LABOUR’S LIFE SCIENCES PLAN ASSESSED
FROM SINGLE-USE TO REUSABLE CONTAINERS IN PHARMA PACKAGING
NAVIGATING THE EU’S NEW HTA REGULATION
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Jan/Feb 2024 | Volume 24 Issue 1
5: EDITORS DESK A New Year
6: A SMALL DOSE
Covering the latest developments coming out of UK universities
14: COVER STORY
Mike Ludlow, Element Materials Technology, assesses single-use systems for biopharmaceutical production
FEATURES
8: Q&A
Cencora’s Herbert Altmann on navigating the EU’s new HTA regulation
10: PACKAGING
Niall Balfour, CEO of Tower Cold Chain, explores the shift from single-use to reusable containers in pharmaceutical packaging
12: SUSTAINABILITY
Rachel Griffiths and Gigi Bat-Erdene of PCI Pharma Services analyse the role of CDMOs in creating a sustainable pharmaceutical supply chain
17: COMMENT SECTION: LABOUR’S LIFE SCIENCE PLAN
We get the thoughts of leading pharma figures on the Labour Party’s proposed Life Science Plan
18: Q&A
Our third and final in a series of interviews with a range of SMEs from pharma powerhouse Lonza
20: PHARMA INNOVATION
Exploring innovation and sustainability with Bormioli Pharma
22: DRUG DELIVERY & DEVICES
Dalip Sethi, Ph.D. and Joy Duemke of Terumo Blood and Cell Technologies discuss how automated apheresis platforms function as therapeutic and enabling technology for cell-based therapies
24: BIOPHARMA & MANUFACTURING
John Cardone OF Bio-Rad Laboratories explores the significance of monitoring antibody drug safety and efficacy in preclinical and clinical development
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Volume 24 Issue 1 Jan/Feb 2024
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Whilst the year may have changed, the everevolving nature of the global pharmaceutical landscape remains much the same.
The new year brings the pharmaceutical sphere one step closer to the end-dates for emissions targets. Scope 3 emissions, those being emissions that encompass the raw material production, distribution, product use, and end-of-life disposal of a product, loom large over a pharma industry looking to rely on its ability to innovate rapidly implementable solutions as the race for net zero rather ironically hots up.
2024 is likely to be the year in which the race to sit atop of the weight-loss
drug pile gets increasingly competitive. I would be willing to wager at this point that everyone reading this is aware of Novo Nordisk’s behemoth drugs Wegovy and Saxenda as well as Eli Lilly’s Zepbound. These drugs work by activating GLP-1 receptors in the brain, lowering appetite, and reducing the calories consumed leading to weight loss. There appears to be little to no doubt that other pharma companies will be aiming to develop their versions of weight loss drugs in a market anticipated to be worth north of $100 billion by the turn of the decade.
Highly effective weight loss drugs have the ability to rapidly improve the quality
unsurprisingly, lower with the drug costing between £199£299 per month in the UK and €170-€300 in Germany. There has also been an uptake in adolescents using weight-loss drugs, with a Reuters investigation highlighting that only 25 adolescents were prescribed Wegovy in 2022 in the United States, whereas in 2023, there were over 1200 adolescent prescriptions.
Given Novo Nordisk’s $11 billion purchase of three manufacturing sites from Catalent on 5th February, for the purpose of expanding weight loss drug production, we expect weight loss drugs, their efficacy, price, and popularity to remain at the forefront of pharma for the foreseeable future.
ISSN No - 2052-4811
of life those taking the medication can experience. Yet, there is, of course, a financial catch. In the United States, Novo Nordisk’s Wegovy costs roughly $1000 per month whilst prices across Europe are,
On 16th February, the FDA approved the use of a Novartis’ Xolair (omalizumab) injection that can “reduce the risk of harmful allergic reactions” for those with immunoglobulin E-mediated food allergies. Xolair is utilised to treat asthma, nasal polyps and urticaria. Kelly Stone, associate director of the division of pulmonology, allergy, and critical care, FDA centre for drug evaluation and research, said: “While it (Xolair) will not eliminate food allergies or allow patients to consume food allergens freely, its repeated use will help reduce the health impact if accidental exposure occurs.”
Increasing supply chain visibility and sustainability, harnessing and maximising the use of AI and machine learning, preparing for the quantum revolution, and innovating packaging will be key challenges for the industry throughout 2024. Exciting times, right?
The ADVANCE (Accelerating Discovery: Actionable NASH Cirrhosis Endpoints) study will be the most detailed observational study of its kind enrolling the largest number of patients and providing a detailed analysis of liver health, it involves Newcastle University, University of Edinburgh and Boehringer Ingelheim. This will enhance the understanding of NASH cirrhosis and help identify translational biomarkers that will accelerate the development of future therapies.
About 444 million people worldwide are estimated to live with a condition called nonalcoholic or metabolic dysfunction-associated steatohepatitis (NASH/ MASH), an inflammatory
liver disease caused by fat accumulation in the liver. Over time, NASH causes the formation of scar tissue leading in many cases to liver cirrhosis. This can result in serious complications, including liver failure
or liver cancer and may result in the patient needing a liver transplant. Currently there are no approved medicines for cirrhosis and so there is an urgent need for earlier diagnosis and new medicines to
prevent MASH cirrhosis progression to liver failure, or to reverse the scarring of the liver once cirrhosis is established.
Professor Quentin Anstee, Professor of Experimental Hepatology at Newcastle University
On February 1st, 2024, the National Institute for Health Research (NIHR) selected the University of Birmingham to run the National Collaborative for its Research Support Service (RSS).
The RSS provides expert research design, methodological support, advice, and collaboration to researchers in England throughout the pre- and post-application/research process, regardless of geographic location and research interest.
Professor Marian Knight, NIHR Scientific Director for Research Infrastructure, said: “The National Collaborative is
Editorial credit: Marso / Shutterstock.com
critical to the successful delivery of the new Research Support Service, which since October has been providing expert advice and support to researchers across England. By leading the Collaborative, the University of Birmingham will work with the other RSS Hubs to ensure all researchers across England are provided with the tailored support they need and to develop an environment of continuous improvement across the service.”
Neil Thomas, Professor of Epidemiology and
and Consultant Hepatologist at Newcastle Hospitals NHS Foundation Trust who is coordinating the global study explained; “Building on Newcastle’s internationally recognised expertise in translational liver research, this study will reveal the fundamental disease processes driving cirrhosis. We aim to work out why, even at the most advanced stages of liver disease, there is substantial variation in how the disease progresses with some people remaining well for many years whilst others rapidly experience liver failure or develop liver cancer. Working internationally with our collaborators, we will then use this knowledge to improve how patients are diagnosed, and to help develop new medicines.”
Research Methods, Operations Director of the RSS National Collaborative, added: “I am looking forward to leading this exciting collaboration alongside Professor Katie Morris, Director of the Birmingham Clinical Trials Unit, who is our Academic and Clinical Lead. We look forward to working with all eight RSS Hubs and Specialist Centres, the NIHR and the wider research community in developing and delivering health and care research. Our vision of collaboration is wide ranging, and we have ambitious plans to build capacity in our
workforce and public contributors, contribute to the development of inclusive and innovative research methodologies, as well as harmonise systems across our service.”
