EPM Sept/Oct 22

REGULARS

5. EDITOR’S DESK: A rocky road ahead.

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

8. PERSPECTIVE ON PHARMA: Siemens examines how smart finance can help CROs invest in technology in a financially sustainable way.

14. COVER: Nemera’s holistic approach to developing combination products.

22. OPINION: Broughton shares their insights on how laboratory services may experience a regulatory shift post Brexit.

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

FEATURES

25. CONTRACT MANUFACTURING:

Almac provides the key reasons for outsourcing your formulation development and manufacturing needs.

26: PACKAGING: Technoprint anecdotally shares how it’s maintaining sustainable packaging in a changing world.

30: DRUG DELIVERY: Particle Works explains how it’s using microfluidics to help forward the development of new nanomedicines.

32: FORMULATION: Catalent highlights the methods to undertake on small quantities of API to progress through drug development.

35: REGULATION:

Celegence discusses how digital technologies enables companies to manage their regulatory compliance.

36: EXCIPIENTS:

Two experts of LLS Health share the API solubility puzzle that the pharma industry faces and how to solve it.

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

Volume 22 Issue 4 June/July 2022

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

A ROCKY ROAD AHEAD

attractive option for international pharmaceutical manufacturers in the long term, compared to the EU and the US. A smaller market with even bigger barriers to entry.

Membership

The Uk’s future role in R&D within the life sciences sector currently stands on unstable ground. On the back of the Brexit vote, the UK left the European Medicines Agency (EMA) – the EU drugs regulator – leaving all future medicines to be vetted and approved by the UK’s equivalent; Medicine and Healthcare products Regulatory Agency (MHRA). Reflecting on the previous year – the first year following the Brexit transition period - the number of medicines

approved in the UK was fewer than that of the EU and US combined. This could mean a wake-up call for the UK and something to consider when the future regulation of medicinal products is firmed up, though if the MHRA’s published consultation on the regulation of medical devices is anything to go by, we can expect alignment with the EU in a lot of areas, with some room for manoeuvre on divergence.

For external drug

EDITOR’S DESK

REBEKAH JORDAN

manufacturers and developers, the UK’s current regulations could mean more paperwork, more time and at higher costs. The emphasis now also lies on the NHS and NICE to recommend which drugs should be made available in the NHS. Consequently, the UK may not appear as an

However, it’s not all bad. The UK possesses a very strong life sciences innovation sector – a turnover of £80bn a year. To see less investments and support into its R&D from external manufacturers and investors would be a disaster to say the least. For instance, the AstraZeneca vaccine was originally developed here in the UK, not to mention, the UK was the first recorded country to approve the Omicron-specific vaccine – reflecting the country’s proactive approach for treatment development. Teams at Oxford University also recently got behind a clinical study for Tecovirimat - a potential treatment for monkeypox – and is now recruiting its first round of patients.

It would be short sighted to say that less medicinal approvals would limit patient access to effective treatments. What we may not be considering is the quality over quantity approach, allowing for a more selective process. The prioritisation of epidemic- or pandemicrelated vaccines could mean patients receive life-saving treatments without delays.

All in all, current trends show that it’s too soon to tell the potential impact severity or duration of the UK-EU break up on the UK’s life science market. So, amongst the majority of things in the UK, we are again faced with uncertainty. In the meantime, I hope you enjoy this issue.

A small dose

BMS is rst biopharma company to be accredited as Menopause Friendly workplace

Bristol Myers Squibb (BMS) UK and Ireland has been announced as the first biopharmaceutical company in the UK to be accredited as a Menopause Friendly Workplace.

Menopause Friendly accreditation is a recognised standard of achievement awarded by an independent panel of judges, recognising employers who put diversity, inclusion, and colleagues’ wellbeing at the centre stage of their business, without feeling that the subject is taboo or off-limits.

Given that nearly 8 in 10 menopausal women are in work, and that this is the fastest growing demographic in the workforce, BMS recognised the need to help make a difference for its staff. This is especially important given that almost three-quarters of businesses do not have a menopause policy in place, according to a YouGov survey.

Panel members described BMS UK&I’s application as “outstanding” and acknowledged the huge strides they have made to help normalise the menopause by fostering an inclusive culture where people feel able

to discuss menopause-related health problems at work.

Scott Cooke, general manager for BMS UK&I, said: “I am so proud that Bristol Myers Squibb UK&I is the first pharmaceutical company to have been officially awarded Menopause Friendly status, highlighting our continued commitment to ensuring that all people affected by the menopause feel supported at work.

I am delighted that we are helping lead the way in changing how businesses think about the menopause, and we remain passionate about accelerating change in workplace best practice and fostering an inclusive culture where everyone can bring their authentic selves to work every day.”

Jog Hundle, Menopause Friendly Independent Panel member, said: “We’re delighted to see Bristol Myers Squibb achieve Independent Menopause Friendly Accreditation. Their application was outstanding and they’ve made such a difference for their colleagues. They set clear objectives to create a movement to normalise menopause with strong senior leadership support. They’ve demonstrated excellent menopause awareness, education and support within their organisation, creating a culture where menopause is easy to talk about and put in place outstanding support. Well done to everyone involved.”

Lisa Macis, Menopause at Work project lead for BMS UK&I, said: “Women should never be pushed out of the workforce because of their experience of the menopause. I am delighted at today’s accreditation announcement, which formally recognises the huge variety of workplace initiatives

BMS UK&I has put in place to support its staff in becoming a menopause-friendly employer. BMS UK&I cares deeply about the wellbeing of its staff, and our advocates have helped educate two thirds of our workforce on the menopause to help raise awareness of how it can impact a person at work. I am delighted BMS UK&I’s efforts have been recognised by experts in the menopause field, and we are excited to continue building on this progress.”

DIGESTIVE SUPPLEMENT TO TACKLE THE ROOT CAUSE OF MANY GUT PROBLEMS

Adigestive supplement known as, JUVIA Digestive Balance Formula, has been launched to treat people with IBS. JUVIA Digestive Balance Formula contains ERME, a unique natural ingredient derived from 100% sustainable barley. Scientists discovered that the active digestive enzymes in ERME help break down carbohydrates before they can cause symptoms such as

bloating, stomach cramps, constipation and diarrhoea, which are associated with IBS.

JUVIA is backed by science, pioneered by investigators in the areas of gut health and metabolic disorders; professor John Hunter, formerly of Addenbrooke’s Hospital, and Dr. Rosemary Waring of the University of Birmingham.

Professor Hunter said: “The active digestive enzymes in ERME work with the body to help it

Kry launches obesity program to help solve chronic disease crisis

Kry is expanding its chronic disease management and population health solutions with the launch of new treatment pathways for obesity this autumn.

By embedding digital to the core of healthcare delivery, Kry’s digitalfirst patient journeys will be a game changer for those living with chronic diseases and conditions through accelerated diagnosis, improved treatment pathways and value driven patient support. Through boosting access to tailored treatment plans, Kry hopes to keep patients healthier for longer, reducing the need for costly medical intervention.

Kalle Conneryd-

Lungren, chief operating officer said: “We’re facing a global obesity crisis and need to prioritise new approaches - that’s why we’re introducing a digital-first approach which will improve the individual patient experience while unlocking long term benefits at a population and system level.”

This autumn, Kry will expand its digital weight management program in Sweden as the country embarks on a national initiative to improve the lives of people living with obesity. The new Kry pathway provides a seamless patient journey including access to digital and physical care, psychology resources, lifestyle content and support for treatment

adherence. The program will be scaled into other markets where Kry has a presence later this year.

