the industry’s attention but its success will ultimately be determined by its ability to bring the technology to the market and integrate it into existing pharmaceutical manufacturing processes.

For more information on the judges, the submission process and more on the TCT Awards 2023 head to: www.tctawards.com

INNOVATION IN INHALATION: THE FUTURE OF DRUG DELIVERY

Inhaled pharmaceuticals have a long history, dating back to ancient times when treatments such as those documented in the Ebers Papyrus, an Egyptian medical text from around 1550 BC, were used to alleviate asthma symptoms. Progressing into the modern age, the U.S. FDA approved inhaled epinephrine for asthma in 1929. This milestone marked a new era in the field, which was further bolstered by the advent of pressurised metered-dose inhalers (MDIs) in the 1950s and dry powder inhalers (DPIs) in the 1960s.

Today, companies like Broughton, a global scientific consultancy-based Contract Research Organisation (CRO), stand on this historical foundation as they innovate in the realm of inhaled pharmaceuticals. Broughton has recently introduced a state-ofthe-art inhalation testing service that leverages their in-house laboratory testing facilities, analytical testing expertise, and an in-depth understanding of aerosol and inhalation science to provide a comprehensive solution for testing, consulting, and compliance requirements.

Chris Allen, CEO of Broughton, stated, “Inhaled medicines provide a viable alternative to traditional drug delivery routes. They act rapidly, often at lower doses, and o er the potential to improve the quality of life for those with respiratory

diseases.” As Allen points out, beyond serving the large global population with asthma and COPD, there are new areas to explore with inhaled medicines. Interest in such drugs has risen notably since the pandemic, with many companies developing novel products.

In recent years, there have been significant advancements in the field. These include the development of new inhaled corticosteroids and biologics, and the emergence of novel delivery systems, such as breath-activated inhalers. These innovations, driven by the rising prevalence of respiratory diseases and demand for e cient delivery systems, have transformed the industry.

Yet, like all medical interventions, inhaled pharmaceuticals have their share of challenges. These include the higher cost compared to oral medications, the need for correct usage technique, and potential side e ects such as coughing and oral thrush. Despite these, the benefits of inhaled pharmaceuticals — rapid symptom relief, improved lung function, and a reduced risk of complications — are notable.

“Bringing a new inhaled drug product to market is a complex process requiring deep scientific understanding,” added Allen. “Our team’s expertise in inhalation devices, aerosolisation, and formulation science can provide valuable insights to clients, assisting them in bringing products to market e ciently and coste ectively.”

The future of inhaled pharmaceuticals appears promising. With companies like Broughton driving innovation and continual advancements in technology, the era of inhaled medications is poised for unprecedented growth and innovation.

Broughton’s new inhalation testing service propels inhaled drug delivery into an innovative future.

Bringing a new inhaled drug product to market is a complex process requiring deep scienti c understanding

OPTIMISING BIOPHARMACEUTICAL PRODUCTION WITH PREPACKED PROCESS-SCALE CHROMATOGRAPHY COLUMNS

Laura Kronbetter, Senior Global Product Manager, Process Chromatography, Bio-Rad Laboratories

The biopharmaceutical industry has made significant strides in optimising drug development and downstream production processes, with the use of chromatography columns critical for the purification of biopharmaceutical products. However, conventional column packing can be a complex and challenging process, which can create production bottlenecks and may result in inconsistencies and errors. The quality and reproducibility of data and the product itself can also be a ected, making it di cult to ensure that approved quality standards are consistently followed. In addition, the use of di erent resins from various suppliers further complicates the column packing process, as each supplier provides their own recommendations. This introduces an additional degree of variability that can lead to inconsistent results. If a column fails to meet the set qualifications and approval requirements, the packing process would need to be repeated, leading to delays and increased costs.

The adoption and implementation of prepacked process-scale chromatography columns has rapidly emerged as a promising solution to overcome these challenges, improving overall processing e ciency while maintaining high levels of quality and reducing costs.