The new function aims to enable the eight hubs to provide consistency of service across the RSS. It will supply a core team, with dedicated academic, clinical, and operational leadership. Since launch, the service has received more than 840 requests for support from researchers through its eight hubs. The centres in social care and public health have received a combined total of 171 requests for support.
This is the firstin-human trial of the ChAdOx1 NipahB vaccine, being developed by researchers at the University’s of Pandemic Sciences Institute - a research facility with a mission to discover, create and enable practical solutions to infectious disease threats worldwide. Fifty-one people aged 18 to 55 will participate in the trial, which is being led by the Oxford Vaccine Group within the Department for Paediatrics, and funded by the Coalition for Epidemic Preparedness Innovations.
Nipah virus can be fatal in around 75% of cases. Outbreaks have occurred in SouthEast Asia, including Singapore, Malaysia, Bangladesh and India, with a recent outbreak in Kerala, India in September 2023. The disease is carried by fruit
bats and may also be transmitted by contact with infected animals (such as pigs) or from person-to-person via close contact.
Nipah, which is recognised by the World Health Organization as a priority disease requiring urgent research, belongs to the same family of paramyxoviruses as more well-known pathogens like measles. Despite the first outbreaks of Nipah virus occurring 25 years ago in Malaysia and Singapore, there are currently no approved vaccines or treatments.
Professor Brian Angus, the trial’s Principal Investigator and Professor of Infectious
Diseases at the Centre for Clinical Tropical Medicine and Global Health, said: “Nipah virus was first identified in 1998, and yet 25 years on the global health community still has no approved vaccines or treatments for this devastating disease. Due to the high mortality rate and the nature of Nipah virus transmission, the disease is identified as a priority pandemic pathogen. This vaccine trial is an important milestone in identifying a solution that could prevent local outbreaks occurring, while also helping the world prepare for a future global pandemic.”
Despite the rst outbreaks occuring 25 years ago, there are currently no approved vaccines or treatments.
Scientists at the University of Liverpool and Liverpool School of Tropical Medicine (LSTM) have been awarded £1.4 million from the Medical Research Council (MRC) to develop a new drug for the treatment of malaria.
The Liverpool team, which consists of medicinal chemists and parasitologists, will collaborate with an international consortium that includes the Medicine’s for Malaria Venture (MMV, Geneva), Imperial College and the University of Milan to develop the new drug treatment.
The primary target of this drug discovery project is the parasite Plasmodium falciparum, the pathogen that causes malaria. The research team will develop novel drugs that inhibit two key malarial protease enzymes known as Plasmepsins IX and X, both of which are required for several stages of the parasite’s life cycle which include the liver, blood, and mosquito stages of parasite development.
Professor Paul O’Neill, a medicinal chemist at the University of Liverpool, is leading the programme, said: “The Liverpool medicinal chemistry team has already identified molecules with exceptional enzymatic and antimalarial potency (<1 pM) in vitro and have developed medicinal chemistry strategies that will deliver a late lead for progression into an effective oral treatment for malaria.”
The multi-stage inhibitory activity coupled with a unique mechanism of inhibition will result in a lowered propensity for resistance development, making these drugs highly attractive targets for drug development.
Jai: How early will pharmaceutical companies need to start their preparation for the implementation of the EU-HTA regulation (JCA (Joint Clinical Assessment))
Altmann: Companies should begin their JCA-specific internal market access planning at least ten months before the anticipated EMA (European Medicines Agency) regulatory file submission so they have sufficient time to prepare for the JCA-dossier requirements and consolidate a high-quality evidence package. Alignment on internal processes should start after the Phase 2 clinical data is read out, ideally before finalising the Phase 3 clinical trial design.
As part of the planning process, companies should prioritise efforts that drive broader cross-functional understanding of the new processes and JCA-dossier requirements and seek to leverage key insights, early JCA submissions and already concluded Joint Action 3 (JA3) pilot assessments. Deeper understanding will help companies define their strategy and align on a smooth action plan for JCA submissions. For example, companies can work with their market access partners to conduct scenario testing, expert interviews, and consolidation workshops —all of which will help inform their JCA strategy as part of the overall launch strategy.
planning, evidence review and a first draft of the dossier. Strategic planning should involve building cross-functional capacity and capabilities, which are critical to execute the JCA-process and subsequent country HTA processes.
Jai: What lessons have we learned from the pilots?
Jai: How can the companies developing oncology medicines or ATMPs (Advanced Therapy Medicinal Products) leverage Joint Scientific Consultations?
Altmann: As you know, the JCA process will go live and become mandatory for oncology drugs and ATMPs on January 12, 2025. We expect the first JCA dossiers will be submitted by manufacturers (so-called Health Technology Developers (HTD)) around the Sep 2025 timelines. These HTDs now have less than a year to engage with the new regulation and its processes to ensure they are wellpositioned to efficiently manage the requirements on their way to finally launching their products across Europe.
The Joint Scientific Consultations (JSC) serves as a great opportunity, enabling companies to seek scientific advice from national Health Technology Assessment (HTA) bodies and the European Medicines Agency (EMA) before finalising their pivotal clinical trial designs (phase 2 or 3). JSC applications are now coordinated by Germany’s G-BA until the final set-up of the secretariate is decided and implemented. By receiving such valuable scientific advice, companies will be better positioned to develop the best possible evidence package for all future HTA assessments, including pan-EU and individual member states.
Jai: What are some of the key milestones in the preparation of the JCA dossier?
Altmann: I briefly mentioned this earlier, but companies need to be familiar with the JCA and JSC templates, evidence requirements and timelines of the process. The tight JCA procedure timeline in terms of dossier preparation, coupled with lingering questions for local HTA processes, underscores the importance of organisational readiness and early planning.
When aligning their internal timelines, companies should aim to complete – or initiate – several key milestones prior to the start of the JCA procedure: vendor selection, PICO simulation, strategic
Altmann: Many of the key takeaways reaffirm what we anticipated, but we also had significant learnings about the potential impact of the new regulation. While the JCA framework holds the potential to help spur pharmaceutical innovation and reduce barriers that can delay access to therapies approved by the EMA, it is a vast undertaking for all involved stakeholders and presents significant complexities to overcome.
In addition to headquarter organisational readiness, it is more critical than ever for pharmaceutical companies’ local affiliates to engage with national HTA bodies, ensuring a robust collaboration throughout the process. That is particularly important for emerging pharmaceutical companies – which may not have wellestablished local market access teams yet are covering twothirds of the molecules in the global R&D pipeline.
Our market access team continues to work closely with pharmaceutical companies to deliver JSC support and JCA-process preparation and implementation guidance within their broader market access strategy, helping to successfully support the path to market authorisation.
Niall Balfour, Chief Executive Officer at Tower Cold Chain, explores the sustainability implications associated with both single-use, semi-reusable and fully reusable temperaturecontrolled shippers.
Increasing numbers of pharmaceutical companies and their third-party logistics partners are now prioritising sustainability in their manufacturing processes and also in the transportation of their products. As more organisations follow suit the popularity of single-use packaging is on the decline within the industry. In contrast, there is a rising preference for long-term solutions, particularly in the context of creating a more sustainable cold chain that incorporates reusable pharmaceutical containers.
Product packaging serves as the initial impression of a brand’s sustainability for most industry consumers. The decision between reusable and singleuse packaging holds substantial sway over the success of a product. About one-third of UK consumers are willing to invest more in sustainable options, underscoring the pivotal role packaging choices play in enhancing product appeal and market acceptance.
