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A FOCUS ON SUSTAINABILITY IN PHARMA
PATIENT CENTRICITY & DRUG DEVELOPMENT
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November/December 2021
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Contents
November/December 2021 | Volume 21 Issue 6 REGULARS 5: EDITOR’S DESK
Why industry may be able to look to pharma to lead the way in sustainable practices.
6: A SMALL DOSE
A brief round-up of some of the latest developments in the industry.
10: OPINION
The role patient intelligence plays in drug development.
13: IN THE NEWS
A short selection of stories from the world of science.
14: COVER STORY
The future of Covid-19 vaccinations and why testing is crucial amidst falling antibody levels.
34: TALKING POINTS
Stories to consider and what to look out for in EPM over the coming weeks.
FEATURES 8: PERSPECTIVE ON PHARMA
Why the pharma sector is lagging behind other industries when it comes to removing plastics from its processes.
16: OSD SUPPLEMENT
The latest advancements in oral solid doses and opinions from global manufacturing experts.
21: BIOPHARMA
Discussing developments in biologics processing.
24: SUSTAINABILITY
A focus on what pharma is doing to become more eco-friendly.
30: CELL & GENE THERAPY
The journey cell & gene therapies need to take to become more accessible.
32: ASEPTIC PROCESSING
Risk mitigation in aseptic production with a view to future developments.
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13 14 34
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he end of 2021 saw sustainability be placed on the global stage. With COP26 featuring a gathering of world leaders, scientists and industry discussing the very real and ongoing threat of climate change, the call was made to what can be done to reduce our impact on the planet. In some respects, the pharmaceutical industry answered this call. The Association of the British Pharmaceutical Industry (ABPI) and other organisations issued a joint statement on the work the biopharma
industry is doing to minimise its impact on the environment. In another major show of force, 10 of the world’s largest pharmaceutical companies signed up to a new programme intended to increase access to renewable energy and help decarbonise the industry’s value chain. These commitments were made during a global event which positioned climate change as possibly the biggest threat to humankind. Cynics might say announcements made during COP26 are simply well-timed PR stunts but in many ways
EDITOR’S DESK the pharma industry’s efforts are encouraging. A report by EcoAct of companies across the DOW 30, Euro Stoxx 50 and the FTSE 100 highlighted that the pharma industry does particularly well when it comes to reporting on emissions. For instance, this year saw all biopharmaceutical companies in the report detail their Scope 1 and 2 emissions,
with 63% disclosing their Scope 3 footprints. More so, ranked within the top 20 performing companies for sustainability were GSK, AstraZeneca, and Sanofi, setting a strong precedent for other pharma companies to follow. That some of the world’s largest pharmaceutical companies can commit to change – especially given their globalised supply chains – should be welcomed by other industries as an example of what is possible. Of course, we know that the pharma industry is an emission-intensive sector and is even believed to have a larger carbon footprint than that of the automotive industry. That changes are happening is welcome, but the key now is to continue to hold companies to account over their sustainability targets. With Covid-19 generating a lot of goodwill towards the life sciences industry, pharma now has the chance to step forward and show the world how emissions across global supply chains can be reduced. The global nature of pharma’s supply chains puts the industry at threat of overlooking resource intensive areas. Outsourced manufacturing, which can take place in countries where regulations surrounding sustainable practices may not have been developed, means pharma has a choice to make of where it does business. That and many other choices will be crucial if climate catastrophe is to be avoided. We know that the health of the planet and its population are interlinked. To ignore climate change is to ignore the lives of billions.
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A small dose
Fujifilm expands centre of excellence in California
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ell culture solutions provider Fujufilm Irvine Scientific has expanded its Armstrong R&D Centre of Excellence at its headquarters in California. The expansion marks the company’s commitment to advancing discovery research, bioproduction, cell and gene therapy, assisted reproductive technologies and cytogenetics in its Life Sciences and Medical Media divisions. “With society’s increasing demand for global access to more high-quality, cost-effective vaccines, biopharmaceuticals, cell-based therapies, gene therapies, and in-vitro fertilization procedures, the need for a broadened focus on innovation is pivotal to expedite critical product and technology development. The expansion project will more than double the R&D facility’s footprint and will allow for more enhanced technical
collaboration between R&D experts and customers to develop personalised solutions and enhance partnership opportunities.” said Bob Newman, chief scientific officer, Fujifilm Irvine Scientific. The expansion comes after Fujifilm has invested in new manufacturing capabilities throughout Europe. The expansion to the company’s Armstrong R&D Centre of Excellence will be essential to the success of new programmes and initiatives FUJIFILM Irvine Scientific offers, the company states. The expanded footprint will include dedicated space for analytical chemistry, virology, Assisted Reproductive Technology (ART), and additional cell culture and molecular-based assay development, increasing employment opportunities and projecting a doubling of growth in R&D headcount by the close of 2022, Fujifilm expects.
Chiesi expands inhaler recycling scheme
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hiesi has expanded a postal scheme designed to help people recycle inhalers that are out-of-date, empty or unwanted. Chiesi launched the Leicestershire Take AIR (Action for Inhaler Recycling) scheme in February this year. The scheme was designed so people could dispose of and recycle their empty, unwanted, or outof-date inhalers through the post, enabling patients with respiratory illnesses to play their part in helping to reduce the impact of inhalers on the environment.
Now, following its success, Chiesi is expanding the scheme across Leicestershire’s hospitals so that patients can receive a pre-paid, pre-addressed envelope from designated parts of the hospitals. The company is also creating a toolkit, so that other areas of the UK can use the lessons learned by Chiesi and partners in the scheme to help implement similar schemes in their local areas. In the UK, around 73 million inhalers are used every year with many of these ending up in landfills. Inhalers comprise
several components, including plastic casings, aluminium canisters, and propellant gases which are known greenhouse gases. Through the Take AIR scheme, many of the components are recovered and recycled and non-recyclable materials are destroyed through a process called energy-from-waste. Around two-thirds (63%) of all pharmacies across the Leicester, Leicestershire, and Rutland (LLR) area are participating in the scheme. To date, there have been nearly 7,000 envelopes issued to
ARRANTA BIO COMPLETES SALE OF FLORIDA MANUFACTURING SITE
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ontract development and manufacturing organisation (CDMO) Arranta Bio has sold its process development and GMP clinical manufacturing site in Gainesville, Florida to oncology-focused company Inceptor Bio.
The deal will also see the transfer of client programmes and key technical employees to Arranta’s Watertown, MA facility. “We are delighted that Inceptor Bio will build on the foundation that we established in Gainesville and wish them every success in
developing life-saving cell therapy products,” said Mark Bamforth, executive chair and CEO at Arranta, “and we are thrilled to continue to build and expand Arranta’s commercialready manufacturing team in Massachusetts, the global hub for biosciences.”
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sustainably dispose of them. We wanted to develop an easy and effective way for inhalers to be recycled, and we owe our thanks to so many pharmacies and patients doing their bit for the environment and helping to make Take AIR such a success.”
The deal means that Arranta’s Watertown facility now has a team of over 160 employees focused on supporting microbiome clients, establishing messenger RNA vaccine capabilities, and manufacturing critical starting materials. “With over 200,000 ft of facilities in Watertown and Boxborough and over $150 million committed to building state-of-the-art facilities, Arranta has the capacity to respond to client needs for complex biopharmaceutical products that will change the lives of patients,” said David Stevens, president and COO at Arranta.
At the company’s Watertown facility, Arranta is progressing the establishment of end-to-end mRNA capabilities and expects to begin laboratory-scale operations in January and to have starting materials, mRNA, lipid nanoparticle formulation, and a robotic sterile fill line installed by the end of Q2 2022. Arranta recently received permitting approval to progress the first build-out phase of laboratory and GMP capacity establishment at a second commercialready site in Boxborough, MA, which will be completed by mid-2022.
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PERSPECTIVE ON PHARMA:
I
t remains common practice amongst pharmaceutical manufacturers that singleuse plastics are being used extensively in the manufacture of their products, and it is common knowledge that this practice is not sustainable. Why then, is the industry struggling to address the problem? Why is it that an industry that does so much to heal the people on our planet does so little to heal the planet itself? The answer lies partially in the way the industry is regulated. Incredible care is taken to ensure that all manufacturers adhere to current Good Manufacturing Practices (GMP). These are laid out in regulations and guidelines that cover much more than manufacturing. The spectrum of topics from clinical practices (used in drug development) and laboratory (used in quality control testing) are all covered. Adhering to these practices assures the patient that the product they are taking is safe and effective. This is a good thing; this is why these regulators exist. However, Gary Connors, partner at Oliver Wight looks at why the pharmaceutical sector is lagging behind other sectors in removing plastic from their products and processes.