Kry will collaborate closely with Novo Nordisk in joint research to elevate and enable population disease awareness, with the aim to promote equitable access to care, improved adherence to treatment plans, and to achieve sustainable healthcare outcomes.

The research will include an

balance the good and bad gut flora. As far as we know, for the first time we have a product that addresses one of the root causes of IBS, rather than just tackling the symptoms. IBS has many different causes; around 50% are related to diet.”

It is estimated that up to 4 in 10 people in the UK experience gut health problems. Digestive issues can have a devastating impact on people’s lives, with many still searching for a longterm solution that really works for them.

The research that has led to JUVIA was the first to establish the role that bacteria and fermentation

observational study to record the health impact of Kry’s obesity program on a cohort of approximately 1,000 patients, tracking improvements in BMI among other factors.

Obesity is a disease that requires long-term management. It is associated with many serious health complications and decreased life expectancy. Approximately 650 million adults are estimated to live with obesity worldwide and specifically 53% of the adults living in the EU are considered to be living with overweight or obesity.

Niels Abel Bonde, general manager at Novo Nordisk Sweden said: “Together, we’re creating a unique opportunity to deliver a study that will support the global ehealth ecosystem to better understand and achieve healthier outcomes for millions of people living with obesity. With digital healthcare we’re moving towards new treatment pathways that will create sustainable and equitable healthcare for all.”

plays in gut health. Published in the Lancet back in 1998 by professor Hunter, the research led to an understanding that when the small intestine doesn’t digest food completely, especially carbohydrates, it can cause malfermentation in the large intestine. In turn, this can lead to the growth of unhealthy flora. This imbalance can irritate the gut.

JUVIA has also created an app to help people track progress and set reminders to take JUVIA Digestive Balance Formula.

Scientists continue to uncover the significant role that the gut flora play

in human health. Links may be found between gut flora and a range of conditions including irritable bowel syndrome (IBS), immune function, colitis, diabetes and obesity.

Dr. Anthony Hobson, clinical director and senior clinical GI scientist at the Functional Gut Clinic, said: “The evidence is showing that ERME works differently to other products by breaking down the carbohydrates before they hit the gut and cause problems. It makes sense that people are feeling the impact of this in reduction of digestive symptoms.”

))

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Can a lter dryer be used with Highly Potent API ?

YES!

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undertaken in Europe with the UK leading the pack in early clinical research. Prior to the pandemic, research from the Association of the British Pharmaceutical Industry (ABPI) recognised the UK as a worldleading expert in the areas of heart disease, immunology and conditions affecting the nervous system.

As part of the global response to the pandemic, research on chronic illnesses and diseases was suspended as scientists focused their knowledge and attention on the urgent need for a COVID-19 defence. Yet the industry faced a challenge on two fronts: social distancing measures severely restricted its ability to perform clinical trials, all the while being under pressure to conduct more trials to aid in the development of a COVID vaccine. Thus, the impact of the pandemic can be felt equally in the design and delivery of clinical trials as well as the quantity carried out.

CROs have subsequently been compelled to reconsider and change strategies, the result being an increase in hybrid models where traditional clinics operate in parallel with decentralised trials and environments. These decentralised trials offer increased patient convenience and engagement, as well as reducing the time required to carry out the trial by an estimated 15%. Continuous studies amid the successive lockdowns and changing restrictions were made possible via hybrid clinical trials and remote patient monitoring, which also resulted in cost reductions of 15-20%.

Furthermore, it is estimated that 50% of clinical trials will be either hybrid or decentralised by 2024, simply put, growth prospects for the CRO market will not be hampered by the lifting of

restrictions. This means those organisations that leverage digital technologies in their approach will be best placed to take advantage.

SCALING THE DRUG DEVELOPMENT PATHWAY

While the pandemic inflicted severe disruption to the day-to-day CRO market, the effectiveness of the industry’s COVID-19 response has helped propel the market to a swift recovery. There is now an elevated standard for solution delivery that CROs of all sizes will be expected to meet. These CROs must therefore rapidly scale their offering in order to deliver these standards and tackle the existing backlog of R&D work delayed by the pandemic.

With this in mind, the pace of future research is now expected to be higher with tighter deadlines where CROs are required to react with total flexibility. This can only be achieved with access to digital ready and high-end clinical chemistry equipment such as high-resolution mass spectrometers that can simultaneously quantify thousands of samples enhancing precision, depth, and throughput. Additionally, smart automation software is breaking down paper barriers, facilitating seamless scheduling, data collation and sharing as well as improved safety and security measures.

The digitalisation of processes is driving modernisation in the industry and accelerating trial speeds, and it is clear that a significant investment in equipment, software and infrastructure, is needed, for research organisations to remain competitive and meet the heightened expectations for seamless drug delivery.

FINANCE AS A KEY ENABLER

Many CROs are turning to smart finance to enable sustainable pathways to investment. Smart financing – offered by specialist financiers – enables the acquisition of technology and equipment for competitive advantage, in a way that is financially sustainable and tailored to the organisation’s specific business and cash-flow needs. Smart financing offers three major advantages over generalist finance: technology expertise which understands real business outcomes; a breadth of financing solutions which can meet every organisation’s exact needs; and smooth, sophisticated processes which makes the use of smart finance seamless and easy. Healthcare financiers who have an in-depth understanding of the drug research and development technology and its applications can provide these tailored financing packages.

CONCLUSION

While COVID-19 has quickened the pace of research, it has also slowed down crucial studies and clinical trials for other illnesses and diseases. To meet these and future challenges, CROs require highend digitalised equipment and technology that can enable processes to get back on track and satisfy the increased demand for their services.

Preserving cash flow is a key concern for any business. This is why more and more CROs are turning to smart finance options from specialist financiers to enable investment. Specialist financiers collaborate with CROs to adapt finance periods and conditions in order to fit with strategic goals and outcomes, drawing on their in-depth expertise of the drug research and development industry.

It is estimated that 50% of clinical trials will be either hybrid or decentralised by 2024.”

FUTUREPROOFING PHARMACEUTICAL FORMULATIONS AGAINST NITROSAMINES: 5 BENEFITS OF USING ANTIOXIDANTS

Nitrosamine contamination of drug products has emerged as a major regulatory issue for the global pharmaceutical industry in recent years – with upcoming legal deadlines requiring drug developers to take timesensitive action.

Ever since the first discovery of N-nitrosamines in valsartan four years ago, nitrosamine mitigation has become a key focus for pharmaceutical manufacturers across the world. To protect patient health, drug developers now have a legal obligation to perform a thorough risk assessment for both new and existing products and, where necessary, implement an appropriate control strategy, which might include reformulation. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have set stringent deadlines by which drug manufacturers are to present their risk mitigation plans for chemical medicines and biological medicines.

WHAT IS NEXT FOR DRUG FORMULATION?

With deadlines from the FDA and EMA fast approaching, drug developers are searching for solutions that will help overcome their formulation challenges in mitigating nitrosamine formation.

Manufacturers can review and look to optimise the formulation process of drug products to limit nitrosamine formation and this, in turn, will support learnings

for future drug development. However, optimisation of formulation processes may not prevent nitrosamine contamination entirely.

For these reasons, manufacturers may look to block nitrosamine formation in drug products. This is considered the best way to mitigate the risk and ensure that impurity levels are below allowable limits – which is an acceptable daily intake of 18 ng for newly emerging nitrosamine impurities according to current EU regulatory guidance and 26.5 ng/day in the US.