But, for the pharmaceutical industry, the challenge extends beyond a straightforward material switch. As one of the largest contributors to global
pollution, the industry faces a delicate balance between complying with stringent regulations whilst satisfying the preferences of environmentally conscious consumers and their environmental targets.
The foremost priority in pharmaceutical shipments is risk mitigation. Despite the growing demand for ‘greener’ practices, three crucial functions are, and will always remain, essential for shipping pharmaceuticals. These are: (1) a robust container capable of safeguarding its cargo against international freight challenges. (2) Said container needs to be optimised for temperature control to prevent deviations that could compromise cargo effectiveness. (3) The container should provide an optimal packaging-to-payload ratio. With such demand for companies to meet the three pillars of the environmental, social, and governance (ESG) triad, many pharmaceutical organisations are reassessing their packaging processes and taking tangible actions to enhance sustainability. Thus, the choice of container emerges as a pivotal factor in making a meaningful difference to these efforts.
Fundamentally, all containers on the market serve the common purpose of facilitating the palletised and sub-palletised delivery of pharmaceutical shipments, ensuring the safety of products against physical damage and temperature excursions.
However, when assessing containers solely through the lens of sustainability, the question arises: which solutions minimise environmental impact without compromising the container’s essential function?
A clear advantage when it comes to sustainability is the choice of fully reusable containers rather than semireusable or single-use alternatives. This should be a key consideration for any pharmaceutical manufacturer seeking to reduce their carbon footprint.
Whilst single-use or disposable containers can offer a shortterm, initially low-cost solution,
as the world moves to become more environmentally conscious, these are becoming increasingly hard to justify. Unlike reusable pharmaceutical containers, single-use packaging is not designed in the same way for maximum durability and reusability after every use, and often focuses more on convenience and cost. When single-use pharmaceutical containers are disposed of after use, there is still a layer of uncertainty as to where they end up; in some cases, the end-of-life disposal regulations are unfortunately not always adhered to – particularly in developing countries.
Similarly, because semireusable systems often prioritise lightweighting, their designs can compromise on longevity and weatherproofing. Consequently, users must assess the complete cost of ownership associated with semi-reusable containers, considering the unavoidable need for periodic replacement of components due to damage or wear. The necessity for maintenance and part replacements throughout the lifespan of these containers can pose challenges, often requiring trade-offs between cost-effectiveness, performance, and efficiency.
Alternatively, fully reusable containers are a compelling proposition, simply by the fact that they stay in market circulation for a long time.
Engineered with robust components to endure years of transportation, these reusable units contribute to a notable reduction in packaging waste compared to their counterparts, thereby significantly lessening their environmental impact. Furthermore, their durability plays a pivotal role in effectively mitigating potential damage, thereby diminishing downtime and cost implications associated with repairs. This resilience also
serves to safeguard the integrity of the products they contain.
Our view on this is backed up by third parties - notably a study conducted by LCA, which evaluated the advantages of reusable vs single-use shippers. As part of the research, pharmaceutical manufacturer Eli Lilly’s shipment data was evaluated, investigating the environmental impact of a reusable container’s payload volume and performance, in comparison to a single-use container. The study found the company saved $2 million per year by using reusable containers, reduced 424,400 lb (about 192504.44 kg) of waste in the first year, and decreased freight costs by 32%. Such results support the need to assess the total cost of the supply chain. One commonly held myth around reusable containers implies that their sustainability benefits are undone by the emissions from return shipping. This can easily be avoided through greater collaboration between partners, and the optimisation of container flow.
Beyond the decision between reusable and single-use containers, manufacturers face another critical choice: opting for either an active or passive packaging system.
An active container uses mechanical and electric systems powered by an energy source, combined with thermostatic control to maintain proper product temperatures. In comparison, passive packaging systems consist of materials intended to keep the internal contents of the package within a specific temperature range for a defined period of transport without any means of mechanical assistance. Passive packaging systems comprise two main components, which are insulation and coolants.
From the pharmaceutical brand’s viewpoint, we all know the critical issue is reliability and quality, and some understandably take
comfort in having a powered solution. However, with ongoing advancements in passive technology, containers now sustain internal temperatures well beyond the industryrecognised standard of 120 hours. This heightened performance redirects attention to other critical factors. From a sustainability viewpoint, it makes sense to eliminate the reliance on electricity during transit.
And for a global industry where containers may be delayed in remote locations – for example, in areas prone to power cuts – there is a practical benefit to passive systems, too.
Beyond the container itself, it is also important to look at the values of the supplier. Has the provider of temperaturecontrolled containers pledged to become carbon neutral, in line with the requirements of pharmaceutical customers?
Are they taking steps towards using renewable and/or zero emission energy sources? Can they demonstrate measurable progress, independently verified through recognised standards such as EcoVadis, ISO:14001 or have published ESG reports?
It always comes back to the container. The pharmaceutical industry’s rapid shift towards sustainability in temperaturecontrolled solutions marks a significant stride in reducing its environmental impact.
The move from single-use to reusable containers reflects a commitment to minimising waste and carbon footprint.
e move om single use to reusable containers re ects a commitment to minimising waste and carbon footprint.
As pharmaceutical organisations navigate the delicate balance between regulatory compliance and environmental consciousness, embracing reusable, sustainable cold chain solutions emerge as a pivotal step towards a greener and more responsible future.
RACHEL GRIFFITHS, Director, Technical Services and GIGI BAT-ERDENE, Global ESG Program Manager, PCI Pharma Services.
f the global community is to limit, or reduce global warming, phase out fossil fuels and create a sustainable future, it will take commitment, collaboration, and innovation. There needs to be a major change in mindset and ways of working, especially in traditionally competitive markets, such as pharmaceutical manufacturing.
As regulations, guidelines and trends develop at a considerable pace, those life science organisations who survive into the future will need to be ahead of the curve. In this context, investing in environmental social governance (ESG), is a necessity. Working together with sustainability assessors, ESG-focused technology providers or supply chain advisors, as well as logistics and packaging companies and their customers, CDMOs have a key role to play in making pharma logistics and supply chain management more sustainable.
Most of the big pharmaceutical manufacturers have committed to reducing CO2 emissions, lowering their generation of waste and consumption of water and energy. According to CPHI’s 2023 annual survey, 60% of executives forecast that innovators will require CDMOs to implement sustainability metrics as a part of contracts within the next two years. 93% of executives stated that “visibility on supply chain partners’ sustainability record’
is either ‘extremely important’ or ‘important”.
While many of the larger pharmaceutical companies will ask CDMOs to find the most sustainable options, smaller companies and start-ups might not have that goal at the forefront of their minds. It is the responsibility of the CDMO to offer advice and guidance on how to achieve their goals in the most sustainable way possible.
More than 70% of the emissions produced by life sciences and health care companies originate in their supply chains, with
logistics being a significant contributor. But balancing the need to ensure the quality, safety, and regulatory compliance of treatments, with the complexities of how they need to be transported, such as with temperature control, can be a challenge.
Rachel Griffiths comments: “At PCI Pharma Services, the clinical team is tasked with transporting products manufactured in one part of the world to clinical trial sites elsewhere, with little or no control over selecting those locations. So, all the options available must be considered, alongside our logistics partners, in optimising the shipments and reducing airmiles.