Cleaner but not Greener
some of the practices prescribed in the regulations and guidance are contrary to what you might consider Good Sustainability Practices. There
is little guidance on this from the regulators. Consequently, it is common, even required, for each
package of a pharmaceutical raw material, intermediate, or finished good to be packaged in two single-use plastic liners and secured with two single-
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use plastic ties. Less common, but equally damaging to the environment, is the use of plastic to line the insides of some equipment to avoid the costly cleaning operation that results before the next product is manufactured. The reason is that it is much easier to throw away the liner, put in a new one and get started straight away. It is hard to argue against the need for these regulations when the fact is they protect patients at the end of the supply chain taking these drugs. Unfortunately, it is also hard
to live with the environmental impact that it is having. The industry can and needs to do better. They have risen to sustainability challenges before. Going back 30 years the use of Chlorofluorocarbons (CFCs) in the manufacturing process was commonplace, Chloroform and Dichloromethane being chief amongst these. The industry led a global movement to eradicate these chemicals from their manufacturing processes and reversed the depletion of the ozone layer in our
atmosphere. If they did this, surely it is now time to address the plastic problem in the industry. It is time for the industry to face this challenge, while single-use plastics make the manufacturing process cleaner, it does not make it greener. The prevalence of plastic is easily observed in the packaging of products in many other sectors. This allows consumers to exercise their preferences by adjusting their choices in favour of more environmentally friendly packaging. The pharmaceutical sector is less influenced by the consumers buying power in this regard. Add to this the fact that the use of plastics in the pharmaceutical sector is hidden in the process and not the packaging. Consumer awareness will catch up with what is happening beyond the appearance of product packaging, and they will start to exercise their choices to influence the manufacturing practices too. Integrating these assumptions into the decision-making forums in the business, having meaningful discussions about the future scenarios, bringing sustainability metrics onto the executive scorecard, and allowing them to impact executive bonuses seems to be the least that they can do. These recommendations make for good advice but are also the right thing to do. It took 30 years to eradicate CFCs from the manufacturing process. The planet does not have the time nor the patience to wait that long to address the plastics problem. The time to act is now.
The prevalence of plastic is easily observed in the packaging of products in many other sectors. Sustainability choices for the industry need to be taken at each step in the integrated business planning process. ● The
portfolio management step should be looking for ways to eradicate single-use plastics from the products by design.
● The
demand management step should be looking to understand consumer sentiment and adjust marketing decisions as a result. They should also be seeking to commercialise their environmental credentials.
● The
supply chain step should be finding ways of optimising the planning and scheduling processes to minimise the use of single-use plastics but ultimately to remove them completely.
● The
executive team should embrace the introduction of sustainability metrics onto their scorecard and incentivise the executive team to do the right thing.
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Opinion
Patients are now much more likely to use digital channels and platforms to vocalise their experiences of taking medicines.
PLACING PATIENTS AT THE FOREFRONT OF MARKETING IN DRUG DEVELOPMENT Author: JO HALLIDAY - CEO and founder of Talking Medicines.
The role that patient intelligence will play in the future of pharmaceutical marketing.
O
ver the past decade, digital transformation has risen up the boardroom agenda, as management teams grapple with both the challenges and opportunities which true digitalisation can bring. From leisure and hospitality to manufacturing and processing, digital transformation functions are now commonplace in businesses large and small as they seek to gain a competitive advantage and secure a sustainable future. Yet, despite its relative wealth of resources, the pharmaceutical industry continues to follow in the footsteps of others when it comes to adopting and utilising new technology. This slower pace of digital adoption is particularly true of marketing functions. Through no fault of their own, and for all the right reasons, heavy and prominent regulatory barriers have meant that pharmaceutical companies have traditionally struggled to gather reliable feedback on medicines directly from patients. This lack of direct user feedback has hampered patient-centric decision making in the development and marketing of medicines. However, the proliferation of social and online media has changed the game in many respects. Patients are now much more likely to use digital channels
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OPINION
and platforms to vocalise their experiences of taking medicines, whether positive or negative. By listening to, and learning from, these experiences, pharma is now much better placed to identify what matters to patients and ultimately provide them with a better product. Commonly termed as ‘social intelligence’, the information gathered from online sources is about much more than hashtags, shares and mentions. Used effectively, it can provide relevant and timely “patient intelligence” on patient confidence at a medicine level within a competitive set, and drive decision-making for more effective marketing spend. BETTER SOCIAL INTELLIGENCE IS KEY TO HELPING PHARMA UNDERSTAND THE PATIENT VOICE. The feedback that pharmaceutical companies can obtain about their products once launched to market is traditionally very limited. Conventional methods rely on focus groups or feedback from clinicians to try and understand patient experience. However, the small size of these groups and limitations in the scope of questions can now be addressed through technologies that enable compliant data collection from patients at a far greater scale on a systematic, and real-time basis Until recently the use of social intelligence within pharma has been limited. However, changes are occurring at an increasingly rapid rate, and have been further accelerated by the Covid-19 pandemic. There is growing recognition that AI, when combined with social intelligence, can be leveraged by pharma to not only listen to how patients are experiencing their medicines in a real-world setting, but also to make sense of this data. Putting patients at the heart of the process and giving them a voice not only benefits the patient, but can also impact the commercial, marketing and drug development process. Using a combination of machine learning and natural language processing, social listening can provide pharma marketing teams with empowering metrics that measure patient confidence in medicines, helping them to make data-based decisions on how and where they allocate financial resources. Since customers express their thoughts and feelings more openly online than ever before, social intelligence is becoming an essential tool to monitor and understand exactly how customers across a range of industries are reacting to a particular product or brand. Automatically analysing customer feedback, such as opinions in survey responses and social media
conversations, allows brands to learn what makes customers happy or frustrated, so that they can tailor products and services to meet their customers’ needs. The same can be said for patients when it comes to understanding their feelings towards medicines. Now more than ever, these conversations are happening online, so there is an opportunity for pharmaceutical brands to take notice and adopt a more patient centric model of marketing. Curating data from social listening over a prolonged period enables businesses to identify barriers patients are facing to access and use their medicines. This data is critical to ensure effective marketing spend and ultimately drive business decisions for better patient experience. Data can also be used to educate healthcare professionals about how people are using specific medication and for allowing patientsupport programmes to ensure that they are designed effectively. For example, Talking Medicines’ AI platform, PatientMetRx, analyses data derived from social media sites and forums where real people discuss their experiences with diseases and medicines. In the new era of social intelligence this is more precise and actionable using AI and mathematical models to filter to the voice of the patient by medicine viewed as realtime patient confidence scores. Curating data with AI precision provides brand owners with a 360 degree understanding of patient confidence in their medicines. Of course, given the highly regulated environment in which pharma operates, it is important that all data capture is fully compliant. The brand insights which social intelligence can provide are driving pharmaceutical companies to listen closer to what patients have to say. With greater recognition of the benefits of social listening, we expect more and more pharma marketing leaders to utilise the technology at their disposal more effectively. This technology, of course, will continue to evolve and innovate. For example, development of seamless communication in both directions with patients and bringing in more molecular and genomic data will further enhance the level of insights that can be provided. In addition, with more investment and research, it will be possible to move from the realm of reaction into predicting opportunities. If pharma wants to benefit from these opportunities, it must start to embrace this technology now. Only by exploring the boundaries of what’s possible through social intelligence technology will brands truly understand their customers and realise their mission of becoming patient centric.
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IN THE NEWS
ABPI sets out recommendations for UK medicines policy The UK needs to develop medicines regulation for emerging technologies so that the country is seen as a globally attractive place for the life sciences sector, according to a new report from the Association of the British Pharmaceutical Industry (ABPI). The report considers factors such as the global pandemic, the UK’s exit from the EU and a renewed domestic policy agenda – things which present both challenges and opportunities for the nation’s life sciences regulatory policy strategy. It sets out a number of recommendations for how to boost global investment into UK life sciences and make the UK a go-to destination for innovations coming through the pipeline. The report points to significant opportunities in areas such as innovation passports, Advanced Therapy Medicinal Products and digitisation of regulatory approvals, where the UK can potentially work faster than its international counterparts. However, the authors warn that UK regulatory agencies risk undermining the future attractiveness of the
nation if they diverge too far from established medicine rules. The report states that the UK should look at co-operating with key trading partners as part of its trade agenda to ensure the position of the MHRA as a gold-standard regulator. In particular, the UK should work with countries including the
United States, Canada, Australia, Singapore and Switzerland to build a coalition of forward-thinking future regulatory leaders and be at the table for setting the rules about the next generation of breakthroughs. Colette Goldrick, executive director, Strategy and Partnerships for the
Association, said: "As the government begins to set out what Britain being a science superpower outside of the EU means, this is the perfect time to look at the important policies which attract companies to launch their products here in the UK. "There are opportunities and pitfalls: we have seen
Did you know?
The UK pharmaceutical sector employs roughly 63,000 people.
By 2023, it’s expected the UK’s pharmaceutical sector will be valued at £25 billion.