One possible strategy is that the formation of nitrosamines typically occurs under acidic conditions and the risk of contamination is much lower in neutral or basic environments. Formulations that incorporate excipients like sodium carbonate – which modify the microenvironment to a neutral or basic pH – should therefore, in principle, inhibit the development of nitrosamines. However, this strategy is not always suitable because some drug substances are not stable at higher pH levels. Another approach is blocking nitrosamines by including antioxidants, namely ascorbic acid (vitamin

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C) and α-tocopherol (vitamin E), in drug formulations. Discover five benefits of choosing this proven, safe and effective mitigation strategy below.

5 KEY BENEFITS OF USING ANTIOXIDANTS IN DRUG FORMULATION

1. Block nitrosamine formation Nitrosamine impurities, like N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), are formed when a nitrosating agent – like nitrous anhydride (N2O3) or nitrosonium ion (NO+) – reacts with a secondary or tertiary amine. Depending on the pH, these nitrosating agents will then react with secondary or tertiary amines to form a nitrosamine.

Any active substance or ingredient whose structure comprises secondary, tertiary amines or tertiary ammonium salts is therefore at risk of nitrosamine formation, as are drugs where the active is stabilised by buffers containing tertiary or quaternary amines. Drug formulations that include any excipient containing secondary or tertiary amines, or quaternary ammonium salts, are also likely to form nitrosamines.

Known as a nitrosation inhibitor, ascorbic acid is a powerful reducing agent that can react with many nitrosating agents (like NO+ and N2O3), converting them into nitric oxide (NO) and effectively blocking nitrosamine formation. By reacting with nitrosating agents at a more rapid rate than nitrite does with secondary amines, the vitamin disarms nitrosating agents and ultimately prevents a reaction between nitrites and vulnerable amines. It has been demonstrated that ascorbic acid inhibits nitrosamine

formation more effectively at pH 3-4 than other nitritereducing agents. Adequate quantities of α-tocopherol are also proven to be effective at reducing the precursor of nitrosating agents, NO2ˉ to NO.

By blocking the formation of nitrosamine impurities, both antioxidants can help to keep nitrosamine levels below the acceptable intake limits, making drug products safe for human use. Emerging research has found that ascorbic acid and α-tocopherol demonstrated greater than 80% inhibition when spiked at 1% levels in solid oral dosage forms.

2. Successfully used across the food industry

For the past 30 years, antioxidants have been used successfully by mitigating nitrosamine formation in foods. Nitrosamines first became a health concern in the 1980s when nitrites were typically added to processed meats to prevent the growth of bacteria. Amines are common chemicals in food products, therefore preserving foods with nitrites induced a reaction and nitrosamines became unintentional byproducts of food preparation and processing. High concentrations of nitrosamine impurities were reported in bacon, sausages and hams at the time – leading to the development of the first mitigation strategies.

Take bacon as an example – when preserved with 150 ppm nitrite, high levels of N-nitrosopyrolidine (NPYR) are formed when the bacon is fried. Reducing the amount of nitrite to 120 ppm and adding 500 ppm ascorbic acid, lowered NPYR levels to 10 ppb. Today, manufacturers using nitrites to preserve food are required

to add ascorbic acid to their products to inhibit nitrosamine formation.

3. FDA-recommended strategy Adding ascorbic acid and α-tocopherol as antioxidants is one of the options recommended by the FDA as a mitigation strategy for pharmaceutical drug products. The inhibitory effect of ascorbic acid on nitrosamine formation was first noted in 1976 when investigators proposed that finished dosage forms of ‘easily and rapidly nitrosatable drugs’ should include the excipient. The most recent nitrosamine update from the FDA examined the effectiveness of antioxidants in oral dosage forms and concluded that ascorbic acid and α-tocopherol are suitable nitrosamine inhibitors in drug products.

4. Offer additional advantages Next to their efficiency in blocking nitrosamine formation, in one study both ascorbic acid and α-tocopherol have been demonstrated to impact the carcinogenicity of preformed nitrosamines and other carcinogens directly – reducing tumour yields by up to 60%. When combined, they may also offer potent antioxidant activity, protecting against oxidative stress-induced damage. One study found that α-tocopherol (plus ferulic acid) increased the effectiveness of ascorbic acid eight-fold. Additionally, ascorbic acid regenerates α-tocopherol after it scavenges free radicals,

further reducing oxidative stress in cells. Both excipients act as stabilisers in finished drug product formulations too – helping to protect the active ingredient from degrading and maintaining the efficacy of the drug.

5. Favourable safety profile Ascorbic acid and α-tocopherol are already well-known excipients used across the pharmaceutical and dietary supplement industries. They can be used at high levels without any safety concerns. However, care should be taken to add only the necessary amounts to avoid Maillard reaction with reactive substances, which can cause undesirable colour changes or odours.

REFORMULATING WITH CONFIDENCE

For drug developers to overcome critical drug formulation issues – like nitrosamine contamination –and develop safer therapies, they must adhere to the latest regulations and guidance. Ascorbic acid and α-tocopherol as antioxidants offer developers reliable opportunities to redesign their pharmaceuticals, or innovate new drugs, with reduced risk of nitrosamine formation. Drug developers can look to specialist industry partners, such as DSM, that can offer scientific and formulation support as well as regulatory expertise to overcome the nitrosamine challenge in the pharmaceutical space.

Antioxidants can help to keep nitrosamine levels below the acceptable intake limits, making drug products safe for human use.

AN INCREASINGLY COMPLEX LANDSCAPE FOR COMBINATION PRODUCTS The complexities involved in selecting or developing the correct device for a combination product have never been more challenging. A convergence of trends, including significant growth in the global drugdevelopment pipeline, the need for more complex delivery devices to address targeted applications and drug attributes, and increased migration of care from clinical to self-administration in home settings have driven demand for a wide range of solutions. This is coupled with a crowded competitive landscape in the biologics, biosimilars and generics segments, in which multiple competitors may be pursuing the same applications. Pharma companies are under increased pressure to driven patient centricity, increase speed to market, reduce their risk, and create value for patients and other stakeholders across the landscape. Beyond the patient, this includes an ecosystem of stakeholders including providers, namely healthcare professionals, but also health systems; payers, to consider factors such as value-based care; and regulators, as the market for product introduction and the intended filing approach can impact device selection and development strategies. These factors then need to be considered within the available or emerging technology landscape. All these factors lead to a need for developers to adopt a holistic approach to developing a device strategy, which is focused on the entire combination product that spans development stages and requires specialised expertise at every step of the process and balancing a variety of factors and influences that need to be considered. This leads to better near- and long-term decision

COVER STORY

A HOLISTIC APPROACH TO DEVELOPING A DELIVERY DEVICE STRATEGY

MARK TUNKEL, GLOBAL CATEGORY DIRECTOR, SERVICES AT NEMERA, EXPLORES THE FACTORS THAT SHOULD BE CONSIDERED WHEN DEVELOPING A DEVICE STRATEGY IN THE CURRENT TECHNOLOGY LANDSCAPE, AND HOW A HOLISTIC APPROACH CAN LEAD TO BETTER AND MORE LONG-TERM DECISION MAKING.

making across the life cycle of drug products.

INTEGRATING THE VOICE OF THE PATIENT INTO DEVELOPMENT

We believe at the earliest stages of establishing the functional requirements and user needs for a new device application, it is critical to fully understand the patient journey as well any related clinical processes.

Our team of design research utilises a method called applied ethnography to achieve this goal. This relies on interviews and in-context observations of practices, processes and experiences within the patient’s home or use environment.

Potential use cases are looked at broadly beyond the administration event or complying with instructions for use. This starts from when a patient is diagnosed, to receiving their device, through the entire process of preparing, administering, and disposal and the times in between treatment to understand how the process changes over time and how frequency of administration may impact the patient experience. It is equally important to gain an understanding of the experience of healthcare professionals to consider relevant settings in clinical environments. This is important in applications where care is being provided in both in home and clinical environments as well as a migration of care, such as an oncology ward, with significant support systems to an environment of selfadministration where clinical personnel are not present and the burden of support falls to a family member or caregiver.