For instance, there are occasions when a product that is made in Europe is requested to be shipped to the US for packaging and sent back to Europe for distribution. We strive to avoid this by, for example, packaging in the local region where possible to reduce our carbon footprint.”
LOGISTICS: FROM SINGLE-USE TO REUSABLE SHIPPERS
Shippers are often temperature controlled, requiring them to be broken down and components separated before they can be
As well as switching to reusable shippers, efficiencies can be gained by designing more streamlined and/or recyclable packaging and minimising the amount of empty space in the shippers.
As more cell and genebased therapies are being developed, tested, and commercialised, their requirement for ultra cold chain logistics and the complexity of their manufacture – which makes tech transfer to
PCI Pharma Services Landfill Avoidance Summary 2022-23
recycled. This process often results in high rates of waste and energy consumption. A move to reusable shippers is one way in which CDMOs such as PCI Pharma Services are reducing their environmental impact.
For example, in the last two years, by using reusable shippers developed by Cold Chain Technologies, PCI’s clinical segment sites prevented nearly two million lbs of waste from ending up in landfill.
For every 100 EcoFlex™ shippers being shipped compared with 100 similar sized single use shippers, it saves: 16 trees, 434 litres of oil, 390,423 litres of water and 990 lbs of waste avoidance – hence a major reduction in landfill.
other locations difficult – means that more innovation will be needed, if the vast potential of these treatments for patients is to be realised, sustainably.
For example, innovation in renewable energy for transportation and refrigeration is going to play a key role in the coming years in enabling the pharma industry to reduce its carbon footprint. Dry ice – a solid form of CO2 – is currently essential for shipping materials below -25°C and finding a more sustainable alternative is a major challenge for the industry to overcome.
It is not just because pharma innovators are demanding better sustainability from their partners that innovation and change are apace in the
pharma supply chain. CDMOs have a key role to play in driving forward sustainability best practices within the complex ecosystem of suppliers and stakeholders that are involved in getting drugs to patients. But it’s not just about talking the talk; life science organisations have to also walk the walk.
Assessing and establishing baselines and benchmarks with the help of organisations such as EcoVadis can be a huge undertaking for CDMOs, but are a critical step towards making measurable change, as well as providing third party analysis for procurement departments. Working with the Science-Based Targets Initiative to set targets in line with the Paris Agreement goals is a reputable approach to track near-term and long-term sustainability performance.
Talking about PCI Pharma Services’ ESG activities, Gigi BatErdene explains: “While implementing impactful measures already, such as rolling out the reusable shippers, initiating a sustainable procurement programme, switching to recyclable packaging and renewable energy where possible, at PCI Pharma Services, we are also finalising a comprehensive ESG strategy, the goal of which is for the organisation to become net zero by 2045.
Three years ago, we surveyed our investors, customers, employees, and local communities and asked them what mattered most to them. From this insight and with the changing guidelines, regulations and trends in mind, we established nine impact targets: carbon footprint; energy efficiency; waste management; water conservation; labour and human rights; health and safety; diversity, equity, and inclusion; community impact and sustainable procurement.
Our first ESG report will be published in 2024, outlining our baselines and clear targets and how we plan to achieve them. We now have 60 representatives across regions focused on ESG and C-level involvement in the ESG steering committee. ESG is embedded throughout the organisation, from the bottom up. We are committed to sharing our ideas, progress, and successes, with the goal of helping to make our industry more sustainable, for good.”
As most of the larger pharma companies have their own Scope 3 net zero targets, they are placing greater emphasis on the ESG credentials and commitments of their suppliers and collaborators. In turn, CDMOs need to collaborate with their suppliers and work together to standardise on data gathering and reporting, as well as leveraging modern technologies.
Cooperating like never before, with, for example, power purchase agreements, sharing innovation and best practice will become the norm. The role of CDMOs in this critical journey of transformation should not be underestimated as gatekeepers of the supply chain.
It’s not just about talking the talk; life science organisations have to also walk the walk.
The growth in the development of biopharmaceuticals has impacted the study design required for the assessment of extractables and leachables deriving from polymeric components used for the storage and production of these products.
The nature of these, aqueous based, product formulations has resulted in a shift towards ‘simulated use’ type extraction solvents rather than the exaggerated system used in the assessment of ’traditional’ small molecule drug applications.
There is a range of biopharmaceutical products. The production process for these products is typically based on recombinant DNA technology using living organisms or biological systems.
Single use systems (SUS) are commonly utilised in the production of biopharmaceuticals. The use of primarily plastic components provides a flexible and costeffective platform, reducing the potential for crosscontamination and minimising the need for cleaning and additional validation between production campaigns.
Several standards and guidelines have been developed by various regulatory bodies and specialised industry groups to assess the use of SUS components and ensure that the potential to adversely impact patient safety and / or product efficacy is minimised.
SUS components used in the production of biopharmaceuticals including:
• Tubing and connectors
• Tank liners and mixing bags
• Sensors and valves
• Elastomeric components e.g., O-rings, gaskets
• Process filters, filtration cassettes and preparative chromatography columns
USP <665> Plastic components and systems used to manufacture pharmaceutical drug products and biopharmaceutical drug substances and products The United States Pharmacopeia (USP) have developed general guidance documents which cover the assessment of plastic components for the production, storage, and delivery of drug products.
USP<665> details a risk-based approach which considers the potential contact of each SUS component with the drug during the production process. An initial paper-based assessment is used to determine the degree of chemical testing required, based on the assigned level of risk.
The standard contains limited information concerning extraction procedures (see Table 1) and some basic acceptance criteria for testing, however the analytical methodology for characterisation of the
extractable profile is not included. These procedures are discussed in USP<1665>, which provides additional guidance on the risk assessment approach for the characterisation and qualification of SUS components, but this chapter is
for informational purposes only and is therefore not considered to be mandatory. The responsibility for the justification and qualification of suitable test methods lies with the product owner.
USP <665> has been developed to complement the existing USP<661> monograph which details the procedure
Several standards have been developed by various regulatory bodies to assess the use of SUS components. Table
for the assessment of plastic packaging systems and their materials of construction.
The Biophorum Operations Group (BPOG) is an industry collaboration group which currently comprises over 90 biopharmaceutical
manufacturers and suppliers. The group has several joint initiatives focused on the production of best practice approaches for the development and manufacture of biopharmaceutical drug products.
Established in 2004, BPOG has since published a series of standardised best practice protocols which detail recommendations for performing extractable studies
2
Small
and leachables evaluation for bioprocessing components and storage devices.
The protocols provide suggested methodologies which include; sampling, sample preparation, extraction conditions and reporting requirements, but as per the USP guidelines BPOG also accepts that individual study parameters may be amended providing valid justification is provided.
The protocols also include an extensive list of key considerations for performing extraction studies which are defined by the nature and intended use of the test item under consideration. Extraction conditions are selected based on the actual use of the individual product component –see Table 2
The BPOG protocol specifies key method performance parameters for organic and
inorganic assays, crossreferencing USP, EP, ASTM, and ISO guidelines, but again leaves the justification of final method parameters to the test laboratory.
Despite the implementation of risk-based assessment becoming standard practice for the pharmaceutical industry there is still a significant lack of alignment between the various guidelines used for the assessment of SUS components – see Table 3
The work of the Biophorum clearly shows the benefits of establishing a cross-industry dialogue to create practical and robust protocols for biopharmaceutical applications. Although there was some early reluctance within the E&L community to become involved with the BPOG initiative, the need for separate protocols specifically relating to these products is now accepted and has been widely implemented by the main regulatory bodies.