BENEFITS OF USING PROCESS-SCALE PREPACKED COLUMNS

Prepacked columns o er numerous operational advantages over traditional in-house column packing methods. They can be produced by specialists in state-of-the-art clean rooms, making them ready for good manufacturing practice (GMP) processing. The use of prepacked columns reduces the risk of columnto-column variability and provides a consistent and reliable purification outcome, contributing to the quality and consistency of the final biopharmaceutical product. Moreover, a wide variety of compressible resins and incompressible media are available in standardised column sizes commonly used for preclinical, clinical, and production processes (e.g. Foresight Pro Columns with CHT Ceramic Hydroxyapatite Media

Addressing time-e ciency challenges, prepacked columns provide significant time savings by eliminating the column packing step, which allows for more streamlined production timelines. This translates to increased productivity and less downtime while eliminating the need for specialised equipment. Similarly, bu er preparations are also reduced by removing packing steps. When a disposable flow path is used in conjunction with prepacked columns, it also saves time on skid preventative maintenance (PM). Moreover, unlike traditional methods, prepacked columns eliminate the need to account for resin lead times, column packing, and possible column packing inconsistencies in the schedule.

OPERATIONAL ADVANTAGES

O ering substantial cost savings, prepacked columns eliminate the need for manual column packing and validation, reducing the material and labour costs associated with traditional column chromatography processes. Prepacked columns also eliminate the need for dedicated column packing areas, freeing up valuable space in the production facility. This allows for simpler suite designs and improved overall e ciency. Furthermore, by managing resin inventory in a prepacked format, biopharmaceutical companies can reduce labour costs associated with resin handling and inventory management. Another benefit of prepacked columns is the increased flexibility they provide by allowing for rapid process turnover, a particularly useful feature in a facility producing multiple biotherapeutics. Process developers can choose from a wider range of resins, as expertise in packing a novel resin may not be required. Many resins can be procured in a prepacked format, thus providing developers more flexibility in adopting new separation technologies and reducing the limitations inherent in the industry concept of “platform” resins.

ABOVE: Bio-Rad Foresight Pro Columns, credit: Bio-Rad Laboratories, Inc.

Improving consistency, prepacked columns are packed with single resin lots in standard bed heights and diameters, providing optimised, consistent slurry and packing conditions. In addition to presanitisation,

reduction of bioburden, and prevention of crosscontamination, each column is shipped with quality and performance documentation, and individual column release testing is performed. This can reduce QC full-time equivalent expenditures and simplify approvals. Moreover, column consistency across facilities is an added benefit when a biotherapeutic is produced at multiple sites.

By outsourcing the column packing step to a resin supplier specialising in column packing under optimal conditions, the risk of inconsistencies in the packed bed is reduced. This allows endusers to focus on more critical aspects of purifying therapeutic proteins. The use of prepacked columns can also reduce

procurement ine ciencies, such as resin inventories, elimination of resin lot matching, and maintenance of spare parts for columns and standard skids. The availability of prepacked columns from resin manufacturers can also reduce lead times as the resin is readily available with the added benefit of a single source for technical support.

In recent years, prepacked columns have emerged as a game-changing solution for commercial manufacturing. They have quickly become a viable approach for commercial manufacturing and are now routinely used by contract manufacturing organisations (CMOs) and innovators to produce biotherapeutics. With their ability to streamline

operations, reduce costs, and improve quality, prepacked columns represent a significant step forward for the biopharmaceutical industry. As such, they are likely to continue to play a major role in the future of biotherapeutic manufacturing.

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By outsourcing the column packing step to a resin supplier specialising in column packing under optimal conditions, the risk of inconsistencies in the packed bed is reduced. is allows end-users to focus on more critical aspects of puri ing therapeutic proteins.

ENHANCING BIOTHERAPEUTIC PROPERTIES WITH CELL LINE ENGINEERING

Neha Mishra, Ph.D. Senior Scientist Bioproduction, Revvity

Monoclonal antibodies (mAb) have established themselves as one of the leading classes of biotherapeutics, making up over 50% of first-time regulatory approvals in recent years. With total mAb sales expected to surpass US$200 billion in 2024, many companies and academic researchers are investing significantly into methods to enhance the therapeutic properties of these proteins.