Two of the world's top 15 pharma businesses operate in the UK – GSK & AstraZeneca.
what friction does to global supply chains and the same principle applies to regulation. Diverging from global medicines standards for the sake of it would be destructive and undermine the attractiveness of the UK. "That’s why we want ministers to instead look at areas where we can do things faster and set the agenda for new types of medicines and vaccines, so that NHS patients can be some of the first in the world to benefit." Key recommendations from the report include developing an internationally competitive regulatory framework so NHS patients can access new breakthroughs. This can be achieved by expanding ‘Innovation Passports’ for medicines that show promise during pre-clinical research; securing adequate and stable funding for the MHRA; and winning the race for regulatory expertise for new types of treatments. Another recommendation is to make sure that the MHRA remains an active and strategic member of international forums that set global medicines policy.
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COVER STORY
HERE TO STAY TBC
The future of Covid-19 vaccination and why testing is crucial amidst falling antibody levels. TBC
A
mid all the ongoing media chatter about vaccine passports and booster jabs, a little read article in Nature recently carried the most important news about the future of the Covid trajectory. While societies across the world continue steadily on a path towards pre-pandemic normality, and lockdown now seems like a distant memory, the science magazine reported that immunity to the virus is declining. Despite the self-congratulatory tone of politicians about the success of the vaccine rollout, people immunised against Covid are losing half of their defensive antibodies every 108 days or so. As a result, those who received their first jab six
months ago – offering, at best, 90% protection against mild infection – now have only around 70% immunity. As it was also reported that uptake of booster shots among the UK population is proving sluggish, should we be concerned about a resurgence of cases and even the spectre of further lockdowns in the future? As far as anyone can tell, we’ll be living with Covid for some time to come, with all signs pointing to it becoming endemic, similar to the cold, flu, or measles. So, if the virus is going to be around forever what will it look like, what impact will it have on our lives and what, if anything, is being done to prepare for that future?
The good news is that, to date, existing vaccines have proved effective in dealing with variants of the SARS-CoV-2 strain first detected in Wuhan, China in December 2019. But that may not always be the case and the three main players in the field – Pfizer, Moderna and AstraZeneca – have spent the past few months wargaming for future strains that may be resistant to current vaccines. By practising on known variants such as Beta and Delta, and learning from dress-rehearsal trials, scientists have been able to fine-tune their processes, so that they can hit the ground running if and when a genuine ‘escape variant’ emerges. Pfizer’s chief executive, Albert Bourla, boldly predicted that
should the need arise, the company could produce a new, clinically tested vaccine within 100 days. If experience of the pandemic has taught us anything, it’s that testing is as important as the rollout of vaccines and the quicker our future ability to test large groups of people, the better it will be for the normal functioning of the economy, education, and travel. Central to the normal functioning of society will be to continue allowing groups to meet in numbers, in offices and classrooms up to larger gatherings at music concerts and sports events. The Technology Partnership, another Cambridge-based diagnostics company, has developed a pioneering
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cartridge and the pupils drop in a chew swab. The samples can be processed as a whole and, if there is any viral RNA present, it can be collected and amplified within 30 minutes. “If something is detected in a classroom cohort, you can then proceed to do individual testing or a smaller cohort to identify which pupil or pupils are Covid positive.” Yet in many areas of our future lives, particularly travel, what will be as important as our testing negative, will be our level of immunity, according to Brendan Farrell, CEO of Guilford-based Luas Diagnostics.
method of significantly speeding-up the screening of large groups of people, using a simple saliva test. It believes the technology will be particularly useful in helping to keep schools and offices safe and open by identifying asymptomatic, Covid positive pupils early. Consultant Giles Sanders said: “We know from our own experience that we can collect the majority of viral RNA from large volume samples – up to 50ml. We can work with up to 50 samples of saliva typically 0.5-1ml per person, using commercial chewing swabs, which are dropped into a cartridge. “In schools there would be a point every day when the teacher comes round with a
The World Health Organisation has produced a safe standard of immunity which could soon be adopted by countries as a requirement of entry, according to Farrell. His company is the distributor of a US-manufactured test to determine a person’s level of Covid antibodies, post infection or vaccination. He said: “That’s going to become increasingly important with vaccination roll out. Those people who have had their vaccination completed are merrily going around feeling warm and fuzzy, but the reality is that up to 15% of people vaccinated will not be protected because they didn’t produce antibodies. “And to take that further, people who have produced antibodies, those antibodies can decline quite quickly.” More concerning is his contention, supported by data from the REACT-2 Study
Author: IVOR CAMPBELL - managing director of Snedden Campbell
of Antibody Prevalence in England, published by the University of Cambridge, that the AstraZeneca vaccine, used most widely in the UK, is less effective at producing antibodies, than either the Moderna or the Pfizer vaccines. Farrell said: “Regretfully for the United Kingdom, the AstraZeneca is certainly less effective than the other vaccines. There’s no doubt about that. “It’s definitely not as effective at all, so Boris and his fellow politicians were flying a very strong flag that they had done a great job in rolling out the vaccine programme, which they did, but their dependence on AstraZeneca is problematic because it definitely does
not produce antibodies in the way the Moderna and Pfizer vaccines do.” He added: “The future for those people and, I don’t know if this will cause political controversy, is to get a booster shot, but not with AstraZeneca. “It’s a British product and so there was a bit of flag flying nationalism, and that’s understandable, but the public discussion about the efficacy of vaccinations is only just beginning. “The whole focus until now, and continues to be, let’s get everybody vaccinated. The next stage is going to be, ‘whoops, we’ve got everybody vaccinated but, do they have antibodies and are they protected?.”
If experience of the pandemic has taught us anything, it’s that testing is as important as the rollout of vaccines.
ORAL SOLID DOSAGE
A look at oral thin films and how they’re becoming a growing solution for patient-centric dosing.
Thinking about the patient
C
hildren and geriatric populations can present unique challenges when it comes to utilising traditional oral drug delivery formats, such as tablets and capsules. These include choking risks, the possibility of dosing inaccuracies due to spitting out the drug and limited dosage size options. In addition, there’s portions of the population who have difficulty with swallowing medications or simply don’t have access to clean water, necessary for dosing. While cutting and grinding tablets may seem like a viable option for overcoming swallowing challenges, doing so can often result in an altered release profile for the drug and poor taste. It can also cause unintended exposure to the active pharmaceutical ingredient (API). Oral thin films (OTF) – a novel drug delivery system consisting of quick-dissolving films placed in the patient’s mouth – may be the answer. They provide a patient-centric alternative for populations that have difficulty swallowing, as well as for patients that may be unconscious, uncooperative or in urgent need of medication. The adaptable design of
Author: SHAWN BRANNING - Global Strategic Marketing Manager at IFF
OTFs allows them to deliver synthetic and natural APIs, as well as nutrients, in an easily consumed format that’s convenient and appealing. GAINING POPULARITY IN THE PHARMACEUTICAL SPACE Currently, OTFs can be used to treat myriad conditions for patients, from allergies to migraines and pain relief to preventative therapies and dietary supplements. The flexibility of the dosage form means there’s plenty of room for future uses like vaccines and biologics. In fact, according to Roots Analysis Market Research, the overall oral thin film drug delivery market is expected to grow to approximately $2.1 billion by 2025.
stability, organoleptic properties like taste, physical strength, drug uniformity and more.
Each type of OTF is designed specifically to solve various patient challenges.
It’s vital to choose the right excipient package to formulate effective but pleasant dosages to ensure patient compliance.
In general, we can break down OTFs into three categories based on drug release timing: 1. Fast Dissolving Orodispersible: Placed directly on the patient’s tongue, these OTFs have a high rate of release, dissolving in one to 30 seconds. Given the speedy dissolution and ease of placement, this format is considered excellent for children and the elderly, as well as those in need of fast medication delivery.
FLEXIBLE DOSING FOR ALL PATIENTS There’s no one size-fits-all approach when it comes to patient needs. OTFs provide options for targeted treatment, ranging from single layer to multi-layer films capable of a variety of structures for specific API and treatment needs.
Understanding the structure and formulation of OTFs is critical for manufacturers looking to break into the market. While the OTF dosage form is highly adaptable, there are challenges to creating an effective and appealing endproduct, including
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2. Buccal Films: The buccal film’s placement is inside of a patient’s mouth on the cheek. With this type of OTF, patients experience a fast onset of action with a moderate to slow dissolution of one to 30 minutes. Benefits of the buccal film include no firstpass effect and a delayed/ reduced Cmax. 3. Sublingual Films: Considered the most prolonged release of the OTF formats, sublingual films take 30 minutes or longer to fully dissolve. The under-the-tongue placement enables a fast onset of action, while also preventing a first-pass effect. With such specific release profiles, it’s critical for formulators to understand the composition of oral thin films to achieve positive outcomes. Each ingredient plays a vital role in delivering the drug to patients, while also contributing to a positive experience overall. UNDERSTANDING KEY PLAYERS IN ORAL THIN FILM COMPOSITION Like other traditional oral drugs, the efficacy of OTFs lies in the careful selection and composition of ingredients. Typical OTF components consist of the API, hydrophilic film forming polymer, plasticizer, stabilizer, pH modifier, buffer, colour, flavour, fillers and taste masking agents. Of those ingredients, the polymer is the backbone for the formation and structure of the physical film. Two of the most common polymers used in OTFs are polyethylene oxide (PEO) and hydroxypropyl methyl
cellulose (HPMC). Our POLYOX technology is an example of a film forming PEO polymer. It forms flexible films that are resistant to tearing, have a fast dissolution rate, a pleasant mouthfeel and no sticky feeling or highly viscous gel formation. Additionally, METHOCEL is our HPMC technology that can be used as a film former in OTFs to create flexible, transparent, flavourless, colourless, tasteless, and water-soluble thin films.