Following the original BPOG protocol in 2014, end-users reviewed a revised version in 2020 containing updates based on industry feedback. These included the following changes:
• Removal of 5M sodium chloride and 1% polysorbate 80 as extraction solvents due to low unique extraction capability
• Elimination of the time point zero interval as results were not deemed to be significant
• Elimination of elemental analysis of 50% ethanol extracts
The timescale taken to implement the BPOG protocol, assess results and to agree and
e responsibility for the justi cation and quali cation of suitable test methods lies with the product owner.Mike Ludlow
Risk Level USP <665> BPOG
LOW Non-Volatile Residue (NVR) UV
MEDIUM Organic extractables profile
HIGH
Three solvent extractables profile. Elemental analysis (as required)
Meets compendial requirements (USP Class VI, EP, etc)
Low-risk requirements plus: Extractables data evaluation that brackets the intended use available as per BIOPHORUM (BPOG) protocol.
Medium-risk requirements plus: satisfactory extractables data evaluation that brackets the intended use and relevant extractable / leachable profile
issue a revised version illustrates a level of agility that would not be possible with the traditional regulatory guidelines and is vital in an area that is developing as rapidly as biopharmaceuticals.
Although there are still gaps in terms of final testing and validation procedures, the establishment of a consistent approach to extraction studies based on exposure of SUS components to actual use conditions, significantly increases the quality and relevance of data submitted to the regulators. This helps to ensure that the key deliverables for E&L assessment are achieved and any potential safety risks to patients resulting from the use of SUS components are controlled during the production process.
2024is the year in which roughly 49% of the global population will, at some point, be heading to the polls. 64 countries and the European Union are to varying extents preparing for change. The UK is one of the 64, and perhaps more so than many other nation, large-scale change is anticipated.
Since May 2010, The Conservative Party have been the elected choice of the UK population, well, some of the population that is. There was also a forgettable five-year period in which the Conservative Party joined forces with Nick Clegg and the Liberal Democrats in a coalition government that tried its best to put people off the idea of coalitions in the future. Despite this flailing attempt at political satire, there is no hiding the fact that there is an underlying assumption that the Conservatives are on the way out, with Kier Starmer’s Labour Party favourites to ascend into the Executive – although writing the Tories off completely has historically proven itself to be an unwise move.
With that in mind, and with political campaigning well underway (when does it stop?), the Labour Party published their Life Sciences Plan on the 30th of January this year. We at EPM HQ wanted to get the thoughts of some of the voices in world of pharma following the announcement of the Life Sciences Plan:
Prof. Ivan Wall, Head of the Advanced Centre for Advanced Therapies Manufacturing
Training at the University of Birmingham stated: “The life sciences sector plan presents some welcome recommendations but there are not any radical reforms in it. The proposal to allow broader spending of the apprentice levy on alternative training courses
is welcome and will increase access to training provision and upskilling opportunities for employees.
I am cautious of the wording of the proposal to increase support to university spinouts, as this implies non-university start-ups will be disadvantaged by not having a founding team from academia. Incentivisation should be more inclusive and not restricted to academic spinouts, and this will create greater diversity amongst entrepreneurs and build a more thriving innovation ecosystem. The definition of life sciences would benefit from broadening beyond just health”.
Anji Miller, Skills Lead, Innovation Hubs for Gene Therapies explained: “Advanced Therapies hold true promise of revolutionising how many conditions are treated, with many holding the promise of a cure. This promise can only be fulfilled with continuous support
and investment to ensure the UK has the required infrastructure, capabilities, and workforce to deliver. It is encouraging to hear Labour’s commitment to turbocharging investment in R&D in the UK. Through our investment and support in the Innovation Hubs for Gene Therapies we hope to make life science life changing, and we will continue to work with this government and the next to deliver on that ambition.”
Richard Torbett, the ABPI’s Chief Executive said: “This strategy reflects the extensive and thoughtful engagement with stakeholders that the Labour party has undertaken. With its focus on the long term, practical measures to boost investment in research, and the emphasis on quality data to underpin future strategy, this plan will help our industry to deliver the innovative treatments NHS patients need and deserve and help the UK to better compete on the global stage.”
Jamie Holyer, Senior Adviser, Healthcare, Rud Pedersen UK: “What then perhaps is of more significance, and no doubt the plan behind the plan, is that the Strategy is a further demonstration of Labour’s readiness for Government. It was not that long ago that the Labour Party was publishing plans around the compulsory licensing of pharmaceuticals.
However, the point of the life sciences industry is to treat serious unmet medical need with innovation in healthcare systems. This is where both Labour and Conservative plans fall short: without a comprehensive refinancing of the NHS, patient access to innovation in the UK is increasingly coming at either the expense of industry, with significant pressure on pricing, or patient communities, subject to ever extending waiting lists.
Without a comprehensive re nancing of the NHS, patient access to innovation in the UK is increasingly coming at the expense of industry.
Jai: “Successful implementation of jet milling requires a robust Quality by Design (QbD) approach that ensures the critical quality attributes of the micronised particles are maintained throughout the process development”. What is the QbD approach that Lonza utilise?
Salvatore Mercuri, Head of New Product Introduction & MSAT: The best approach is to acquire as much information as possible during the development phase to reduce the risk associated with the subsequent scale-up and validation phase. Interaction with the customer is crucial during the initial phase, as they own most of the information related to the solid state and stability of the API (if they are an API manufacturer) or the final CQAs (Critical Quality Attributes) for the formulation phase (if they are responsible for the drug product).
This is the third and last in a series of interviews with a collection of subject matter experts (SMEs) operating throughout Lonza. We have, over the last six months, covered a range of topics that the company covers, and heard from some of the foremost experts in the world of pharma - this final collection of questions and answers is no di erent.
Author: Jai McIntoshWith this preliminary information, an appropriate DoE methodology is applied to define the correlation between the CPPs (predefined considering the risk assessment and preliminary micronisation runs) and the CQAs and to define an initial PAR (Proven Acceptable Range). After this preliminary phase, some post-DoE analyses, such as Monte Carlo simulation, are conducted to predict how known variabilities encountered during the scale-up phase may affect the PAR.
All the data generated so far will be used to update the risk assessment and to define the scale-up and design space (DS)
verification strategy; at least three experimental points are used. At this stage, at least one engineering batch is used to assess process reliability (intensive sampling) and interbatch variability if multiple batches are used. Finally, process validation is performed (PAR is verified) and continuous monitoring and improvement are carried out using the appropriate control charts and PQR.
This approach will ensure that by controlling the CPPs the process will be stable, predictable, and capable.
Jai: Insolubility is, as Lonza has repeatedly stated, a large issue. What approaches do Lonza use to address challenges of insolubility?
Corey Bloom, Lead Principal Investigator: There are several
formulation technologies that can be used to address poor solubility. The most appropriate approach depends on the specifics of the molecule, the dose, and the target product profile. Examples include salt or cocrystal formation, amorphous dispersions prepared using spray drying or hot melt extrusion, and micronisation by jet milling, among others.
Jai: Can you detail the process and benefits of spray-dried dispersion technologies and how this technology can impact solubility?