CHOOSING THE RIGHT CELL LINE

Chinese Hamster Ovary (CHO) cell lines have long been established as the most popular

cell line for the production of biotherapeutics. With short doubling times (16-22 hours), CHO cells e ectively grow in suspension culture as well as chemically-defined media. These key attributes allow biotherapeutic developers to establish controlled manufacturing pipelines that support scale-up. Perhaps most importantly, CHO cells have been heavily involved in biotherapeutic production since they were used in the first mammalian-expressed recombinant therapeutic— human tissue plasminogen activator, in 1987. Hence, CHO cells have a long history of safety

data that helps to ensure that the resulting biotherapeutics can navigate a stringent modern regulatory landscape.

In addition, CHO cells possess the ability to produce biotherapeutics with human-like post-translational modifications (PTMs). They are also significantly less susceptible to viral infection than alternative cell lines. These factors combined highlight CHO cells as an extremely robust cell line able to produce biotherapeutics with reduced potential immunogenic responses, alongside minimising risk of potentially adventitous agents that may cause safety concerns.

GLYCOSYLATION

Post-translational modifications, such as glycosylation, play a key role in several aspects of monoclonal antibodies, including e cacy and half-life. As such, the presence and type of PTMs on therapeutic antibodies is something that must be closely monitored and controlled. The process of glycosylation involves the addition of oligosaccharide units to individual amino acid residues within a protein structure. Oligosaccharide addition occurs within the endoplasmic reticulum (ER) and Golgi apparatus, and the two most common types of glycosylation, di erentiated

based on the type of linkages are:

i) Nitrogen (N)-linked glycosylation: when oligosaccharides are attached to the nitrogen of an asparagine residue

ii) Oxygen (O)-linked glycosylation: when sugars are attached to the oxygen of a serine or threonine residue

The majority of the mammalian proteins are glycoproteins with N-linked glycans, which often confer specific properties to the polypeptide chain. Variation of glycosylation patterns within N-linked glycans is particularly pertinent to biotherapeutics since they can have an e ect on protein folding, stability, pharmacokinetics and immunogenicity, among others. Glycosylation variations and their impacts on biotherapeutics are also highly dependent on the region of the protein.

Antibody-dependent cellmediated cytotoxicity (ADCC) is an important immune response to foreign antigens, through which FcγRIIIa receptor-bearing natural killer (NK) cells are recruited to attack targets that express antigens derived from, for example, tumours or pathogens. ADCC response is mediated by the binding of antibodies to specific ligands present on the surface of a target cell. The Fc region of the antibody then binds to the FcγRIIIa receptor expressed by NK cells, which are then activated to release cytotoxic granules that ultimately eliminate the target cells. The ADCC response is extremely variable and dependent on the binding a nity of a given antibody to the receptor. Given the importance of the ADCC response on the e cacy of mAb therapeutics, it is important to ensure this response is controlled and consistent. Consequently, structural studies conducted

by Ferrera etal . suggest that the presence of fucose within the core glycan structure of the Fc region of an antibody can significantly decrease receptor:antibody binding a nity. The absence of fucose from a given molecule, called afucosylation, is an important consideration when designing more potent therapeutic antibodies. Increased binding a nity and cytotoxic e ects o ers several advantages when compared to fucosylated counterparts. Stronger binding a nity to receptors leads to less competition with circulating antibodies present in serum, which allows for lower dose requirements and a minimised risk of undesirable side e ects. Moreover, afucosylation can support the development of anticancer biopharmaceuticals for tumours that express low levels of surface antigens, with the potential to target a wide range of cancer types.

GENOME EDITING TO ALTER GLYCAN COMPOSITION

Monoclonal antibodies

generated using CHO cells are typically characterized by a glycan core structure that is fucosylated. This attribute can have implications for the biological activity of the therapeutic antibodies, as well as for their e ector function in the case of ADCC reponse. As a result, modifying the glycosylation pathways in CHO cells could lead to improved therapeutic properties. For many years, there has been a growing interest in developing methodologies able to control the glycan composition in therapeutic proteins. Several strategies have been explored to enrich the proportion of afucosylated antibodies in the final product such as, controlling cell host metabolism, using fucosylation enzyme inhibitors, expressing enzymes to reduce

available fucose within the cells, and using RNAi to reduce the expression of key fucosylation enzymes. Nevertheless, glycan composition is highly sensitive to process and media conditions, product and overall behaviour of cells in culture, and the use of most of these technologies make it virtually impossible to generate therapeutic preparations with 0% or 100% of their molecules containing a specific glycan composition. Additionally, batch-to-batch glycosylation variability that is inherent to the nature of the cell culture control systems, may have significant e ects on controlling drug potency and safety, posing additional pressure during the manufacturing and quality control in bioproduction.