It’s vital to choose the right excipient package to formulate effective but pleasant dosages to ensure patient compliance. OVERCOMING TASTERELATED FORMULATION CHALLENGES Patient compliance is largely tied to the overall drug experience, with taste being a key organoleptic property for this drug format since they dissolve in the mouth of the patient. Understanding taste and how to appropriately mask taste in thin films can be especially challenging for formulators because the addition of taste masking agents can reduce the potential maximum drug load of the OTF. Fortunately, there are several avenues for formulators to explore when it comes to improving taste in OTFs.
Anionic polymers are another class of materials providing unique benefits in OTFs. Sodium carboxymethyl cellulose (NaCMC) polymers provide excellent clarity in films and can be easily plasticized using materials such as glycerol and sorbitol. Alternatively, seaweed-based biopolymers, like alginates and carrageenan, are another polymer material option that deliver solubility properties, while also being a plant-based, vegan-friendly option for formulators.
Taste modulation through flavouring is one of the simplest ways to make an OTF palatable. With our deep background and understanding of flavours, we’ve developed an effective approach to help select the best flavour for a formulation based on market understanding, demographic analysis, product base flavour and the type of product. However, flavours can’t always overpower the unpleasant taste of other ingredients. Various products such as receptor blocking agents, cooling agents and sweeteners can also be successful at masking tastes.
Although polymer selection is crucial to the success of the physical film structure and stability, it’s important to consider the patient. Polymers play a role in developing the OTF’s organoleptic properties, which is why it’s important to choose the right ones for your specific formulation needs. However, sometimes there’s no avoiding additional ingredients to ensure a pleasant drug experience. The challenge here becomes optimising ingredient selection to avoid having to add too many components to the formulation.
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Employing taste masking technologies is also effective. One option is utilising a barrier coating to block unpleasant tastes. Reverse enteric and water insoluble polymers such as our ETHOCEL technology are efficacious barrier coatings. Other options include microencapsulation, solid dispersion, and inclusion and complexation. Regardless of the formulation route you take for taste, the best way to ensure success is partnering with an experienced supplier. PARTNERING FOR ORAL THIN FILM FORMULATION SUCCESS OTFs continue to evolve in the pharmaceutical space, expanding beyond over-thecounter products to a drug delivery format suitable to treat a variety of conditions. And, as personalised drug treatment becomes the norm, oral films will play an even more substantial part in drug delivery. However, OTFs are an emerging dosage form and there’s little compendial guidance for drug developers. That’s why it’s essential to have a partner that can help navigate the complexities of various quality standards and get your product to the market safely and quickly.
ORAL SOLID DOSAGE
Expert Opinion EPM speaks to leading players within pharmaceutical development to explore the complexities and innovations occurring within the oral solid dosage (OSD) market.
Q: What MR techniques are trending with innovators relative to the OSD programmes currently running in your facilities?
techniques, what aspects of your offering are overcoming developer (customer) dose form and delivery challenges most?
BORA: Enteric-coated active beads is a modified release (MR) technology proving effective at managing active pharmaceutical ingredient (API) release and bioavailability - it also supports managing solubility and dosing in formulations. Enteric coating is a proven technique and because formulated beads exhibit a slow drug release rate at acidic pH, followed by a controlled drug release at neutral pH. For most oral solid dose drug formulations MR systems fall into one of three basic categories: Matrix; Reservoir (or membrane controlled), or Osmotic systems.
LONZA CAPSULES AND HEALTH INGREDIENTS: The capsule - it’s hard to understate the utility and versatility capsules are providing to pharma’s developers right now. Relative to patient centricity, oral administration routes have become a development priority. For most patients, the form is preferred, partly because it is so familiar and partly because capsules are perceived as easy to swallow. Capsules provide the perfect primary container and make drugs more accessible and affordable to patients around the world.
Teams at Bora's facilities have many years of experience developing and manufacturing finished drug products using matrix and reservoir processes for investigative new drug (IND) and new molecular entity (NME) formulations for example. Q: Given operational capabilities and considering specialised
Although ancient in application, capsules stand ready to deliver the future’s most innovative and sophisticated formulations, using advanced capsule materials and sealing technologies to help developers reach myriad dosing and bioavailability goals. Capsules present fewer formulation and manufacturing barriers than other oral solid dose technologies and introduce a range of economies that support
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efficient drug development and manufacture. Q: What technologies or manufacturing techniques are serving complex MR formulation, manufacturing optimisation and marketing strategies today? RECIPHARM: Coated pellets are hugely versatile, as release characteristics can be varied by both the thickness of the coating and the excipients as the functionalised polymer used in the coating, and by mixing different types of pellets. It is also very easy to adjust the dose by altering the number of pellets in a capsule. Different drug substances can also be combined into fixed-dose combinations (FDCs) with minimal risk for incompatibilities and wider scope for individual drug release profiles. FDCs are advantageous to a patient population for whom treatment with a particular combination of APIs in a fixed ratio of doses has been shown to be safe and effective. They also improve patient compliance and enhance self-administration as fewer doses are required each
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It’s hard to understate the utility and versatility capsules are providing to pharma’s developers right now.” day. Manufacturers can combine several types of pellets and demonstrate their stability in a final dosage form after developing the MR formulation and obtaining regulatory approval of each API pellet separately. This leads to advantages such as lower manufacturing costs compared to the costs of producing separate products and administering them concurrently. It can also reduce the amount of packaging and simplify the logistics of distribution. Matrix tablets may be less versatile than pellets but, in most instances, they are able to provide the desired release profile. The manufacturing process for these tablets is less complex than for pellets. Additionally, larger quantities of the drug substance can be administered per dose, resulting in lower manufacturing costs overall. Q: What approaches to MR formulation and processing are yielding best results for programme economies and efficiencies? What best practices are accelerating programmes to market? METRICS CONTRACT SERVICES: Targeted use, and sometimes the combination, of enteric coated, delayed release and extendedrelease dosage forms tend to yield the best results.
a. Enteric coated tablets or capsules prevent release of drug substance (DS) in the stomach to either overcome gastric irritation caused by DS or to protect the DS due to instability in gastric conditions. b. Delayed release formulations in the form of multiparticulate, minitablets release the DS at specific gastrointestinal site for targeted delivery. c. Sustained or extended-release dosage forms as matrix tablets, polymer coated multiparticulate compressed in tablets or in capsules, and polymer coated minitablets in capsules extend the release of the DS such that the drug is dosed either once or twice daily. Employing Quality by Design (QbD) principles during MR product development often accelerates programmes to market. An essential first step is to define the Target Product Profile (TPP) for the MR dosage form. The TPP leads to defining Critical Process Parameters (CPP) and Critical Quality Attributes (CQA). In addition, risk assessment should be conducted on each unit operations to ensure that medium and high-risk formulation and process variables are identified and acceptable ranges for the variables are established and included in the control strategy. BORA: The matrix system is considered the gold standard. It has been widely utilised to provide extended delivery of drug substances because of its effectiveness and capability of accommodating both low-
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and high-loading of APIs while exhibiting a wide range of useful physical and chemical properties. From a product development point of view, it is one of the more cost-effective and easier to scaleup and manufacturing techniques. Additionally, this type of system is also suitable for in-house development since it is usually manufactured using conventional processes and equipment. Q: Finished dose form manufacturing is extremely manufacturing and process technology focused. What technologies and innovations are optimising manufacturing economies and quality? LONZA CAPSULES AND HEALTH INGREDIENTS: In any commercial setting, large or small, successfully filling formulations and manufacturing finished encapsulated doses requires a relatively high level of manufacturing and operational sophistication. Certainly filling capsules at commercial volumes is well understood, but pharma’s developers and manufacturers are increasingly looking to us, and our products and systems for new ways to assure product quality and manufacturing productivity. One area of particular note is the filling of lipid formulations into capsules. Not only is this an increasingly popular tactic to deliver formerly parenteral formulations orally, but an assured way to deliver all kinds of semisolid or liquid small and large compounds.