The outputs include patient journey maps, clinical process maps, an understanding of prioritised user needs and values, and pain points that can be leveraged toward improving

the patient and provider experience.

This supports meeting needs holistically while making decisions around assessing the technology landscape to identify existing IP or platforms that may be fit for the intended purposes related to function and drug product attributes. This includes decisions around modality and variations within if considering existing IP platforms. This may also lead to the development of a novel delivery system in which this foundation can be utilised to establish user needs and functional device requirements.

SURROUNDING THE DEVICE FOR SAFE, EFFECTIVE AND DIFFERENTIATED COMBINATION PRODUCTS

Once a technology or development project has been initiated its human factors and patient experience, activities must be integrated to ensure an efficient development process. The selected device, in combination with the drug, is appropriate, safe and effective for the target population. This also extends to optimising the patient experience to create competitive differentiation, and to ensure adherence and engagement with patients and clinical stakeholders. A good example of this approach might be the consideration of a biosimilar application where competitors are targeting the same reference drug and devices. Alternately, for NDAs and new device development programmes, the company needs to project what a future use case might look like and anticipate areas of risk to ensure that development is tailored to mitigate them. In both instances, the company needs to be sure that it is addressing the defined user groups populations and early use-related risk analysis activities to define the human factors and usability program.

Clinical risks must be identified through conducting formative and summative usability testing for all aspects of the device and supporting assets in alignment with the human factors programme definition, including the production of human factors engineering report documentation for use in for regulatory submissions. This process is linked to developing instructions for use, valueadded packaging, as well as leveraging digital health related add-ons to support patient engagement/ adherence, as well as extend the value of a device platform. This can also be augmented by fit for purpose pre-clinical, clinical, and small series device supply to accelerate development timelines and defer capital expenses. It is crucial this is all

completed holistically.

BENEFITS OF PARTNERING WITH AN INTEGRATED SERVICE PROVIDER Nemera’s integrated development, consulting, and manufacturing services allows customers to achieve the outcome of a successful regulatory submission and commercial launch of safe, effective, and differentiated combination products with a single partner applying an agile process across the device and combination product value chain. This will drive patient centricity, reduction of risk, and increased speed of market access. This approach can be applied to our IP platforms or with organic development and allow customers to focus on their core business.

At the earliest stages of establishing the nctional requirements and user needs for a new device application, it is critical to lly understand the patient journey as well any related clinical processes.

INTRODUCING AIDAPTUS:

THE PLATFORM AUTO-INJECTOR THAT ANTICIPATES FUTURE TRENDS IN DRUG DEVELOPMENT

FACILITATING THE INJECTION PROCESS

The aim of platform devices is to accommodate a broad range of possible drug delivery options, and allow use with a variety of formulations from the clinical trial phase through the product lifecycle. This minimises the level of validation testing and regulatory requirements when selecting a device for each drug and formulation. However, this means that during device development, the needs of multiple potential patient groups must be considered – as the final therapy area is not yet determined – and any identified risk factors related to use of the product need to be addressed. These considerations need to cover the whole injection process, from use to disposal.

The Aidaptus disposable auto-injector introduces a consistent injection process for users. The injection process has two phases, where needle insertion and dose delivery are controlled by two separate springs. The needle is automatically activated with pressure on the injection site, followed by delivery of the drug. This two-step delivery makes it less likely that patients will experience drug wastage or ‘wet injections’ before completing their injection.

They can also check dose progression and that they’ve administered the full dose with the help of the bright yellow plunger rod clearly visible in the viewing window, and audible clicks at the start and end of dose delivery. The window also allows users to clearly inspect the drug before injection, and check drug clarity and colour.

Injecting medication can cause anxiety for many patients, and some may suffer from needle phobia. Aidaptus’ design keeps the needle hidden before, during and after use; this feature can help to make injection less intimidating and may encourage treatment adherence as a result. To protect patients from needlestick injury, the safety shroud locks in place once injection is complete, so that the needle is not exposed to the user before disposal into a sharps container.

CREATING A VERSATILE PRODUCT

Timescales from drug development to clinical trials and final regulatory approval have shortened in recent years. This places some pressure on drug delivery devices, as they should ideally be able to accommodate modifications to

the drug during the formulation, development and life-cycle management process – without significantly impacting the final product timelines.

Aidaptus’ design aims to provide pharma manufacturers the option to modify drug volumes and viscosities, without needing to change their selected delivery device. The self-adjusting plunger with its patented design adapts to a range of syringe fill volumes without any changes to the device and with no change in parts. The auto-injector is also compatible with either a 1mL or 2.25mL prefilled syringe, with a minimal number of change

parts and without affecting the product’s small, discreet size (162mm x 18mm). For further flexibility, both vented and vacuum filling are possible, allowing for a choice of contract filling partners.

As the market for drug delivery devices develops, Aidaptus’ over wrap can be tailored to integrate additions or Near Field Communication (NFC) to enable connectivity. With this level of versatility, drug developers can focus on optimising their products for patients, with minimal concern about selecting a device that is both suitable for the drug formulation and user-friendly.

Michael Earl, director, Pharmaceutical Services at Owen Mumford, explains how Owen Mumford’s Covidcompliant study design and careful planning allowed them to finalise their product design and present this innovative product, Aidaptus, to the market.

SMART SOLUTIONS FOR CLINICAL TRIALS

EFFICIENT PROCESSES

Faubel Pharma Services has developed from a label manufacturer for clinical trial samples to a multiservice provider along the clinical trial supply chain. It has positioned itself as a leading innovator.

LEARNING TO MANAGE THE RISKS INVOLVED IN HIGH POTENCY DRUGS MANUFACTURING

The increasing use of high potent active pharmaceutical ingredients (HPAPIs) in cancer treatment drugs is proving highly effective in saving lives, but they can pose a severe risk to process technicians and process engineers during production – and if mistakes are made the results could be fatal.

For example, Dolastatin 10 and Ansamitocin are amazing drugs. One is harvested from a marine mollusc and the other from an African shrub – and while they have two very different backstories, what they have in common is that they are both cytotoxic. Used in microscopic doses, this quality enables a targeted approach to modern treatments that are transforming oncology.

They form part of the HPAPI section of the pharmaceutical industry, which now accounts for 25% of all drugs produced. It’s a sector that is projected to be worth $40 billion by 2027.

POTENTIAL DANGERS

The challenge with HPAPIs, however, lies in their efficacy. Intended to be toxic to cells, they have a typical occupational exposure limit that is under 10 micrograms per cubic metre, and this requires tight manufacturing controls – as their high potency means the consequences of even a small mistake can lead to a range of life-threatening side effects and even death to the operator.

Mistakes would also leave drug manufacturers exposed financially if something goes wrong as the penalties can be huge. The potential implication of such a mistake was illustrated by the record $500 million a global leading

drug manufacturer had to pay in 2013 when safety violations were found to have occurred while manufacturing generic drugs at its plant.

With the pharmaceutical industry relying on a network of specialist contract manufacturers, it’s conceivable that such an incident could force these companies out of business if a violation or contaminated batch was traced back to their sites.

MANAGING TOXICITY

With HPAPIs, manufacturers need to be particularly wary of the dangers, as their physical nature heightens the risks involved during production. Some are dense compounds, but others are highly micronised and exist almost as a gas. This makes the risk of cross-contamination significantly worse since standard cleaning procedures, used after the manufacturing of conventional drugs, may not be effective, and visible checks would not be enough to validate the process.