For this purpose, nextgeneration genome editing tools provide an e ective means for engineering expression host cells capable of producing therapeutics with specific characteristics. CHO host cells can be engineered to lack entirely the ability to incorporate a fucose molecule in the glycan structure. This can be achieved by generating a complete

functional knockout (KO) of the fucosyltransferase gene in CHO cells using gene editing tools such as recombinant AdenoAssociated Virus (rAAV) or CRISPR-based technologies to generate enzymatically inactive fucosyltransferase proteins.

CHO cell lines that lack the fucosyltransferase gene show similar growth and productivity performance to the parental cell line and are capable of consistently producing fully afucosylated mAbs (0% fucose) without any batch-to-batch variation. In addition, monoclonal antibodies produced in CHO hosts with fucosyltransferase gene KO exhibit a markedly higher e cacy in eliciting an ADCC response, when compared to those expressed in the parental cell line.

Genetically modified CHO cells can enable production of afucosylated antibodies with enhanced ADCC activity, which can make possible the development of more e ective treatments in oncology, infectious diseases or autoimmune disorders, enabling better control over product quality and potency of new therapeutics.

Genetically modi ed CHO cells can enable production of a cosylated antibodies with enhanced activity, which can make possible the development of more e ective treatments in oncology, infectious diseases or autoimmune disorders, enabling be er control over product quality and potency of new therapeutics

KEY DRIVER IDENTIFICATION: MINIMISING VARIABILITY IN BIOPHARMACEUTICAL PRODUCTION

Author: Neelanjan Sengupta, Ph.D. Sta Scientist, Research and Development for Cell Culture and Cell Therapy at Thermo Fisher Scientific

Enhancing process consistency and lessening variability is pivotal for enduring success in biopharmaceutical manufacturing. Variability can stem from various sources; one frequent source is inconsistencies in the composition of cell culture media and supplements from one batch to another. Particularly, unexpected impurities in raw materials, as well as natural variability in non-chemically defined components, may result in less-than-ideal bioprocess outcomes.

Owing to this risk of variability, there has been an increasing focus on using chemically defined media and supplements in biopharmaceutical production. However, even chemically defined raw materials may contain unexpected impurities which could a ect productivity. Hence, non-chemically defined components remain a valuable alternative that developers should contemplate, particularly when measures to reduce risk are employed. These involve selecting a supplier with strict production controls and undertaking comprehensive analyses to understand which components a cell culture process is most sensitive to, then implementing suitable mitigation measures.

One strategy that developers can utilise to attain this insight and lessen the risk of variability is key driver identification (KDI).

WHAT ARE KEY DRIVERS?

To better manage variability and maximise consistency in a specific process, it’s crucial to comprehend what is driving critical cell culture outcomes, such as product titers and quality. Key drivers are media or supplement components

Key Driver Identi cation (KDI) o ers a potentially transformative approach to enhancing consistency and reducing variability in biopharmaceutical manufacturing.

that significantly impact process performance either positively or negatively. To achieve optimal results, the concentrations of these components need to be within a specific range, with any deviation from this leading to variability.

HOW CAN KEY DRIVERS BE IDENTIFIED?

To assist in improving consistency from one batch to another, it’s essential to first identify the key driver components that influence process productivity. Due to the complexity of these components and their interactions, determining causation when observing individual components presents

a challenge. Therefore, utilising a holistic approach such as KDI, which takes into account the interactions between components, can aid in enhancing process understanding.

The identification process starts with the analytical characterisation of the composition of several lots of media and supplements. By combining performance data, such as yield or product quality, and analytical data from each lot, numerous competing predictive models, which replicate biological behaviour and function, are generated using statistical methods.

These biomimetic models are employed to compile a consolidated list of potential key driver components. At this stage, the aim is to eliminate factors that aren’t impacting performance and gain valuable insights into those that are. This aids in identifying the components that show a statistical correlation of performance across the medium or supplement of interest. Parameters that merely correlate with variability need to be di erentiated from those that genuinely impact performance through statistical analysis and experimental data.