ORAL SOLID DOSAGE
Q: What therapeutic area (oncology, CNS, etc.,) are most of your MR-centred OSD programmes coming from? BORA: At Bora we’re applying MR techniques to optimise a variety of advanced therapeutics. One is a central nervous system product designed to treat Parkinson's disease that we worked with the sponsor on timing and programming release profiles to create an optimal therapeutic plasma concentration for better symptomatic control over time and with fewer doses. Through an integrated approach to MR formulation development and particle processing, we were able to improve the drug’s therapeutic performance and patient compliance.
hypertension, is also expected to boost the market growth. The rising geriatric and paediatric population globally is one of the major factors driving market growth, largely due to the nonadherence to the medication regimen as it is very common among these age groups. Thus, the demand for controlled release drug delivery systems is expected to witness growth with the steeply rising patient population.
METRICS: At Metrics most of our MR based OSD programmes are in the oncology space. These molecules require a combination of either enteric, sustained or delayed release with the objective of extending the release profile and/or delivery at the intended site of absorption. RECIPHARM: As part of a highly competitive and fragmented market, pharmaceutical companies are proactive with the changing requirements and are continuously investing in developing controlled release drug delivery systems. Rising R&D expenditure by pharmaceutical companies developing therapies for chronic and non-communicable diseases, such as cancer, diabetes, and
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BIOPHARMA
Discussing the developments in biologics processing. of vectors upon expansion. Despite this, the technologies and strategies required to address these challenges continue to improve rapidly. Suspension platforms are preferred wherever viable as they allow for substantially more cells to be grown to increase yield. Organisations are increasingly looking to outsource this to partners with the required niche expertise as adaptation to new mediums can be tricky.
Quick questions with Pratima Cherukuri, chief scientific officer at Genezen. Bioprocessing at commercial scale is becoming industrial in scope. Given your offerings and capabilities, what protein/gene expression or chemistry platforms are offering developers and sponsors better yields, efficiencies, and programme success? Producer cell lines offer an attractive alternative to transient transfection when it comes to larger-scale manufacturing. They reduce or eliminate the need for plasmid transfection, which decreases process complexity and the risk of batch-to-batch variation or human error. Producer cell lines also use less expensive raw materials and labour as compared with transient transfection, resulting in lower associated costs. However, using producer cell lines for viral vector production can be a challenge as some of the gene products required for vector generation are toxic to cells, and cell lines do not necessarily continue to produce a high titer
What aspects of biopharmaceutical technical transfer and scale-up are proving challenging? What sets a biotechnical transfer apart from a small molecule drug? Unlike small-molecule drugs, biologics and cell and gene therapies (CGTs) are inherently variable. They are also much larger in size and structurally more complex as they are living entities. The inherent variability of CGT products makes them impractical to replicate. Their heterogeneity is influenced both by biological processes inside the cells that are used to express them and by the manufacturing process used to produce them. The complexity of CGT products can best be described by the properties that define them. These include their physical (size, structure), chemical (charges and ability to bond/clump), and biological properties (activities, interactions). These properties are known as quality attributes. Each product, including retroviruses and adeno-associated viruses, can differ in its attributes. A subset of these quality attributes will have a direct impact on the efficacy and safety of the product, and these are known as
critical quality attributes (CQAs). In process, these attributes need to be identified and analysed to ensure biological activity is maintained. Continuous, and continuous flow manufacturing is being promoted to improve the quality outcomes of drug manufacturing and processing. Are you introducing any of these principles into your cGMP manufacturing environment? Genezen continuously explores ways to further improve quality outcomes. Our equipment and processes allow for closed and semi-automated manufacturing of viral vectors wherever this is technologically possible. We are also investing in research and development to ensure that innovation is continued, and we can fully realise the potential of any CGT product that we support. There is an adage in biopharma that says: “The process is the product.” Does this still hold true? CGT products are highly complex molecules produced in live cells through a multistep manufacturing process. The key characteristics of these molecules (CQAs) can vary based on the cellular environment or during the process of manufacturing. If changes to CQAs occur during the manufacturing process, even small modifications can alter the critical characteristics of the CGT product. These changes can go on to impact clinical effectiveness and safety. Therefore, yes, the process defines the product. As a result, CGT processes need to be built, innovated, and evolved continuously to consistently make the highest quality products.
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GARY BUTLER Vice President and General Manager of Commercial Operations for Europe at PCI Pharma Services
Outsourcing Biologics: Key Considerations OUTSOURCING BIOLOGICS: KEY CONSIDERATIONS
Biologics are a more complex class of pharmaceuticals to manufacture, package, store and distribute than their chemical counterparts. Often with strict thermal requirements for the drug substance and drug product, specialist expertise is required to move the product through clinical phases to commercial launch and beyond. Outsourcing of any aspect of the supply chain means that pharmaceutical companies and their chosen vendors need to work in true and complete partnership, with clear communication and navigating the complex
process together to ultimately ensure speed to market. Gary Butler, Vice President and General Manager of Commercial Operations for Europe at PCI Pharma Services, explains some of the key considerations when partnering with a CDMO for the supply of biologic medicines. HOW DO BIOLOGICS DIFFER FROM OTHER DOSAGE FORMS IN TERMS OF COMPLEXITY?
There are many aspects of biologics that result in a more complex supply chain than oral dosage forms. For example, thermal stability requirements mean that
cold- and ultra-cold chain storage conditions are a necessity, particularly for live vaccines. Drug products stored in frozen conditions and packaged at refrigerated or ambient conditions require close monitoring. Rigorous control of “time out of refrigeration” (TOR) is required and should form part of a validated process. Other drug products may be significantly less stable than some of the older and more established biologics. Such products may be manufactured as lyophilized powders, requiring reconstitution by the end user; this may cause
challenges if the end user is a patient rather than a healthcare professional. That said, there is a drive to use more patient-centric devices such as prefilled syringes and auto injectors, although this does impact cost and complexity due to the unique nature of the final product. When you consider the many factors involved in the supply of biologics, it’s no surprise that logistical operations are affected as a consequence. For example, biologics require additional packaging precautions such as absorbent pads in the event of vial breakage or damage in transit. Also, during early
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phase clinical trials safety data may be limited, meaning that obtaining declarations and permits for transportation can pose challenges to the supply chain. Fortunately, PCI’s extensive expertise in pharmaceutical supply chain solutions is something we pride ourselves on, and positions us as a strong CDMO partner. HOW HAS THE COVID-19 PANDEMIC AFFECTED THE MANUFACTURE AND SUPPLY OF BIOLOGICS?
Unsurprisingly, the pandemic has created many challenges within the pharmaceutical industry. Accelerated vaccine programs have consumed a lot of capacity in both drug discovery organizations and their CDMO partners, a situation which has been compounded by the increased demand for raw materials, consumables and analytical materials. PCI, as a global CDMO, had to react quickly. We changed our standard business model to secure the supply of raw materials and store inventory on behalf of clients. If the pandemic has taught us anything, it’s that every business in the supply chain is essential, irrespective of where they sit.
Temperature-controlled shipping boxes are also in short supply, resulting in longer lead times and therefore longer-term, proactive procurement strategies. This shortage is due to multiple factors, not least of which being the increased demand in line with the general growth in the biologics market. Many patients also now receive medications directly, resulting
in shipping container manufacturers themselves experiencing their own supply chain challenges. The pandemic also impacted the frequency of commercial flights, meaning that PCI began using standard courier cargo flights to move products on behalf of our clients. WHAT STRATEGIES CAN BE EMPLOYED TO MITIGATE RISK AND DELAYS DURING THE DRUG DEVELOPMENT AND COMMERCIALIZATION JOURNEY?
The early evaluation of stability data can be advantageous, however many companies don’t generate this type of data early on; in some cases it may not have been considered, or deemed too costly at the early stages. By initiating stability studies early on, it can save time and money later on and mitigate issues that may arise during shipment, such as stability, freeze/thaw and temperature range excursions. Testing with multiple excipients can also reduce uncertainty and risk during the product life cycle. The pandemic has taught us to find more efficient ways of working, expediting timelines and reducing bureaucracy, meaning lifesaving medicines are more accessible to patients. SO HOW CAN YOU ENSURE A SUCCESSFUL COLLABORATION WHEN OUTSOURCING THE PACKAGING OF BIOLOGICS?
In our experience there are three main aspects to a successful partnership between the sponsor company and their vendors.
Working with one partner for the life cycle of the product is one such aspect, ensuring an understanding of the product and maintaining the knowledge and experience needed. Moving between CDMOs is not a straightforward task and so working together to deliver an end-to-end solution and navigate challenges along the way leads to success. The process by which a third party is chosen and the assessment criteria is also critical. This should not only take into account the CDMO’s technical capabilities, but also some of the more subjective factors such as how the company communicates, how they approach a problem, their proactivity and the emphasis placed on building a true partnership, whereby the vendor becomes a
seamless extension of the sponsor team. The team at PCI, from Project Managers through to line operators, are all highly experienced and trained to be an extension of the client team, offering the best partnership possible. The third aspect, and one that PCI feels is crucial to long-term success, is to continually educate employees about the nature of the actual drug product itself. This drives care and ownership to a different level; rather than employees feeling they are simply filling a vial, employees truly understand the impact of what they are doing in human terms, i.e. improving or even saving lives. We’re in no doubt that this promotes a feeling of really making a difference and taking pride in what we do.