This can add major costs to manufacturing as facilities require more intensive cleaning before any further work can take place on site. It also means companies are paying for a facility to stand idle while these processes are carried out.

While the competitive nature of the market means that businesses will want to minimise the cost of production, they need to be careful how they do this when it comes to HPAPIs. Fundamentally, ensuring that engineering controls are in place that properly contain manufacturing lines – and they are not placing unrealistic faith in personal protective equipment (PPE).

Where operators are dealing with microscopic amounts of toxic, gaseous compounds, PPE is only

the last line of defence. In some cases, failure to provide proper containment systems has led to deaths of workers – despite the fact they were wearing PPE.

CONTAINMENT SOLUTIONS In contrast to PPE, containment solutions safely separate workers from the production process and remove the risk of exposure. Traditionally this would involve rigid isolators – but, while these units are still popular, they can be costly and they still require intense cleaning and validation after every use.

This is a key reason why many manufacturers are increasingly turning their attention to flexible alternatives, such as polymer glove bag isolators, that are more cost effective. These flexible solutions use specialist protective films made of polyurethane, polyethylene and PVC, to prevent any harmful ingredients reaching the operators. This film typically fits on an ergonomically sound rigid structural stainless steel frame, with other necessary equipment installed around it.

One of the big benefits of this is that when production is complete, the flexible film isolator glove bag can be removed and safely disposed of until a new containment enclosure is installed. The cleaning process is greatly reduced and often not required, meaning downtime validation is minimised. All that needs to be replaced is the protective film itself, and this keeps costs to an absolute minimum.

INCREASING SPEED TO MARKET

Flexible solutions also provide huge advantages in that they can be quickly installed in different spaces and contexts. Broadly speaking, any pharmaceutical manufacturing environment where a support structure can

be installed is suitable for these containment systems.

Many operators are surprised these flexible solutions can deliver the necessary protection, but this type of high containment has been proven to achieve less than 1 µg/ m3 (OEB 5). This technology can also support products with OELs in the nanogram range.

This approach, along with the reduced cleaning validation, is helping manufacturers overcome a broad range of problems that would otherwise be preventing the pharmaceutical industry from manufacturing life-saving HPAPI compounds and getting them to patients faster.

In an industry where getting to market quickly can make a big difference to a company’s prospects, this is providing manufacturers with an alternative solution that helps them to be more competitive – without risking the health or safety of their workers, and effecting the quality of their products, in the process.

Author: MARK ARNOLD, MD of ONFAB, part of Envair Technology

e HPAPI section of the pharmaceutical industry now accounts for 25% of all drugs produced and is projected to be worth $40 billion by 2027.

A FLEXIBLE PLATFORM DEVICE TO STREAMLINE MARKET LAUNCHES

Chronic diseases are one of the world’s major challenges, causing staggering human and economic costs. As well as affecting quality of life for patients and their families, they place a huge burden on overstretched healthcare systems and global economies, while also presenting an important challenge to pharma companies.

One such example is diabetes. Worldwide, around

537 million adults are living with diabetes, and that figure is expected to rise to 643 million by 2030 and 783 million by 2045 [1]. It is a disease that accounted for more than $966 billion of health expenditure in 2021 – 9% of total spending on adults – although it is understood that half of people with diabetes do not meet treatment goals for glucose lowering, which is key to managing their condition.

One of the major drivers behind the growing number of diabetic patients is rising rates of obesity, a factor that is known to put patients at greater risk of developing diabetes. Currently, more than 650 million people around the world are living with obesity and this figure is expected to reach more than one billion people by 2030 [2]. The condition accounts for 8% of global healthcare budgets and in the US alone the economic impact

associated with obesity is more than $1 trillion. Despite these startling statistics, however, fewer than 3% of people with obesity are pharmacologically treated for it.

Pharma innovation continues to play a key role in addressing the human and financial burden of managing chronic conditions such as diabetes and obesity. The growing emphasis on selfadministration of medication,

for example, provides the means to ease the pressure on health services, improve compliance and make everyday life more convenient for patients. And with the Covid-19 pandemic accelerating this trend as routine patient visits to healthcare facilities plummeted, pharma companies have intensified their focus on drug delivery devices that patients can use in their own homes.

Key to the success of any drug delivery device are factors such as proven technology, low development costs, fast time-to-market and a strong intellectual property (IP) position for the pharma company. Against this background, platform drug delivery devices have become more important than ever, providing an ‘off-the-shelf’ choice that minimises project risk and avoids the requirement for an up-front investment of millions of dollars to fund the development of new bespoke devices. Instead, the availability of customisation options to suit a variety of different drugs and primary packaging with minimal change in components keeps costs down and offers faster timeto-market, enabling patients to benefit from new therapies sooner rather than later.

Stevanato Group’s Alina pen-injector is an example of a platform device for variable and multi-dose treatments for conditions such as diabetes and obesity. The device has a user-friendly

design to improve the patient experience. It is intuitive for patients, with minimal user steps, and is designed to give confidence and reassurance.

To help patients select the right dose, Alina has only one number visible in the dosing window at any given time and the dose can be corrected with a simple dial back. Patients receive visual, audible and tactile feedback for dose setting, correction and injection, and the injection force is optimised for patient comfort.

For pharma companies choosing Alina, there are many advantages. The device can be used for different applications as it can deliver a range of different maximum doses –0.30mL, 0.50mL and 0.6mL – in one shot. In addition, the availability of a range of branding and customisation options means that individual colours can be selected for each market segment.

Design for manufacturing and ease of final assembly have also been taken into account to optimise the production process. The device is manufactured at Stevanato Group’s FDAinspected facility in Germany, where access to tooling and sub-assembly equipment is available to clients aiming to maximise the return on investment in their device programmes and reduce time to market. Dedicated production tooling and lines are available on request for customisation or to support

overall risk mitigation strategies.

Alina is fully compatible with Stevanato Group’s range of glass cartridges – such as bulk and ready-to-use EZ-fill cartridges – as well as the company’s final assembly equipment. Moreover, Alina is compatible with a variety of fill-and-finish systems.

Alina can be provided as a flexible device platform because, as a full solution provider, Stevanato Group has a deep understanding of how pharmaceutical products, containers, closures and drug delivery devices interact with each other and work together to form a cohesive system. This holistic approach means pharma companies looking for customised drug delivery and containment solutions can benefit from tailored solutions that combine products and technologies into a coherent, integrated offering.

Stevanato Group’s scalable approach allows for straightforward technology transfer from low volumes –typical in the clinical phase – to mass production on

high-volume equipment, enabling pharma companies to anticipate challenges, mitigate risk and reduce investment costs.

By working closely with a supplier who can provide a holistic strategy – offering optimised glass containment and device services as well as the appropriate equipment and analytical testing – companies can simplify their commercial journey.

Indeed, Alina was developed to address the need to reduce the complexity of the supply chain, and this philosophy of efficiency is applied to all processes relevant to the development of a combination product, from initial concept through to its launch on the market.

Through the combined support of a platform such as Alina and the complementary Stevanato Group’s expertise as full-solution provider, therefore, pharma companies have the flexibility and capability to streamline the market launch of new drug delivery devices, and patients are ultimately given greater flexibility in managing their chronic conditions.

1. “Diabetes facts & figures”. International Diabetes Federation, Dec 2021.

2. “World Obesity Atlas 2022”. World Obesity, Mar 2022.