Based on these data, prototype media or supplements with enhanced levels of the identified key drivers are created. These prototypes are then tested to validate the outputs of the models and confirm that the identified key drivers are having a causative e ect. Data from these prototype experiments are also used to refine the models, creating a final, validated biomimetic process model and helping to determine key driver optimal ranges. These insights can then assist developers in addressing any consistency challenges that may be impacting their process.

HOW CAN KDI INSIGHTS HELP REDUCE VARIABILITY?

As previously mentioned, one potential source of process inconsistency is natural variability in nonchemically defined media and supplements. Using the finalised biomimetic model and the information gathered during KDI, developers can screen non-chemically defined raw material lots to help safeguard against variability from one batch to another.

Moreover, by understanding the key drivers within their process, developers can aim to maintain the concentrations of key components at their optimal levels, helping to optimise productivity. Using KDI, developers can make data-driven decisions to tackle sources of inconsistency and make adjustments, including microadditions of key components, to mitigate their impact. This can save developers from resorting to hit-and-miss solutions, which can be both time and resourceintensive.

This can be particularly beneficial when employing peptone supplements. As an alternative to serum, peptones are a popular, cost-e ective choice as they provide essential nutrients that can boost performance across a range of cell culture applications. They also have protective e ects, including anti-apoptotic properties, helping to bolster cell cultures and enhance overall productivity. However, as they are not fully chemically defined, the precise nutritional composition of each peptone lot can vary. As a result, screening each lot to validate that the levels of key driver components are within their optimal ranges can enable manufacturers to fully reap the benefits of peptones without increasing the risk of inconsistency.

MAXIMISING THE BENEFITS OF KDI

By enabling developers to implement an optimised raw material selection process and other strategies to reduce the risk of variability, KDI can have a potentially transformative e ect on process consistency. By establishing a thorough understanding of their process, the KDI approach can be a powerful analytical tool, o ering significant longterm advantages.

Given the complexity of the biostatistical modelling involved, collaborating with a vendor with experience and access to comprehensive KDI capabilities can substantially simplify the analytical workflow. Additionally, in-house media development capabilities can be advantageous to support the implementation of the data generated and the development of an optimised solution. Through this, it can help developers achieve their bioproduction goals and provide innovative treatments to the patients who need them the most.

As for the readability, this text would likely score around 14-16 on the Flesch-Kincaid readability scale, which is roughly equivalent to a university undergraduate level. This is because it uses fairly complex terminology and sentence structure, making it suitable for a professional or academic audience with a background in biopharmaceutical manufacturing.

CELL LINE DEVELOPMENT STRATEGIES FIT FOR A NEW ERA OF BISPECIFIC ANTIBODIES

Nicole Wakes, Senior Director Cell Line Development, and Simon Keen, Vice President Cell Line Development at Abzena, outline the strategies that developers must consider to overcome the challenges of developing BsAbs under increasing pressure for speed.

Advances in biotechnologies using molecules of complexity — such as bispecific antibodies (BsAbs) — o er broad applications in many disease areas, including asthma, macular degeneration, arthritis, and Crohn’s disease. When considering the production of these new-era biologics, a clear strategy is needed from the outset.

COMPLEX MOLECULE PRODUCTION CHALLENGES

BsAbs are di cult to express due to their heterogeneity and multiple specific activities so there is no “one-size-fits-all” approach to their development and manufacturing. As a result, cell line development (CLD), upstream development (USP), and downstream development (DSP) must be carefully optimised to ensure maximum yield and quality for each project. The growing demand for these molecules from patients, investors, and developers means that rapid timelines are required. This can be achieved through building a robust CLD strategy, identifying molecule liabilities, adopting technologies for optimal speed, and working with experienced partners.

BUILDING A ROBUST CLD STRATEGY

The right CLD approach can shorten timelines for investigational new drugs (IND) considerably. As CLD impacts

every process, decisions made from the outset could proactively prevent delays. Developers should therefore consider the following parameters when designing their CLD strategy:

● Analytics and validation: Critical quality attributes should be determined and monitored throughout the development process.