Hannah Worrest, Group Lead, Bioavailability Enhancement Engineering: The process of spray drying is in common usage and involves solubilising an API along with a polymer in an organic solvent, disrupting the API’s crystalline structure. By rapidly drying the solution via spray drying, the API can be trapped in a stable, higherenergy amorphous form that is more soluble than the crystalline form. The enhanced bioavailability that results can be the difference between success and failure for a new drug product.
Here at Lonza in Bend, we have implemented further improvements to the spraydrying process and associated technology. One example is our use of novel solvents, including acetic acid and ammonia, to enhance the solubility of APIs
in various solvent systems. This increase in organic solubility creates the opportunity to evaluate bioavailability enhancement for brick dust compounds, opening the market to more potential treatments.
We have also developed internal modelling tools to optimise the process and increase throughput. These include thermodynamic and particle size modelling, which helps us design a right-first-time, high-throughput process. In conjunction with our chemistry analysis, these models allow us to balance the risks posed by physical and chemical stability in spray dried dispersions with creating an optimised process.
The models reduce the amount of process optimisation and scale-up activities required, with the need for additional experimentation often eliminated as risks will have been modelled and understood beforehand. Importantly, this means less material is required for the work.
Finally, enhancing solubility and optimising manufacturing processes are a significant contributor to the overall sustainability of the process.
Designing an optimised, highthroughput process decreases our operating times and requirements for processing aids and, with greater drug solubility, less solvent will be required. For those solvents that we do use, we have been working hard to expand our
capabilities for solvent capture and recycling.
Jai: Can you describe what brick dust compounds are and their utility?
Michael Morgen, Head of Advanced Drug Delivery Technologies: In the pharmaceutical industry, ‘brick dust’ refers to APIs that have poor solubility in water, and in many common processing solvents. This typically results from the compounds having very high melting points, as is often the case for planar molecules that stack well. These types of API structures are particularly common for oncology drugs developed in the past 10-15 years, but they are also seen in other therapeutic areas. The strong crystal forces in these compounds make it difficult to dissolve such compounds in many solvents, and this is a particular challenge for drug development. Solubilisation is necessary for oral absorption, and often also for effective parenteral delivery, and innovative approaches are often required to improve solubility if they are to be formulated as effective drug products.
Jai: There appears to be a larger fraction of orally administered small molecules that have poor oral absorption due to low aqueous solubility. How do Lonza approach a
problem such as this and what solutions have been presented?
Corey Bloom, Lead Principal Investigator: A paper evaluation of the specific problem statement is an important first step, along with measuring important parameters including solubility in biorelevant aqueous media, plus biomodelling simulations to guide formulation selection.
Selection of the preferred solid form of API is important. In some cases, a salt form with increased solubility and acceptable stability can be identified. Salt forms can also be used in tandem with concentration enhancing polymers or other excipients in the dosage form to provide improved bioavailability.
At specific dose-to-solubility ratios, a small fraction of low solubility molecules can achieve acceptable oral bioavailability by increasing the dissolution rate relative to bulk crystalline API. Micronisation or wet bead milling of bulk crystalline API can be employed, and the resulting micro- or nanocrystals can be incorporated into standard tablet or capsule formulations.
Many low solubility compounds at higher doseto-solubility ratios require increased solubility relative to the most stable crystalline form. Amorphous solid dispersions (ASDs) are a common and very effective approach to deliver these compounds. Spray dried dispersions (SDDs) can employ a wide range of performance enhancing polymers and are widely applicable. In addition, depending on the molecular properties, these molecules can also be delivered using hot melt extrusion (HME) technology. Both ASDs can be incorporated into tablets or capsules for oral solid dosage forms.
Bormioli Pharma, a global leader in pharmaceutical packaging and medical devices, set its footprint at Pharmapack Paris in January, and presented its wide, fullservice product range, with a growing quota of low-impact, industrial solutions, together with an innovative and robust consultancy approach, confirming its position as a reliable, forward-looking and valuable partner for the pharma industry.
This distinct dichotomy is discernible in the designed layout of the booths, wherein the showcase of the products was integrated with a dedicated consultancy area where the Group’s experts
could interact with interested visitors and establish the groundwork for potential future co-developments, fostering collaborative endeavours and advancing the industry’s collective pursuit of cuttingedge solutions.
Bormioli Pharma, a solid innovation mobiliser partnering with the pharma industry
Delving further into specifics, Bormioli Pharma has recently introduced a state-of-the-art consultancy approach, stemming from a transformative journey that has occurred over the years under the purpose of making the vision of future care more effective. This has materialised
into the establishment of an innovation platform, named Invents, positioning the company into an innovation mobiliser able to partner with the pharmaceutical industry to transform emerging healthcare trends and needs into concrete’s industrial solutions.
The platform derives substantial advantages from a well-grounded ecosystem of partners, encompassing strategic collaborations with Innovation Hubs and accelerators. This network allows the Group to stay on the edge of innovation, using a crowdsourcing approach to multiply and accelerate its development efforts. Customer’s needs and rigorous
lab verification are crucial variables before the transition of prototypes into large-scale production. This process includes the application of a scrum development approach, which guarantees the implementation of each new product’s cycle in an iterative and incremental way, ensuring product’s effectiveness and faster time to market.
With this new platform, Bormioli Pharma confirms its role as a forerunner of innovation in the pharmaceutical packaging world, making drug administration simpler, easier, and more accessible for everyone, including the elderly and people with disabilities.
The new Bormioli Pharma’s consultancy approach, aimed at materialising the vision of future care, has been implemented with the Invents innovation platform and will play an ever growing, pivotal role thanks to its manufacturing know-how combined with the ability to match emerging healthcare trends in terms of usability, connectivity and traceability transforming them into solutions ready to be industrialised.
Three prototypes have been shown at Pharmapack 2024 to make Bormioli Pharma’s commitment on these emerging trends concrete: for example, MediClicker highlighted the growing importance of connectivity, incorporating IoT functionalities to display additional information and an enhanced level of service in terms of therapy adherence; Trax took traceability to the next level through a laser marking technique that prevents product counterfeiting, also offering different layers of information for consumer and industrial scanning systems, while meeting the latest regulatory production tracking requirements. Finally, Andy showed an unprecedented level of service in terms of usability, combining a dosage system and a closure, crafting the ultimate accessible oral liquid medications’ dispenser.
Enabling sustainability with already available, new industrial solutions
At Pharmapack 2024, the Company also has remarked its standing as a sustainability enabler, presenting the latest EcoPositive solutions, with over 50% of the products in Bormioli Pharma range that is manufactured with materials characterised by lower environmental impact. During the fair, a spotlight has been shed on Advanced
rPET bottles, showcasing sophisticated solutions featuring a collaboration with Loop Industries, a clean technology company specialised in the production of 100% recycled virgin quality Loop PET resin. These bottles, produced through a depolymerisation process, which achieves a “virgin quality” polymer, also feature the absence of migrating compounds. Another important introduction was Bio PET 2.0, a bio-based plastic (propylene glycol extract) crafted from wood collected in responsibly managed certified forests, emphasising material renewability in all product’s phases.
Besides these new, groundbreaking achievements in terms of safety, Bormioli Pharma has also presented additional research in terms of extractables, confirming once again, its role as a data-based, scientific player able to partner all pharmaceutical companies throughout the entire packaging value chain, from the materials’ choice to the design and the product’s implementation in the industrial lines.