Opinion

THE REGULATORY SHIFT:

LABORATORY SERVICES POST-BREXIT

MUTUAL RECOGNITION

Author: CHRIS ALLEN, CEO of Broughton

Although the UK officially left the European Union (EU) over two and a half years ago, the impact of Brexit is still being felt by Britain’s pharmaceutical industry. Since then, we’ve noticed that areas like Qualified Person (QP), batch release testing and product manufacturing have been impacted. Manufacturers’ questions remain unanswered in the absence of a Mutual Recognition Agreement (MRA) between the UK and the EMA that would facilitate market access. Chris Allen, CEO of UK-based analytical testing and scientific consultancy provider

We all remember the extensive negotiations that lasted several years after the 2016 referendum and, arguably, the pharmaceutical industry was one of the most important industries to come up in these discussions. And it’s no wonder, Linklaters estimates that each month 37 million packs of medicines are supplied to the UK from European nations, with 45 million heading in the opposite direction. Patients, researchers, universities, businesses, and this pivotal trade flow have all been affected by the regulatory shift.

Fast-forward to 2022, and much uncertainty remains. This is true for both analytical testing services like QC batch testing and in how we can attract the skilled professionals our pharmaceutical industry needs.

Trade of medicines and pharmaceuticals has continued because the UK Medicines and Health Products Regulatory Agency (MHRA) remains aligned with many areas of the European Medicines Agency (EMA). Despite the UK still recognising European standards, the EU no longer accepts generic drugs and other drug products manufactured in the UK, unless they have been tested in an EU member state, or one where an MRA is in place.

It’s no longer a level playing field; one area where this imbalance is clear is batch release testing. The UK has a mutual recognition of audits, but not a mutual recognition of batch release testing data or QP certification. Since the end of the Brexit transition period, the UK has continued to accept batch testing results from the European Economic Area (EEA) and will do so until December 31, 2022. What happens after that remains unknown, but if the UK Government does change its position, pharmaceutical firms in Europe will have two years to adapt to any legislative changes, potentially having to set up new batch testing operations in the UK so that they can continue selling into the UK.

However, we can take comfort in how quickly the UK scientific industry upscaled and adapted when faced with an unprecedented pandemic, rapidly launching the world’s most comprehensive coronavirus testing service.

Broughton, explains the challenges — and opportunities — that Brexit offers.

While not knowing what will happen after January 1, 2023 is a concern for the pharmaceutical industry, the UK scientific community has proven its ability to adapt to whatever changes come into force.

ACCELERATED PATHWAYS

Following Brexit on January 1, 2021, the UK MHRA introduced the UK Innovative Licensing and Access Pathway (ILAP) to deliver safe and financially sustainable accelerated patient access to innovative medicines.

A new rolling review framework has also enabled the modular evaluation of treatments as data becomes available to simplify and accelerate their UK approval. The first COVID-19 vaccines underwent rolling reviews, speeding up patient access compared with other European countries.

As an analytical testing services provider, Broughton has predominantly been working with manufacturers selling into the UK, and we’ve seen the advantage that these accelerated pathways can provide. In the past, UK manufacturers benefited from funding such as the EMA’s Horizon Europe program, but, since Brexit, EU funding has reduced significantly. We’d like to see the UK Government not just matching the funding lost through leaving the EU but increasing manufacturers’ access to funding at both the national and local level so companies like ours can take full advantage of working within a more flexible MHRA framework.

SKILLS AND TRAINING

Although access to technical skills and training was a cornerstone of Brexit negotiations, there are still signs of a scientific skills gap in the UK. In May 2021, the Home

Office even placed specialist pharma roles on a business shortfall list, making it easier for foreign specialists to apply for post-Brexit skilled worker visas. For analytical testing companies, a skills gap could manifest in a shortage of experience across multiple areas such as quality control, quality assurance or product manufacturing.

Analytical testing and scientific consultancy companies like Broughton are not working in isolation ― they’re an essential part of the pipeline feeding other parts of the UK pharmaceutical industry. Without this pipeline, there will be fewer people to step into technical research and development (R&D) roles, undermining future growth opportunities for manufacturers.

We have fantastic scientific skills in this country and need to make the most of them. At Broughton, we benefit from being close to many northern science universities, meaning we can tap into a wide talent pool without being part of the Oxbridge-London triangle. We also noticed that more young people are looking at alternatives to university, so we expanded our apprenticeship programmes as

a way of promoting careers in analytical science. I also participated in the Government’s apprenticeship trailblazer scheme, which focuses on gaining a better understanding of the industry’s skills. This insight helps develop apprenticeships that train young people with the right expertise, helping to close skill gaps for businesses like ours.

No one can deny that Brexit profoundly impacted the UK’s pharmaceutical industry, and analytical testing services are on the frontline. While much uncertainty remains, especially in the run-up to January 1, 2023, there are many reasons for hope. If we can continue feeding the industry pipeline with strong home-grown technical skills and the UK Government provides the necessary level of investment, the pharmaceutical industry could harness immense benefits from working within a more flexible regulatory environment.

We can take comfort in how quickly the UK scienti c industry upscaled and adapted when faced with an unprecedented pandemic, rapidly launching the world’s most comprehensive coronavirus testing service.

KEY REASONS

for Outsourcing Your Formulation Development and Manufacturing Needs

Partnering with a Contract Development and Manufacturing Organisation for your formulation development and manufacturing needs can provide a solution to help compress timelines and mitigate risk. A CDMO can provide services from early-stage clinical development through to clinical and commercial manufacturing and packaging, including full technical and analytical support, launch capabilities and final distribution. It is a compelling argument as to why engaging in this service model in the early stages of drug development can yield a positive process for all involved.

Managing development activities to compressed timelines, the identification and timely resolution of development challenges, as well as the alignment of the various components in the supply chain, has never been more important. This is leading to more companies seeking out the benefits of accessing external capacity and capabilities at CDMOs as they look to manage these pressures and access resources to progress their pipelines.

Outsourcing early development activities is something Almac is increasingly experiencing as companies look to accelerate

from candidate selection to clinical trial entry, and ultimately get to proof-of-concept as quickly and efficiently as possible. Traditionally smaller pharma companies outsourced these activities, but there has been an increasing number of large-scale pharma companies utilising CDMOs for early phase development. This includes pursuing ‘reserved capacity models’ to guarantee access to formulation, analytical, and manufacturing capabilities and capacity so that they can move multiple assets in their portfolios forward quickly when the need arises.

Almac Pharma Services supports many key elements of the clinical and commercial supply chain. Availing of single source integration of development and commercial resources including Technical, Analytical, Quality and Project Management ensures scientific continuity and simplified effort, saving time and expense whilst reducing

vendor management and mitigating risk to the overall project. This alleviates unnecessary concerns for the sponsor company, providing a cohesive and smooth transition from development to production.

Selecting a CDMO with a high level of experience is key to a successful partnership. Providing the client with a wealth of previous knowledge in early development and manufacture and being able to deliver quality data in pre-formulation and formulation of oral solid dosage forms. Collaboration through a products development and commercial lifecycle can provide the client with access to teams with specialist knowledge and experience as and when the product demands it, for example, in fields such as development and manufacture of paediatric formulations.

Engaging with a company like Almac Pharma Services not

only provides a client with the benefit of knowledge and proven experience, but also access to a wide range of capabilities, technologies, and development facilities for both non-GMP and GMP product batches. This ensures not only complementary equipment trains, but also integrated technical teams to facilitate a products increasing scale demands through the development lifecycle. Dedicated pharmaceutical development teams provide analytical resources that support manufacturing activities from early phase development through registration stability, and process validation, and ultimately into commercial supply.

Partnerships with CDMOs mean that clients can expect peace of mind as development and commercial teams work together to ensure a smooth transition of their products from development into commercial manufacture.

ere has been an increasing number of large-scale pharma companies utilising CDMOs for early phase development.