● Scalability: Developers should consider how conditions such as oxygen transfer capacity and shear stress may change throughout scaling, as these may impact cell growth and target protein expression. It is essential to ensure variations do not impact the scale up to manufacture.

● USP methods: Developers should aim for USP methods that allow for rapid progression of products throughout development. This should involve selecting clones that are a good platform fit, and considering productivity and product quality.

● DSP methods: For e cient DSP, developers should consider the physicochemical properties of the product to ensure product consistency. Lead candidates should have minimal heterogeneity and production clones should consistently express in platform USP conditions.

IDENTIFYING POTENTIAL MOLECULE LIABILITIES

Resolving issues that have not been considered proactively from the outset of CLD can be costly and time consuming for development and manufacturing, with possible strategy redesign requirements. With antibody-based molecules such as BsAbs, molecular structures and sequences — such as sites for isomerisation, oxidation, glycation, and deamidation

— can present liabilities. Reactions at any of these sites could result in changes to the molecule’s physical properties, leading to high risks of product heterogeneity and batch-tobatch variation.

To overcome these challenges, developers should conduct a risk assessment at the early design stage, determining where these sites of liability are, and how they may impact the functionality and stability of the molecule. At this stage, the molecule could be redesigned. Alternatively, if engineering out liability is too great a risk, development can continue, with the acceptance that potential issues further down the production chain may occur.

ADOPTING TECHNOLOGIES TO ENSURE HIGH QUALITY AND SPEED

Building a robust CLD strategy requires the adoption of technologies such as vector selection, integration, and fast stable pools that can accelerate timelines without being detrimental to product quality. Developers should carefully consider the pros and cons of di erent integration techniques to determine which will produce the most stable cell line.

1. Vector selection

To accelerate CLD for the delivery of the target genes, choose a vector that encodes the desired biologic, with a library of carefully designed plasmids, alongside a standard backbone. The method employed for gene integration should also be carefully considered to select the approach that will produce a stable cell line that consistently expresses the right quality of the product.

2. Integration and transparency Traditionally, integration of transgenes in antibody-

based CLD into the host genome has been achieved via random non-homologous recombination. Although e ective, this is time-consuming. Targeted integration can increase productivity, where the site for integration into the genome has been predetermined and can be achieved using site-specific recombinases.

Another approach is transposase-mediated integration. Transposases recognize common sequences within the genome and will preferentially insert transposable elements into these sites. Cell line stability is improved as these sites are often associated with high transcription activity and are less prone to gene silencing e ects. This method can reduce the screening e orts needed to identify highly productive clones.

3. Fast stable pools

Another technique that can significantly reduce timelines for IND filing is the generation of fast stable pools. Following molecule design and development, small amounts of protein can be rapidly generated through transient expression for basic screening of a primary characteristic. However, transiently produced material does come with a risk of altered product quality attributes. Bulk fast stable pools of potential drug candidates can be generated in a matter of a few weeks for more in-depth analysis.

PROCESS SUPPORT FROM PARTNERS WITH EXPERIENCE AND EXPERTISE

There is a clear need for developers to adapt to the rapidly changing antibody-based biologics market as these drugs will be essential in targeting diseases of growing prevalence. Delivering these vital biologics to patients at speed will require developers to employ a robust strategy, with CLD at the core.

A robust CLD strategy will incorporate a proactive approach to determining potential challenges and avoiding delays and employ methods to enable development activities to be initiated in parallel, such as generating fast stable pools. Seeking support from a trusted and proficient partner with years of experience and a thorough understanding of the market can help ease the burdens involved in successfully delivering these critical biologics to patients.

Building a robust CLD strategy requires the adoption of technologies such as vector selection, integration, and fast stable pools that can accelerate timelines without being detrimental to product quality

DELIVERING INNOVATIVE ANTIBODY THERAPEUTICS NECESSITATES IMPROVED ACCESS TO PIONEERING PURIFICATION MATERIALS.

Author: Aaron Moulin, Field Application Specialist at Purolite, explores the need for a straightforward, qualityby-design (QbD) led approach to switching chromatography resin suppliers so that when new antibody types are developed, novel purification challenges can be overcome.