YOUR BRIDGE BETWEEN LIFE-CHANGING THERAPIES AND PATIENTS
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SUSTAINABILITY
Why sustainability needn’t come at huge expense.
Reaching the holy grail of sustainability and lower cost I Author: PETER GISELEKDAHL - CEO of Envirotainer
t’s a stark fact that aviation emissions are a significant contributor to climate change. Worldwide, flights produced 915 million tonnes of CO2 in 2019, according to the Air Transport Action Group. This is a small proportion at about 2% of the overall human-caused volume. However, planes have strong warming effects owing to nitrogen oxides, vapour trails and cloud formation. In this context, transporting drugs via air freight could have a major impact on a pharmaceutical company’s overall global warming impact. Yet in many cases, there is no choice. Treatments often require very careful cold-chain handling to ensure they get from the manufacturer to the customer in perfect condition and on time. Keeping a shipment at very low temperatures requires herculean effort and there is a limited time window for doing so. Air transport is vital to the process.
This creates a huge challenge: how do manufacturers balance logistical demands, cost and environmental impact? These competing factors seem irreconcilable at first glance. Experts would be forgiven for thinking that to reduce emissions,
the cost will be higher. Or that using more air freight is going to reduce sustainability. But this simply isn’t true. It is possible to become more sustainable and reduce costs. The trick is to consider which factors are in the control of the pharmaceutical firm and then optimise them. For example, while it might not be possible to choose a less polluting plane, it is possible to choose packaging that has a lower environmental impact and cost. PACKAGING, BUT BETTER This may sound peripheral. But we need to remember that there is a huge amount of waste and cost involved in traditional methods of cold-chain packaging. Keeping a pallet of vaccines at a maximum of 6-8°C for an entire journey traditionally requires lots of single-use plastics, dry ice, cooling, cardboard and lots of handling and manual work. Considering AstraZeneca is aiming to manufacture up to 3 billion doses of Covid-19 vaccines this year alone, this all adds up. Compare this “passive” type of packaging to an “active” solution. Instead of all the wasteful materials and resources of what
is essentially a complex, yet throw-away picnic box, an active solution is more like a reusable, battery-powered fridge. These are used in a circular economy where sharing, leasing, reusing, repairing, refurbishing and recycling is central to their design. Over the lifetime of their use, these thermally-controlled containers are environmentally superior. In fact, greenhouse gas emissions associated with active solutions are more than 75% lower than passive, even considering an extra leg of return transport. The reusable option also has 60% less acidification potential, 65% less eutrophication potential, 85% less photochemical ozone potential, 85% less human toxicity potential, and 95% less postconsumer waste. This doesn’t even account for the handling and manpower wasted with a passive solution. Preparation can take up to five days, with coolants requiring up to three days for pre-conditioning, followed by manual assembly. Some active solutions can be fully charged from zero power in 11 hours, providing temperature
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How do manufacturers balance logistical demands, cost and environmental impact? stability for over a week. Some of the active containers can also be up to 35% more space efficient, which can significantly reduce the emissions per shipment. Furthermore, when all factors are taken into account, the active solution is cheaper – or at the very least comparable in price despite much better performance. Calculating the Total Landed Cost (TLC) proves this. Put simply, TLC is the cost of packaging added to the cost of air freight, plus any auxiliary costs and the probability of the cost of product loss owing to a temperature deviation. In most cases, TLC is proven to be lower for active. STOPPING MEDICAL WASTE Having said this, we must remember that while it all adds up, packaging is responsible for a relatively small proportion
of carbon emissions for most pharmaceutical companies. It stands at about 3% for GlaxoSmithKline and 7% for Sanofi. The vast majority comes from manufacturing. Therefore, it’s absolutely vital that every batch made gets to its destination without a temperature deviation that would see it going to waste and therefore doubling emissions. This is where active solutions come into their own. They truly maximise the safety of medical shipments. An active temperature-controlled container can continually keep the temperature inside constant despite it varying outside. In addition, it provides data logging and comes with a trackrecord of zero product losses. Put simply, active solutions are so effective that they offset their own costs.
MANUFACTURERS’ SUSTAINABILITY With such a strong environmental case for the use of active solutions, the only other question that a pharmaceutical firm may ask is whether the manufacturers themselves can prove they’re operating sustainably. In the case of Envirotainer, it became the first CO2 neutral cold-chain company in the world in 2020. This is mainly down to the impact of its containers, which have the lowest total CO2 per cubic meter of pharmaceutical product shipped in relation to competitors. However, it also has a sustainability strategy linked to the UN’s Sustainable Development Goals (SDGs). These are a set of 17 global goals aimed at transforming our world by 2030. Envirotainer is supporting a number of these by working with the highest
standards of compliance, building strong governance structures and ethical operations. As a result, the business not only helps its customers become more sustainable in a world where reducing environmental impact is paramount, but the firm itself is a sustainable one. And we would encourage the sector to follow suit. Let’s not forget. The logistics industry is a well-known polluter. While aviation might be a small part of that, 8.26 gigatons, or about 26%, of CO2 emissions globally are from transportation and many drugs do travel by truck, ship and rail. It’s therefore vital that the entire industry has a razor-sharp focus on sustainability at a time when the UN says current plans for cutting carbon emissions would lead to climate catastrophe.
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SUSTAINABILITY
Why the Green Claims Code is set to hold life sciences companies to account for their sustainability claims.
Going GREEN I
Author: JOANNA STEPHENSON - MD at PHD Marketing
n a world of ever-shifting commercial and consumer environments, one of the most important market changes on the horizon is the Green Claims Code. Where new initiatives such as the UK Plastic Tax and EU Packaging Levy affect businesses and industries differently depending on their input and output, the Green Claims Code is set to impact all sectors equally, both business to business (B2B) and business to consumer (B2C). As a communications specialist for the life sciences sector, we have seen clients of every size shift and adapt their external and internal communications in preparation, but there still seems to be some uncertainty of what exactly it means for pharmaceutical and life sciences businesses – and what the actionable changes will be. WHAT IS THE GREEN CLAIMS CODE? Today, any business worth its salt has an externally communicated sustainability strategy. One of the most pervading trends in commerce is that consumers want to know that their purchase decisions are making a positive change to the world around them and that the products they back are playing their part. The UK’s Competition & Markets Authority (CMA) has issued new guidance in the form of the Green
Claims Code. The new document, which applies to all externally communicated sustainability claims, provides six key principles that every claim must adhere to. Green Claims Code Six Key Principles ● Be truthful and accurate ● Be clear and unambiguous ● Not omit or hide important relevant information ● Be fair and meaningful ● Consider the full life cycle of the product or service ● Be substantiated For most of us, these principles might seem like a given – but the reality is that to this point, that isn’t necessarily the case. While the Green Claims Code targets businesses operating in the UK, it reflects a number of initiatives coming to fruition across the continent and beyond. The European Commission (EC), for example, is aiming to bring more structure to sustainability claims following a public consultation in late 2020. With regards to the Green Claims Code and its principles, the CMA will formally review misleading claims from January 2022. WHY DO WE NEED IT? The pharmaceuticals and life sciences sectors, perhaps more than most, know the benefits of regulation in creating fairer market
conditions and greater clarity. A growing problem for all businesses – including health and wellness - is that ‘greenwashing’ has become a significant challenge, and as a by-product, has removed any commercial punch from ‘sustainability’. The term itself has lost all meaning and has become little more than wallpaper. If a business describes its activities as sustainable, what would that mean to you? For example, it could be responsibly sourced ingredients, research practices, packaging or logistics models that support better use of resources – or any combination. Ask 10 people what a sustainable life sciences business looks like, and you’re likely to get 10 different answers. The Green Claims Code is all about removing ambiguity and levelling the playing field. Because sustainability has always been open to interpretation, there has been no real contextual benchmark for the consumer. Instead, by creating this benchmark, the code provides new protections for the consumer and for commercial buyers too. WHAT DOES IT MEAN FOR THE LIFE SCIENCES AND PHARMACEUTICAL SECTORS? Retail and commerce – whatever this looks like in practice – must reflect the changing needs of
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the consumer. As the gap between health and consumerled FMCG, personal care and food closes, this becomes increasingly important for companies in the life sciences and pharmaceuticals space.
great pains to reduce CO2 in its logistics or its commitment to natural or fair trade ingredients, but this needs to be wholly separate from the claims made on-pack when it comes to end products.
Areas such as health and wellbeing, supplements and medicines haven’t typically focused on sustainability as a competitive edge, but as the market progresses and shelves become more crowded, it’s likely to take a more prominent role. Crucially, this directive includes business to business communications, such as the sale of ingredients in new product development.
In addition, sustainability claims that are necessary or compulsory, in order to be legally compliant, should be avoided altogether. They’re a ‘given’, which doesn’t assist the customer in gauging the environmental impact and leaves more space for ambiguity. It could, in fact, fall foul of the new Green Claims Code under the principle of ‘meaningful’.