Author: James Hurst, vice president of Operations at Almac Pharma Services and site head of the organisation’s Charnwood facility in Loughborough, England

PRINTING PILS: HOW ONE BUSINESS IS KEEPING IT GREEN WHILE NAVIGATING A CHANGING WORLD

Sustainability is a hot topic across the board and the printing industry is no different. Businesses from SMEs to large corporations are feeling the pressure to make sure they are green and have squeaky clean environmental and CSR strategies.

Alan Ryan, managing director of Technoprint, a UK independent supplier of patient information leaflets (PILs), outlines some of the ways the business makes sure it stays ahead of the game when it comes to sustainability. From credentials to E-PILs, Alan delves deeper into the topic of leaflets, packaging and sourcing products sustainability.

GROWING PATIENT INFORMATION LEAFLETS

One packaging challenge faced by Technoprint over the past decade has been the growing level of information required on patient information leaflets. Despite the need for bigger leaflets, the requirement is to still fit these leaflets into the same size packaging as the smaller leaflet.

Alan explains: “It can be complex and costly for customers to change the size of packaging, as well as potentially having more impact on the environment. So one thing we’ve had to adapt to is making sure they can still use the existing packaging even when the leaflets have changed. Legal requirements mean that text size must be readable, and spacing is right, yet there’s much more text to be included on the leaflets. As well as this, our customers will have one type of packaging that will be sent across the world, so the

leaflets must include various languages, as changing leaflets and packaging by country is once again a logistical nightmare for them.

“We’ve addressed this issue in a couple of ways. Firstly, sourcing and using one of the most lightweight papers on the market, Pharmalite. There are not many commercial printers that can handle paper that is

less than 60 grams but using papers that are more like 45 to 50 grams like Pharmalite has lots of advantages. This kind of paper requires particular skill and machinery, as well as the right conditions. Lightweight paper means that all the information can fit onto larger paper whilst the packaging, weight, transport etc does not have to change.”

Transportation is of course

another factor when it comes to sustainability, and one that will be addressed later in the article.

Alan continues: “Handling, printing, folding, and guillotining lightweight paper is a specialist skill. It’s crucial that premises have 24/7 365 days a year humidity control to prevent any paper being spoilt, as if it does get bowed or bent it can be difficult to print on at high

speed and folding becomes almost impossible. We’ve also introduced tagserts, self-adhesive labels to hold leaflets closed so they fit into the packaging.”

CREDENTIALS

Technoprint has found having the right credentials in place is crucial, not only for the sake of the environment but also for obtaining new clients.

Alan explains: “We’ve found a lot of our customers are facing the task of reducing their packaging and waste and there’s a lot of talk around how to achieve this and it’s

something we work closely with clients on.

“We’ve always valued the importance of having environmental credentials and we are proud to have obtained them. ISO 14001 and FSC (Forest Stewardship Council) are the main ones for us. They show that our paper and products are sourced ethically and responsibly, we’re committed to the environment having PS9000 and that any packaging we use falls in-line with good manufacturing practises.”

Technoprint has also been awarded an EcoVardis gold sustainability rating, meaning that it has been assessed in the four areas of environment, labour and human rights, ethics and sustainable procurement and has scored highly across the board.

Alan continues: “We’ve made lots of adaptions and small changes over the years in order to obtain these kinds of high standard accreditations, for example our leaflets used to be packed open top trays that are shrink wrapped but we changed to integrated trays which have a single waste stream that is recyclable about five years ago and this is something that our clients appreciate.”

BUYING BRITISH

Alan says he’s seen a shift in the industry of late, with more businesses choosing to buy British in order to save on fuel and travel costs as well as reducing air miles and the impact on the environment.

“Our customers are recognising more and more that sourcing locally can be more cost effective, especially after the UK left the EU. Sourcing locally of course means travel time and fuel consumption is reduced which is always good for the environment. One example is a recent vape customer of

ours that have brought their production from China into the UK. There are on-going supply chain issues everywhere, but being an independent business means we’ve been able to keep on top of supplies and keep customers happy, which is always a positive thing!”

LOOKING TO THE FUTURE

Alan concludes: “Businesses need to constantly adapt to keep up with supply and demand. We recently updated our machines to allow for a bigger sheet size, for example. I think the pharma industry as a whole has a long way to go though, e-PILs are sometimes spoken about, to reduce the use of paper, but nobody has found a way to properly introduce these across the board safely. Paper is, and always will be, the fool proof solution.”

Lightweight paper means that all the information can t onto larger paper whilst the packaging, weight, transport etc. does not have to change.

Author: ALAN RYAN, managing director at Technoprint

FIVE WAYS PHARMA COMPANIES CAN MEET DEMAND AND STAY COMPLIANT

Scientific advances have made it possible to live longer. One UN study predicts that people aged over 65 will represent 16% of the global population by 2050, up from 9%, and the proportion of over 80s will triple. However, an ageing population increases the demand for healthcare at a time when 30% of the population already has no access to essential medicines. The pharmaceutical industry faces a long-term challenge and opportunity to produce medicines and treatments in greater quantities, such as those used to manage conditions in later life.

Increasing the capacity of manufacturers to meet future demand is vitally important. Failures in product or facility quality cause 66% of all drug shortages, while failure to comply with stringent regulations across the pharma and life sciences industries can also result in significant cost penalties, which have increased by 43% globally during the past decade.

These are five important areas pharmaceutical facilities need to be aware of to transform their operations and improve production.

1. CONTROLLING ENVIRONMENTAL FACTORS

Pharmaceutical production and storage require optimised conditions. Poor management of the production environment and product lifecycle can impact quality standards and risk regulatory violations and delayed approvals, slowing the release of products. Currently, 60% of electrical energy is consumed by environmental control, and approximately 8% of energy is lost per annum

due to failures to monitor and manage environmental conditions accurately. Poorly managed environmental conditions often deteriorate equipment, producing an inconsistent final product, which presents financial and environmental costs for the business.

Plant operations need to be highly responsive to maintain production and minimise the impact of disruption, whilst all drug manufacturers must comply with good manufacturing practices (GMP).

Three things are needed to effectively maintain

environmental conditions: a dedicated system to control and monitor environmental conditions, real-time energy monitoring and production correlation, and an awareness of effective regulatory compliance. Combined, not only will they manage environmental conditions, but they also have the added benefit of controlling energy use.

2. FAILURE OF THE PHYSICAL INFRASTRUCTURE

Maintaining plant equipment and utilities is paramount. An unreliable power supply can lead to momentary dropouts,

brownouts or complete failure and even the briefest break in power continuity can result in loss of sterility, failure of crucial assets, and product loss.

As companies look to revamp their physical infrastructures, simulation allows them to conduct real-time tests and gain insight without disruption. Artificial intelligence, virtual reality and augmented reality can also address the risks of physical infrastructure failure.

Advancements in analytics have shifted from historical operational dashboards to real-time analysis – diagnosing and visualising data from the

Author: MARK YEELES, VP Industrial Automation, Schneider Electric

plant without having physical contact with machinery or control enclosures through the industrial internet of things (IIoT) sensors.

With global power demand mounting and the strain on national utility grids clear, a combination of on and off-site renewable energy is often used to supplement grid usage. Once the infrastructure is in place, renewable energy provides a source of energy that meets sustainability targets and takes the pressure off grids.

3. USING DATA FOR COMPLIANCE

Regulatory requirements are in place to ensure medicines are safe for consumption and failure to comply comes with a hefty cost. It is estimated that non-compliance costs 2.71x times more than maintaining or meeting compliance.