Chromatography is a crucial component of downstream processing, removing or reducing contaminants to acceptable levels and achieving a highly pure end product. For monoclonal antibody (mAb) therapies, Protein A a nity chromatography is typically employed as a critical step in purification, with the target molecule generally eluted under acidic conditions, between pH 3 and 3.5. As antibody-based therapies continue to progress and antibody properties become increasingly diverse and complex, a wider operational window for elution is sometimes necessary to maintain high yields. Access to alternative Protein A resins that allow for elution at higher pH levels can maintain high yields and retain the use of a classic Protein A and Ion Exchange mAb purification. However, established regulatory frameworks and best practices for optimal evaluation and selection of alternative Protein A resins are lacking.

CHROMATOGRAPHY IS KEY FOR DOWNSTREAM BIOLOGIC PROCESSING.

Removal of unwanted impurities and contaminants is crucial for producing a high-quality drug product. For biologics like mAbs, a nity chromatography is used to preferentially bind the target molecule and separate it from unwanted materials before a change in conditions releases it. In mAb purification, it is common to use chromatography resins composed of cross-linked

agarose, glass, or polymerderived beads bound to a Protein A ligand via a linker. Protein A specifically attaches to antibodybased materials and forms a complex at pH 5 to 8. The bound antibody is eluted upon a change in pH to acidic conditions. This method is generally adopted early during the development stage and carried through to commercial production.

As we move towards an era of novel antibody-based products, such as Fc-fusion proteins and

bispecifics, — common Protein A resins may no longer be a viable option for purifying pH-sensitive molecules. Instead, an innovative solution is required: a resin that doesn’t rely on acidic pH for elution. While maintaining easy access, these resins provide manufacturing advantages as they are chosen specifically based on the characteristics of the biologic in question.

Regrettably, there is currently no standardised approach for implementing a new resin into

a pre-approved process. The current regulatory framework also means switching to these alternatives cannot occur without notifying the relevant regulatory agencies. If a new resin is adopted, it can lead to the entire manufacturing process requiring revalidation for regulatory approval, which can be costly and time-consuming. With this in mind, the biopharmaceutical industry has come together through BioPhorum to outline a regulatory-acceptable solution.

USING A QBD APPROACH FOR REGULATORY ACCEPTABLE CMA SOLUTION

Accessing alternative materials is currently a significant challenge and that prevents the incorporation of innovative resins into downstream processes. Despite the manufacturing advantages in antibody downstream processing, current regulatory frameworks mean switching to these alternatives cannot occur without regulatory notification, which can result in having to re-evaluate the process for approval.

This inflexibility has prompted the biopharmaceutical industry to come up with a regulatory-recognised solution for implementing materials from an alternative supplier or source based on a QbD approach, in the form of BioPhorum. Adopting the BioPhorum convention of defining a material by its function and critical material attributes (CMAs) could allow materials to undergo an equivalency investigation instead of manufacturing revalidation.

Target material profile

Summarising the raw material characteristics to ensure drug product and process, quality, and safety.

Material attributes

Author: AARON MOULIN Field Application Specialist at Purolite

Defining the raw material attributes, including chemical, physical, microbial, and other safety attributes.

Summary control strategy

Defining controls derived from the understanding of current products and processes to assure performance and quality.

Bringing it all together

Collating the information from the three steps above to define the CMAs.

Using these four steps, this solution aims to increase supplier flexibility and ease regulatory approval. Applied to the pH Protein A challenge, the BioPhorum approach sets a precedent for incorporating resins compatible with pHsensitive materials into existing processes.

A SUPPORTIVE SUPPLIER PARTNERSHIP PROVIDES PROTEIN A SOLUTIONS.

Forming a fluid and comprehensive partnership can assist in implementing innovative resins for pH-sensitive antibody testing. Following the BioPhorum guidelines, providing detailed documentation on CMA enables interchangeability, making manufacturing integration and regulatory approval easier. When applied to Protein A resin, the BioPhorum approach deems the resins interchangeable if the same process and critical quality attribute outputs are achieved. To ensure consistent product quality and safety when alternative Protein A resins are used, the following controls are required:

● Testing of specific attributes of Protein A by the supplier, providing a corresponding statement certificate

● An accompanying manufacturing study with defined parameters completed.