To avoid conflicting with the Green Claims Code, all existing claims made should be audited against the principles and when creating new communications, these tenements should be front and centre.
In life sciences and pharmaceuticals, sustainability claims aren’t applied to products often – but this may well change as the market reacts to consumer demand. We are expecting to see sustainability more front and centre in marketing communications. We have recently shared a guide with our clients on what the Green Claims Code means for their business, while assuring that, as a communications expert, we will take the strain in ensuring commercial messaging is compliant.
As mentioned, it’s likely that sustainability will play a much greater commercial role for the life sciences sector so it’s a fantastic opportunity to start collecting, collating and using sustainability data in a way that complies with the Green Claims Code and adding a new valuable and accurate messaging to new and existing products. One of the most crucial pieces of ‘good practice’ that the sector can glean from its more retail-oriented counterparts is that there needs to be very clear separation of business sustainability strategy and specific claims relating to a product. A business may take
We look forward to seeing how the pharmaceutical and life sciences sectors adapt over the coming year – the Green Claims Code looks set to play into the accelerating sustainability focus in the industry and may present a lot of strong commercial potential.
Today, any business worth its salt has an externally communicated sustainability strategy.
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SUSTAINABILITY
NET ZERO AND POWER RESILIENCE Future proofing pharmaceutical manufacturing in a changing energy landscape.
I
n an unprecedented move, on 6 September more than 200 health journals worldwide simultaneously published the same editorial, calling for urgent action on climate change in advance of the COP26 summit.
Author: ALASTAIR MORRIS - chief commercial officer at Powerstar
Now more than ever is the time to consider the implications of the goals of the Paris Climate Agreement and the effects of the healthcare sector’s demands for cleaner, responsible energy production and usage. As an emission-intensive sector, and one that involves both high-value and high-volume manufacturing processes and technologies, power resilience will be crucial for pharma and the broader life sciences. The energy requirements for research and development and the global nature of distribution and logistics, often combined with large infrastructure bases and
As an emission-intensive sector, and one that involves both high-value and high-volume manufacturing processes and technologies, power resilience will be crucial for pharma and the broader life sciences.
manufacturing sites, make reliable power particularly crucial. Within the UK, government targets are an 80% reduction in CO2 by 2035 and the National Health Service (NHS) is committed to achieving an 80% reduction between 2028 and 2032, reaching net zero by 2040. In addition, the ‘NHS Carbon Footprint Plus’ sets target dates for its supply chain to achieve net zero by 2045 with an ambition that companies should reach an 80% reduction by 2036 – 2039. This stated aim - for an organisation that procures products from more than 80,000 suppliers - shows the NHS using its considerable purchasing power to influence environmental change through the explicit intention to extend current procurement policies, specifically excluding those companies not actively working towards net zero. A fundamental aspect of the path to net zero is, as we all know, a move away from fossil fuels, and last year nearly 40% of the UK’s power came from renewables. While this is positive, it brings with it a range of issues that ought to inform a company’s energy strategy, both to preempt production problems as well as to harness the potential opportunities that a shift to renewables can offer. Fossil fuels have been a reliable source of energy but as we move to
fully renewable energy, power generation becomes more inflexible and potentially unstable which, in turn, impacts on the electricity grid. At Powerstar, we are seeing more and more forward-thinking companies looking to future-proof operations while simultaneously working to reduce carbon emissions and reach net zero targets. For pharmaceutical manufacturers, an uninterruptible power supply (UPS) is critical, both to protect high-value equipment and processes, and to maintain profitability with high-volume production. Across the general UK manufacturing sector, the operational effects of power disruption such as a blackout or brownout costs 3% of working days, losing an average UK business 17% of its annual revenue, estimated at £2.8 million per business per year. For pharmaceutical manufacturers, these costs are likely to be higher, given the sector’s spearheading of Industry 4.0 and the aforementioned highvalue, high-volume focus. To combat the effects of disruptions to power supply, many companies rely on a UPS – an uninterruptible power supply solution – which kicks in when the energy supply to designated equipment is interrupted. Historically, this has worked
29 but, now that we focus with increasing urgency on climate change and carbon emission reduction, such a solution may be becoming untenable. For example, most of the time the UPS will be sitting idle, yet still using power as it switches between AC and DC, losing between 10-20% capacity. For a 1MW system, that’s about £200,000 per year in energy costs, as well as adding significantly to a company’s carbon footprint. Continued reliance on a traditional UPS looks increasingly costly and inefficient, both in financial terms as energy costs look set to rise next April, as well as in reputational terms – particularly relevant in pharma, life sciences and the healthcare sectors. One area where pharmaceutical manufacturers can make significant strides in carbon emission reduction is through a shift to electric vehicle (EV) fleets and in the UK non EV car sales are set to be phased
out by 2035. Transportation is identified by the NHS as one of the major aspects of their own carbon footprint, and so it makes sense for current or prospective suppliers to implement the move to EVs. That said, there are important factors to consider when looking towards such a policy. Many companies do not have the capacity for on-site EV charging and the significant additional energy supply required may well take them above their authorised capacity, which could lead to such an initiative being blocked by their distribution network operator. This can make the move to an EV fleet prohibitively expensive or even a non-starter unless the company has an energy generation option in place. A Battery Energy Storage System (BESS) can be an important asset to overcome this major issue while contributing to a net zero strategy. Functioning as a
smart microgrid and providing a protected power supply to an entire site, rather than solely specified equipment, a BESS can offer the energy security necessary to maintain production – critical when energy requirements are predicted to double and given the strain this puts on the grid. Combining on-site renewable energy generation, such as solar, with the capacity to store energy means that excess power generated on-site when the sun is shining can be saved until needed – for manufacturing, for critical production processes or for EV charging, transport and logistics. This can reduce reliance on the grid, helping to avoid the issues around additional energy requirements for EV charging, as well as offering cost-savings through energy production rather than purchasing. It also opens up the potential for an additional revenue stream through sale of power back to the grid. Additionally, with a BESS,
there is no conversion from AC to DC and back again, meaning only about a 1% loss of capacity, so replacing a traditional UPS with a BESS will reduce carbon emissions, while reducing inefficiency and running costs. There is a clear impetus for pharmaceutical manufacturing as a significant energy-intensive sector, to work towards an imminent net zero future. The impact of this, in terms of energy demands, the need for energy security and the CSR aspects of carbon emission reduction plans and audits, all combine to indicate that an energy management strategy must factor in resilience. While net zero may seem a daunting challenge for the pharmaceutical supply chain, future-proofing steps can both inform and enhance efficiency in manufacturing, operations, logistics and, ultimately, net zero product development.
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CELL AND GENE THERAPY
The journey cell and gene therapies need to take to become more accessible.
C
ell and gene therapy holds so much promise for humanity. But despite intense interest, the biopharmaceutical industry is still very early in this journey. Viral vectors, which will continue to underpin most therapies for the next 10 to 15 years, are very complex molecules to manufacture. However, there is an opportunity to learn from the monoclonal industry’s journey, understanding first
the importance of scale, and second, the key role that technology innovation plays. With that valuable context, the industry can work together to reach the future faster. GENE THERAPIES TODAY Today, the near term gene therapy pipeline is primarily focused on rare genetic disorders, where efficacy is incredible and patient populations are small. These are a great starting point for
the industry. Looking farther out in the clinical pipeline, it is apparent that the future will look very different than it does today. With heavy risk adjustment, data shows that the current annual patient population for the top four viral vectors used in gene therapy is in the low tens of thousands. It is predicted that by 2030, this number will jump to the hundreds of thousands,
as indications with larger patient populations reach commercialisation. Many of these indications will also require higher dosing per patient. The ability to produce vastly larger quantities of viral vector would have a positive impact on the lives of people who need these therapies. But how do we travel there from where we are today? THE mAb CASE STUDY Cell and gene therapies are not the first complex biological modality to take this journey. The first licensed monoclonal antibody (mAb) was approved in 1986. Titers of 50 to 100 mg/L were typical for mAb production systems of the era. Over the following three decades, numerous improvements raised typical titers to 5 g/L in the mid-2000s to approximately 10 g/L today. The improvements came from a broad mix of upstream process improvements. These improvements are more than a two-log increase just from productivity. In the 1980s, production was in roller flasks, which were somewhat parallelized. A harvest might yield 100L of production. Today, the industry has standardised on 2000L single use bioreactors. Putting that
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in perspective for the top mAb today: in 1986, it was possible to produce enough drug for approximately 75 doses in a batch; today it is 300,000 doses. This productivity improvement is an impressive target for viral vector manufacturing.
aren’t just due to more stringent purification at a unit operation, they’re due to technologies not being optimised or fit-for-purpose. A common, but not best-in-class, process may yield only 15% to 20% of what was produced upstream.
THE PATHS FOR INCREASING PRODUCTION There are two ways to increase production: scale and technology improvement.