To pinpoint, Bormioli Pharma rHDPE solutions show a 28% reduction in migrating compounds compared to conventional solutions, while rPET solutions, derived from mechanical recycling, show levels of extractables 150 times below the worst-case risk index, as well as a 37.2% reduction in environmental impact.
Full-service primary packaging range to address every industry’s need
At Pharmapack Paris 2024
Bormioli Pharma showcased its full-service primary packaging range, arranged in three distinct portfolios focusing on the needs of specific segments:
high-value prescription drugs (forTherapy), daily medications and OTCs (forHealth), and nutraceuticals and food supplements (forLife).
This wide array of plastic and glass options are designed to be fully matchable to each other, allowing customers to configure complete packaging, leveraging on the convenience of a single supplier, and building process efficiency.
High-quality containers and vials, including Type I moulded and tubing glass, along with diverse aluminium and rubber closures and accessories, together with the new recycled PP cap for tear-off closure, are part of Bormioli Pharma’s forTherapy Portfolio. In the same portfolio, the Group enhances its offer with Readyto-sterilise and Ready-touse options, which shorten operational timelines while guaranteeing consistency in the sterilisation process, ensuring compliance with industry regulations. ForHealth portfolio provides a spectrum of solutions for daily medications and OTC
drug, encompassing a range from primary packaging to accessories and closures, featuring barrier additives that enhance product safety and efficacy, while positively impacting the environmental sustainability of the process.
Simultaneously, ForLife portfolio answers to nowadays demand for nutraceuticals and supplements with its innovative dual chamber systems which enhance the shelf life of active ingredients with active layers. At Pharmapack, two new developments of this range had been presented. The first was tethered tamper-evident cap, built on the trajectory in the food and beverage sector following European Directive 2019/904. The second one was a monodose Green PE cap, reflecting Bormioli Pharma’s commitment to expand its EcoPositive catalogue.
The Group offers a holistic goto-market platform, fostering collaborations with key value chain partners, to accelerate product launches and increase efficiency.
Until recently, even within the biopharma sphere, most people have not thought about blood in the context of therapeutic interventions. However, recent technological advances have forced a rethink about the therapeutic role blood plays well beyond transfusion.
This new focus has largely been spurred by the progress of cell and gene therapies (CGTs), which are underpinned by blood products derived from donors and patients themselves. Efficient development and manufacture of these medicines typically relies on automated apheresis devices, significantly reducing the time it takes to perform a cell collection and easing the burden on both patients and donors, while maintaining quality.
Blood is now part of complex supply chains that support both development of therapeutics and their commercial deployment, with components often genetically modified to confer diseasemodifying attributes. In addition, for a growing list of indications, automated apheresis technology – the same platforms used to collect material for modification – is being deployed to help patients manage their symptoms as they wait for curative therapies to become available.
The progress in CGTs is often measured in continued regulatory successes, which reflect a growing list of intractable illnesses that have recently become tractable. These include late-stage blood cancers, treated with autologous chimeric antigen receptor (CAR)-T cell therapies made from patients’ own mononucleated or T cells collected via apheresis. Some patients who had failed every
other treatment experienced a curative turnabout following CAR-T treatment.
The most recent CGT buzz surrounds two new therapies for sickle cell disease (SCD), bluebird bio’s Lyfgenia and Vertex/CRISPR Therapeutics’ Casgevy (also approved for β-thalassemia). The former will be bluebird’s third marketed gene therapy, while the latter became the first FDAapproved, CRISPR-based gene-editing therapy. And both therapies – as well as bluebird’s Skysona to treat cerebral adrenoleukodystrophy and Zynteglo for β-thalassemia – are made by modifying CD34+ hematopoietic stem cells that have been derived from patients’ own blood via apheresis.
In fact, apheresis is used to collect CD34+ cells for at least five approved therapies and two in late-stage clinical trials (see table).
As a result, optimising
apheresis protocols has become a crucial part of clinical development for cell-based therapies. Much like the other stages of CGT manufacturing, standardisation is the goal in order to reduce
Dalip Sethi, Ph.D., Commercial Leader, Cell Therapy Technologies and Joy Duemke, Director of Marketing, North America, at Terumo Blood and Cell Technologies.
time required, complexity, and cost. Developers therefore rely increasingly on automated apheresis platforms, given their speed, consistency and ability to generate data that can be used iteratively to improve the process.
In a recent example of such efforts, a team led by John Manis, M.D. from Boston Children’s Hospital and Harvard Medical School shared data last year demonstrating how data gleaned from an automated apheresis system could be leveraged to improve collection. Dr. Manis’ team performed a retrospective analysis of collection procedures for patients with SCD, performed on automated Spectra Optia systems.
Sickled red blood cells can change blood viscosity, leading to unique challenges like clumping that can make it more difficult to separate blood components. This can make it harder to collect the high yields of patient CD34+ cells needed to make an autologous
Drug Company Indication Stage Description
Casgevy (exagamglogene autotemcel)
Vertex/CRISPR Therapeutics
Lyfgenia (lovotibeglogene autotemcel) bluebird bio
Libmeldy (OTL200) Orchard Therapeutics
Skysona (elivaldogene autotemcel) bluebird bio
Sickle cell disease (SCD), β-thalassemia
Metachromatic leukodystrophy (MLD)
Cerebral adrenoleukodystrophy
Zynteglo (betibeglogene autotemcel) bluebird bio β-thalassemia
MDR-101
Medeor Therapeutics
Kidney transplant rejection
Approved by US FDA and European Commision (EC)
Approved by US FDA
Approved by EC In review by US FDA
Approved by US FDA and EC
Approved by US FDA and EC
Phase 3
OTL-203 Orchard Therapeutics
Mucopolysaccharidosis type I (MPS-I) Phase 3
gene therapy dose, sometimes extending the collection process over several days. But the team analysed apheresis data to identify opportunities for optimisation. By implementing new methods from these suggestions, the group saw CD34+ collection efficiency
Autologous, genetically modified CD34+ cells
Autologous, genetically modified CD34+ cells
Autologous, genetically modified CD34+ cells
Autologous, genetically modified CD34+ cells
Autologous, genetically modified CD34+ cells
Allogeneic, unmodified CD34+ hematopoietic stem cells and CD3+ T-cells
Allogeneic, genetically modified CD34+ cells
increase from 4.9% to 36.8% –more cells in less time.
In addition, apheresis is now the most common method of CD34+ collection for hematopoietic stem cell transplantation, less invasive than bone marrow harvest and generating higher yields. Over 20,000 such transplants are performed each year in the U.S. for a variety of cancers and immune-related diseases. This includes both autologous procedures (where a patient’s own cells are apheresed and then later used to help reconstitute their immune system) and allogeneic transplants from a matched donor.
Beyond fueling the development and production of cells for advanced therapies, apheresis itself is also used as a therapy. Therapeutic apheresis procedures can
remove or exchange specific cell types, antibodies, red blood cells and other harmful components. As is the case for patients with SCD, this includes replacing sickled cells with those from healthy matched donor cells. Often, apheresis is done in conjunction with an infusion of donated material, such as therapeutic plasma exchange (TPE) or automated red blood cell exchange (RBCX).
Groups such as the American Society of Hematology (ASH) recommend RBCX over simple transfusion in certain circumstances. Patients with SCD, for example, may regularly be treated with transfusions that can improve an excruciating pain episode. However, too many infusions may cause a dangerous condition called iron overload. By contrast, in automated RBCX, the sickled red blood cells are rapidly removed and replaced with health donor cells. The procedure can also be optimised in order to utilise the ideal amount of blood for each patient.