● Verification of the viral control strategy

● Assessment of downstream process capacity to remove unwanted materials, leaving a

high-quality product that is safe and e cacious at release.

● Conformation of the extractable and leachable profile of the resin with a risk assessment

● Validation of the lifetime, cleaning, sanitisation, and storage conditions used to maintain the quality of the resin.

● A detailed and comprehensive regulatory support file for the resin, which contains the defined content.

● A statement on freedom from materials of animal origin for the Protein A resin. With all the necessary documentation in place, the interchangeability of Protein A resin is enabled. As a result, BioPhorum has set a precedent for delivering flexibility into the manufacturing process.

LOOKING AHEAD

By using the BioPhorum convention to replace the traditional Protein A a nity chromatography with innovative resin solutions, we can now explore the use of this process for other manufacturing challenges currently facing the industry. Moving toward new and complex biologics that often have unique handling requirements opens new possibilities for tailored downstream processing without hindering regulatory approval timelines.

Working with a resin supplier with the BioPhorum QbD approach in place allows for manufacturing flexibility and eases process optimisation.

Catalysing the ture of antibody therapeutics, a quality-by-design led approach can conquer novel puri cation challenges, ushering in an era of tailored downstream processing

ALIGNED WITH THE LATEST ICH GUIDELINES, ICH Q12, THE REGULATORYAPPROVED PROCESS CONSISTS OF FOUR STEPS:

New report shines a light on age inclusivity in clinical trials

RBW Consulting and The International Longevity Centre (ILC) have released a report on age inclusivity in clinical trials. The “Trial and Error” report, backed by expert interviews and a roundtable discussion, prompts regulators, pharmaceutical companies, and researchers to prioritise age diversity in trials. It explores why older people are underrepresented in clinical trials and o ers eight improvement suggestions.

The report is part of RBW’s IMPACT programme, which invests pro bono in patientfocused projects where there’s a lack of knowledge or implementation in the life science sector.

Emma Thorp, CCO at RBW, stated: “We are proud to have partnered with the ILC on this project. Against the backdrop of the UN decade of healthy ageing, it felt like the right time to drill down into the needs of older people as part of the movement to make clinical trials more representative. It’s our hope that this work will support our clients and the industry in general with inclusive trial design. The more we can identify and share practical solutions, the more progress we will make, and our hope is that this work will sit alongside the excellent e orts of others to make real change happen.”

Talking points

SANOFI SOLIQUA WILL FACE FIERCE COMPETITION IN PRICE SENSITIVE INDIAN T2D INSULIN MARKET

Sanofi (India) has gained approval from the Central Drugs Standard Control Organization (CDSCO) for soliqua (Insulin glargine and lixisenatide recombinant fixed dose combination) for adults with obesity and type 2 diabetes (T2D). However, it will face competition from existing and upcoming biosimilars, due to the price-sensitive nature of the Indian T2D insulin market, according to GlobalData.

In 2022, India had 80.1 million diagnosed T2D cases, and its pipeline includes one innovator insulin and four biosimilar insulins in various clinical development stages. Oral insulin could significantly change the market dynamics if trials are successful.

Anupama Mishra, pharma analyst at GlobalData, comments: “India’s T2D insulin market is dominated by multinational pharmaceutical companies such as Novo Nordisk and Sanofi. Currently, there are 15 insulin formulations marketed in India for T2D and type 1 diabetes. The recently launched Soliqua will provide sti competition to the existing insulin brands. In addition, several biosimilar insulins are currently in the pipeline for T2D treatment in India, and they are expected to pose a significant threat to the leading branded

insulins’ market share due to their lower cost. Hence, there is a need for branded insulins to di erentiate themselves in terms of the ease of administration or create a ordable pricing alternatives to gain market share in the price-sensitive market.”

Reportedly, soliqua demonstrated less hypoglycaemia and weight benefits in the Solimix study. Mishra concludes: “As the middle class in India experiences a surge in disposable income and T2D awareness continues to rise, it is expected that patients will prefer e ective branded insulins. Nevertheless, branded insulin products are likely to encounter market access obstacles, and thus, they must be priced reasonably to penetrate deeper into this pricesensitive market.”

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

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