When looking at this data, the potential is strikingly clear. There is a lot of work to do on the downstream side, but the maximum improvement is approximately five times. On the upstream side, there is potential to find one to two orders of magnitude in the coming decade.
For scale, the industry is working to leverage the economies of scale already available in mAb production. Scale-up can buy the industry its first order of magnitude improvement. In 2020 alone, $700 million of capacity increases were announced across the industry. Technology improvement requires the innovators to think differently about their therapeutic than they do today. Today, each viral vector is treated as something uniquely special. When we approach manufacturing in a unique, bespoke manner, we miss the opportunity to build on the successes of the industry. If we step back, it is helpful to simplify manufacturing into two goals: make more and keep more. Upstream is where the virus is made; downstream is where it is purified. Innovation in upstream processing results in two things: scale, especially from switching adherent to suspension cell culture, and productivity from better cell lines and processes. Downstream processing (DSP) provides purity, but this has to be balanced with mitigating losses to keep as much of the material as possible. And a lot of the losses
DRIVING ACCESSIBILITY FORWARD As an example, Merck has developed a platform, starting with a system focused on Lentivirus, that links a highperforming HEK293T cell line with a chemically defined media and a scaled-up production process. This results in productivity improvements with cell line selection, transfection optimisation and media formulation. In a two-year timeframe, lentiviral productivity has increased by almost a log, working with the same clone. This embodies the potential of the upstream as a place for maximising throughput: Make more vector to start. A welldefined system has benefits downstream as well, with significantly higher recovery using standard processes. Of course, there is still more that can be done with cell line innovation, from transient to stable production systems. Processing will be easier, helping keep more material
during purification. And all of it is available, in increasingly templated form, as a CDMO service. CONCLUSION The biopharmaceutical industry has an opportunity and mandate to make cell and gene therapies accessible to patients. To reach this potential, it is helpful to take inspiration from the productivity gains that the monoclonal antibody industry was able to achieve. The catch? We need to do it in the next 10 years, rather than 30 years.
Author: JERRY KEYBL - head of Cell and Gene Therapy at Merck
Cell and gene therapies are not the first complex biological modality to take this journey.
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ASEPTIC PROCESSING
s s e n i s u B y k s i R Risk mitigation in aseptic production with a view to future developments.
Author: MARTIN MUFFLER - senior process engineer at CRB
The European Pharmacopoeia’s definition is simple and comprehensible: “The aim of production under aseptic conditions is to preserve the sterility of a preparation composed of sterilised components. This means that the raw materials necessary for production, including primary packaging, should be sterilised before aseptic further processing, provided that this is possible, and no contamination may occur during production.” The greatest risk of contamination in aseptic production comes from humans. Reduced number of interventions in critical zones leads to higher product safety. THE OPERATOR AS A SOURCE OF CONTAMINATION This was recognised early on and the processes have been further developed and improved in recent years or decades with special attention to the rooms, gowning of the employees, the training of the employees and the physical and microbiological monitoring. A contamination-free filling is proven by a variety of measurements such as microbiological monitoring, physical monitoring, monitoring of air velocities and smoke studies in the cleanroom. Improvements were achieved through changes in cleaning and disinfection cycles, division of the production rooms into separate zones and separate air locks for employees and materials.
The entire filling process is validated by periodic media fill. Here, all interventions during the past production period are simulated and evaluated back to the last successful media fill. Here it becomes clear what risks can emanate from an intervention or an incorrect assessment of the intervention. In the event of contamination during media fill, all batches are potentially affected. This not only represents a very high risk for drug and patient safety but also a very high business risk for the company.
The evaluations are time-consuming, cost-intensive and due to the high number of measurements, there is an additional risk of a false positive result due to human error. This is followed by intensive time-consuming risk assessments with a worst case of having to discard the filled product. MICROORGANISMS ARE NOT VISIBLE Microbiological contamination only becomes visible days after production through the incubation of the culture media. The conclusion is obvious, how can interventions be avoided and how can the risk be minimised? A major milestone in reducing product risk has been achieved through the use of closed restricted access barrier systems (RABS) and isolator technology. These systems allow the separation of the product from the intervening operator. Annex 1 of the EU GMP Guide
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The greatest risk of contamination in aseptic production comes from humans.
"Manufacture of Sterile Medicinal Products" regulates the manufacture of sterile medicinal products in Europe. On 20 February, 2021, the European Commission published a second draft revision of the document after 2017. Chapter 4 of the new draft, which deals with the design and qualification of premises contains very strict requirements. The draft elevates RABS and isolators as the primary means when it comes to minimising microbial contamination from direct human intervention in the critical zone. The draft is very clear in describing the requirement. "Any alternative approaches to the use of RABS or isolators should be justified". Therefore, companies must inevitably and intensively deal with the topic of containment. Presumably, good reasons are needed for not considering the use of containment in future pharmaceutical production. Containment goes from a "can" to a "must". The pharmaceutical world is changing. New active ingredients, biotherapeutics, ATMPs, ADCs are leading to the future of medicine. Personalised medicine could promise a cure or relief with only a few drug doses. This will almost certainly lead to smaller batch sizes. Also, the future APIs will be time and cost-intensive to produce, which will further increase the business risk on the process of fill and finish. But as recent events have shown, even large batches are likely to continue to be of great importance in the future. The fight against the Covid-19 pandemic is certainly surprising here, who would have thought of such a high demand for vaccine doses worldwide before the outbreak of the pandemic? Both directions and the upcoming stricter requirements for
33 containment show impressively that future solutions in the pharmaceutical world will have to be considered in a very individually targeted manner. All possibilities and risks must be systematically considered well in advance of a new production. Here it is important to consider whether all disciplines are present and available in a company. Involving external experts will be of great importance for successful projects in the future. Looking to the future, robots in aseptic production have a great potential to operate aseptic processes without human intervention. This has the advantage of minimising the aforementioned drug safety risks. Another consideration to the use of robots in aseptic production is cost effectiveness. The use of robots requires virtually troublefree equipment which makes the output more predictable and reliable. Safety stocks can be safely reconsidered at this high level of value creation. Due to the high investments and changeover times, such plants will probably be reserved for products with large batch sizes, high value and consistent formats for the time being. The increasing demand for small batch sizes poses a new challenge, and the market offers modular solutions that meet the respective requirements by combining individual modules. In addition to the high requirements for drug safety, the decisive factors are the flexibility of such systems with regard to different formats and the variability to produce vials, carpules and prefilled syringes for the market with short cleaning and changeover times. The cleaning and changeover of such modules can be done separately from the production line and thus significantly increase the line output.
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Talking points
OUTSIDE EPM
NASAL SPRAY DEVELOPED TO PROTECT AGAINST COVID-19 Over-70s experiencing drop in Covid antibodies A drop in the levels of Covid antibodies found in 70–74-yearolds has been recorded, prompting calls for the UK government to step up its booster campaign and to introduce more widespread antibody testing. New data from the Office for National Statistics (ONS) show an 11.6% decline in the number of over-70s with detectable Covid-19 antibodies. Figures recorded up until 3 October show over 98% of 70–74-year-olds have been jabbed twice, but only 86% still retain antibodies for the disease. Compare this to June where 97.3% of this group showed detectable antibodies. The ONS report does highlight that those who have tested negative for antibodies received their vaccinations in the early stages of the UK’s vaccination programme. “Along with age, the early stages of the vaccination programme prioritised individuals on a range of factors (such as long-term health conditions and type of employment) and this may help to explain the declining trend appearing in different age groups now,” the report reads.
Birmingham Biotech and the University of Birmingham have signed a licensing agreement to commercialise an anti-viral nasal spray that protects against Covid-19. The spray is designed to work by encapsulating and deactivating the virus while it is still in the nose, preventing its wider uptake in the body. With the nose being a major viral entry point for viruses such as SARS-CoV-2, it is an ideal target for approaches designed to reduce person-to-person transmission. The spray consists of two compounds, the first being a polysaccharide gel which can ‘plume’ rather than ‘jet spray’ when applied with a typical nasal spray applicator. It is retained on the mucous-coated epithelia in the nose where it
coats and retains the virus, so it does not travel further down the respiratory tract. The second compound is a potent antiviral agent called carrageenan. Professor Liam Grover from the university’s Healthcare Technologies Institute engineered the formulation. He said: “As Covid-19 restrictions around the world are gradually lifting, there is a real need for effective methods of viral protection. While existing measures like wearing masks and handwashing remain essential, this nasal spray provides an additional protective measure with the potential to reduce transmission. We are thrilled to be working with Birmingham Biotech to bring the anti-viral nasal spray to individuals around the world.”
Dr Katy Taylor, director of Science and Regulatory Affairs at Cruelty Free International discusses the use of dogs within toxicology assessments and why change is needed. Make sure to read the full article at www. epmmagazine.com
BE SURE TO LISTEN TO
The latest episode of The MedTalk Podcast sees EPM speaking to Professor David Nutt about his recent decision to join the biotech Awakn Life Sciences to help the company bring about a change to mental health treatments through the use of psychedelic medicines.
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