Therapeutic apheresis is also used for hundreds of other indications through management of blood components, everything from neurological conditions to cardiac diseases. It has typically been performed in large medical centers, limiting its utility to those located nearby or others willing to travel for treatment of an acute crisis. However, recent regulatory changes and government investments are expected to make the procedure more broadly available, and offered closer to home. By improving access, it may be possible to leverage apheresis in some instances as a maintenance therapy, reducing the patient burden and systemic costs connected to acute care.
Antibody-based therapeutics are a powerful modality developed for a range of diseases, including cancer, autoimmune disorders, and infections with over 170 antibodies in regulatory review or approved currently. An inherent high target specificity and affinity, often associated with fewer adverse events, and potential for modification and refinement through genetic engineering has aided in the recent clinical success of antibody drugs.
However, antibody therapeutic development remains a complex process. Close observation of drug safety and efficacy through pharmacokinetic (PK) assessment is critical to progressing candidates from discovery to clinical trials. At the same time, regulatory agencies now require patient immune response to the drug
John Cardone, Marketing Manager, Custom Antibodies, Bio-Rad Laboratories.
to be monitored throughout this process. An immune response resulting in the generation of anti-drug antibodies (ADAs), which bind the drug and neutralise its activity or accelerate its biological removal, can cause adverse events, impacting drug safety, and could cause a loss in efficacy.
To determine the best antibody candidates for preclinical and clinical progression, highly specific and sensitive assays that inform on a drug’s safety and efficacy, as well as the potential to trigger an immune response, are essential.
The development of robust PK and ADA assays comes with several challenges, especially for human or humanised therapeutic monoclonal antibodies. When administered to the patient, the concentration levels of human or humanised antibody drugs can be a million times lower than the human serum antibody concentration, making the drug difficult to detect and quantify. PK assays, used to measure free and/or target-bound drug levels in patient serum samples, therefore rely on highly specific and sensitive detection reagents that bind the drug and no other similar antibodies.
Likewise, an appropriate surrogate positive control or reference standard is used to accurately assess anti-drug immune response in an ADA. In the clinical stage of development, these assays should use multiple antibody controls with varying affinities and/
or immunoglobulin subclasses to offer a more accurate representation of a patient’s natural immune response. Reflecting on ADA assay sensitivity, which is defined as the lowest concentration at which the antibody concentration consistently produces either a positive result or is equal to a pre-determined readout, the U.S FDA recommends that such assays achieve a sensitivity of at least 100 ng/ml . This level of sensitivity should be sufficient to enable detection of ADA’s before they reach hazardous levels associated with altered pharmacodynamic, PK, safety, or efficacy profiles.
Anti-idiotypic antibodies are recognised as optimal detection reagents in PK assays and as surrogate positive controls or reference standards in ADA assays. However, traditional sources
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0.3mL - 1mL* 0.5mL - 2.0mL* Auto-adjust plunger technology 2.25mL 1mL Auto-adjust plunger technologyfor anti-idiotypic antibodies, including rodent monoclonal anti-idiotypic antibodies and primate polyclonal serum, bring several challenges. For example, rare specificities for drug-target complex specific antibodies would be extremely challenging to identify through immunisation. Moreover, affinities of IgG antibodies generated through immunisations are difficult to determine given their bivalent format (i.e., each Ig monomer contains two antigen-binding sites); monovalent formats (e.g., monovalent Fabs) are the ideal antibody format to define intrinsic affinity given each Fab monomer contains one antigen binding site.
Alongside ethical considerations for the use of laboratory animals, successful immunisation is not guaranteed with primate polyclonal serum. Although human sera obtained from early clinical trials does present an alternative, obtaining material consistently and in the quality and quantity needed is difficult, and continual assay validation is required throughout the clinical development stage.
THE SOLUTION:
Recombinant Monoclonal
Anti-Idiotypic Antibodies
Sophisticated antibody libraries, specifically created by de novo synthesis to represent the structural diversity of the human antibody repertoire and optimised for expression in E. coli, combined with phage display technology have paved the way for recombinant monoclonal antiidiotypic antibodies. These antibodies are well-established in the development of human therapeutics and alleviate some of the familiar challenges in antibody production. Generated using fully in vitro processes, recombinant anti-idiotypic antibodies offer greater
predictability, flexibility, and opportunity for optimisation, and guarantee a long-term supply of sequence-defined, fully human antibodies, without the use of animal-derived components or laboratory animals.
By implementing different screening strategies, phage display technology enables the generation of anti-idiotypic antibodies with varying binding modes specific to different forms of the antibody drug (i.e., free, target-bound), and with varying affinities. Selection carried out in the presence of isotype subclass-matched antibodies leads to the creation of paratope specific (i.e. antigen binding site-specific) anti-idiotypic antibodies (i.e., Type 1). These antibodies are inhibitory as they do not allow the drug to bind its target and can be used to measure free drug as well as positive controls in ADA assays. Alternative selection strategies can produce a non-inhibitory anti-idiotypic antibody specific to an idiotope outside the drug’s antigen binding site (i.e., Type 2), which can be used to detect total drug – free, partially bound, and fully bound. Finally, guided selection can be used to create antibodies capable of detecting rare specificities, such as drug-target complex binders (i.e., Type 3). By using a drug-target bound antibody as bait throughout phage display, whilst the library is alternatingly blocked using individual components of the complex, antibodies that recognise a feature unique to the drug-target complex can be isolated.
Armed with a complete toolbox of Type 1, Type 2, and Type 3 anti-idiotypic antibodies, PK and ADA assay developers have greater flexibility and, for PK assessment, a more complete analysis of the availability and state of the antibody candidate. For example, combining Type 2 or Type 3 anti-idiotypic antibodies with an antigen capture ELISA provides a solution to detecting monovalent antibodies or Fab fragments in serum, such as ranibizumab, which cannot be detected using Type 1 anti-idiotypic antibodies in an ELISA bridging format due to the drug only have one binding domain.
Similarly, quantitating levels of intact natalizumab has been challenging. Natalizumab, a humanised IgG4 monoclonal antibody drug used to treat multiple sclerosis and Crohn’s disease, undergoes halfantibody exchange in vivo with other antibodies of the same isotype, resulting in molecules comprising one drug heavy-light pair coupled to one heavylight chain pair of unknown specificity. Using recombinant anti-idiotypic antibodies instead of the antigen to capture antibody drug, two ELISAs have been designed to successfully assess natalizumab levels in vivo, one ELISA measuring total antibody drug (i.e., intact and exchanged molecules) and the other measuring intact antibody drug only. Validation studies confirmed that the PK assays were specific, accurate, and precise.
Phage display technology also allows a panel of antiidiotypic antibodies with high, medium, and low affinity to the target drug to be selected, representing the variation in human immune responses to a drug, critical to ADA assay development.
Robust drug safety, efficacy, and immunogenicity assessment are essential to therapeutic antibody development. Recombinant antiidiotypic antibodies, generated in vitro through sophisticated antibody libraries and phage display technology, provide a reproducible, long-term supply of the sensitive and highly specific detection reagents and controls needed for PK and ADA assays, respectively. These anti-idiotypic antibodies are an innovative solution for faster assay optimisation and more effective resource and cost management during preclinical and clinical stages, avoiding continual assay validation.