Data is crucial to inform key decisions and ensure requirements are honoured; this is one of the industry’s biggest challenges. The FDA found incorrect data on 79% of drug warning letters over the last five years. Missing or inaccurate data can itself lead to non-noncompliance, delays, or even shutdowns in production. Additionally, two-thirds of pharmaceutical companies have suffered serious data breaches due to cyber hacking, with the cost impact running into the millions alongside the reputational damage that follows a breach. Whether non-compliance stems from incorrect data or not, manufacturing companies often receive hefty fines and license suspension or removal if found to be in breach of regulation.

Instead, digitising operations and workflow management helps reduce the risk of human error, one of the biggest risks to quality control. This helps guide employees through the correct steps of protocol. Digitising document validation processes

in a digital environment saves time and enables companies to adhere to regulatory requirements, promote data integrity and ensure complete traceability throughout the lifecycle.

4. RESPONDING TO OPERATIONAL CONCERNS

The ability to quickly adjust to shifting requirements is essential for facilities. Failure to remain agile has much to do with system complexity, procedural restrictions, and a lack of a standardised approach to incidents. An overly complex system, and heavily loaded communication network, can reduce the operator’s effectiveness. Constraints from numerous regulations, extensive signoffs, and a lack of standard operating procedures (SOP) make it difficult for operators to resolve a situation quickly. This can have a considerable knockon effect on production.

SOP adoption can be crucial in promoting agility across facilities. Without routine standardisation, complexity and undesirable variability can be introduced. Pre-configured standards assist in streamlining methods in cases where businesses must respond quickly and stop situations from getting worse.

Introducing a digitised dashboard means data is easily viewed on devices, saving time and increasing efficiency. Through simulation, data modelling, and analytics, businesses can make decisions based on real-time data on individual assets, processes, or entire systems. By anticipating and avoiding operator error, efficiency and safety are boosted.

5. OPERATIONS AND SUSTAINABILITY OBJECTIVES

Overall, there is a societal perception that the pharma industry or ‘big pharma’ is unconcerned about

environmental impact, which they are working to reverse.

Pharmaceutical businesses must prioritise energy management and sustainability to demonstrate how resources are managed to optimise production costs and meet sustainability obligations.

With data being generated from multiple locations at any one time, the ideal solution is a platform which provides central visibility and detailed reporting to manage these different data streams. Enterprisewide visibility offers complete transparency to help develop and benchmark sustainability KPIs and track their progress towards company targets.

A robust energy monitoring and targeting tool can also compare and benchmark performance to identify energy efficiency and carbon net zero opportunities. This provides a single source of information for projects to drive energy efficiency, water usage and the journey towards carbon net zero. Sharing digital dashboard platforms allows teams to modify goals or projects midcycle and track the progress of environmental objectives.

THE POWER OF DIGITALISATION

Businesses in the pharma sector are under pressure to provide products that adhere to strict regulatory standards while also pursuing operational efficiencies and sustainability. Digitalisation enables companies to unite real-time data from previously siloed sources to provide contextualised information helping to drive business decisions, boost sustainability performance and ease regulatory compliance. Utilising tools for digital project delivery of new facilities will ensure that the next generation of manufacturing facilities will be adept at facing risks and uncertainties that impact their production capabilities.

AUTOMATED MICROFLUIDICS FOR NANOPARTICLE FABRICATION

Effective drug delivery ensures that therapeutic agents reach their intended destination, releasing the active pharmaceutical ingredient at the target site while avoiding off-target effects. Nanoparticles can be used to encapsulate drug molecules, preventing premature metabolism as they pass through the body, as well as increasing penetration of the cell membrane. Some nanoparticle formulations also have the ability to target specific tissues where the treatment is needed. However, it has so far proven difficult to create optimised nanoparticle constructions with consistent particle monodispersity using conventional batch methods. Dr. Julia Rashba-Step is the VP of R&D and Alliance Management at Phosphorex, a CDMO specialising in the formulation and manufacture of particles. She explains how the organisation is using microfluidics to help its clients accelerate their nanoparticle fabrication and forward the development of new nanomedicines.

Interest in lipid nanoparticles (LNP), has grown significantly in the last decade, and the tremendous success of LNPbased mRNA vaccines during the COVID-19 pandemic has led to further explosive growth and new opportunities in this area. Nucleic acids – including plasmid DNA, oligonucleotides, small interfering RNA (siRNA), messenger RNA (mRNA) and microRNA (miRNA) – have shown a lot of promise for treating complex diseases.

However, the effectiveness of these therapeutic agents strongly depends on them being able to reach the target tissue without deteriorating on route.

TRADITIONAL BARRIERS TO LNP PRODUCTION

LNPs are excellent delivery vehicles for the controlled release of these molecules, as they are capable of supplying the active pharmaceutical ingredient (API) to a specific action site while protecting it from premature degradation. Unfortunately, the fabrication of these important nanoparticles brings with it several

challenges, and finding the correct composition can be both complex and extremely resource intensive. Properties such as the monodispersity and size of the particles are extremely important, but current production methods are either batch based or use large-scale continuous flow equipment, such as membranes, which produce inconsistent particle sizes.

These techniques also have poor encapsulation efficiency – the amount of drug or other cargo that ends up contained inside the particle – and require constant revalidation, resulting in the wastage of expensive materials and valuable time. The minimum sample size for existing fabrication methods is also typically large, further exacerbating the problem with the high costs and limited availability of both specialised lipids and the API. In addition, most drug development projects have very tight timelines, so it is necessary to rapidly establish a cost-efficient method for largescale particle-encapsulated drug production once a good candidate had been discovered.

A NOVEL METHOD FOR PARTICLE FORMULATION

Microfluidics is emerging as an excellent alternative for nanoparticle fabrication, as it allows experiments to be carried out with small quantities of materials and offers exceptional particle size monodispersity and encapsulation efficiency. The technique can also be scaled up to high throughput without requiring any changes in the fundamental particle formation method. Phosphorex is taking advantage of a dedicated nanoparticle production platform – the Automated Nanoparticle System (ANP System, Particle Works) – which uses microfluidics to offer automated set-up and processing of multiple samples.

The ANP System optimises the fabrication process through the rapid, automatic adjustment of different microfluidic parameters – such as flow rate or temperature – in order to find the ideal particle size, shape and structure, and has the potential to improve tissue targeting and drug encapsulation. The workflow begins with lipid and

cargo being loaded into software-controlled reagent injection loops – the sole manual step in the protocol – then the system executes a series of experiments automatically, controlling pump operation, loop switching and washing without operator input.

The system reliably and repeatably generates particles ranging from 40 to 800 nm, and automation streamlines the screening of nanoparticles against a wide range of biological targets to allow the selection of candidates with the most promising performance. Other parameters – such as stability, charge, solubility and viscosity – can also be easily adjusted by using different lipids, reagents and microfluidic chips.

Phosphorex has successfully used this system to fabricate mRNA LNPs with a controlled particle size of between 80 and 150 nm, at rates between100 µl/min and 16 ml/min per channel, with encapsulation efficiencies of up to 98 per cent. This has allowed the team to work with small amounts of material during the development stage, reducing wastage of expensive APIs early on. The process can then be scaled up to a higher throughput without the need to revalidate the protocol at every stage, providing both fast and economical product development.

CONCLUSION

Automated lipid nanoparticle production offers a complete and convenient nanoparticle fabrication pathway, stretching from initial protocol development all the way to final manufacture, cutting out the need to continually change and revalidate methods between stages. Thanks to the ANP System, the team at Phosphorex now has a flexible and cost-effective tool for generating new LNP libraries and optimising the whole production process.

The platform allows better control of particle size distribution and, crucially, improves API encapsulation efficiency. The system is also highly scalable, as it operates in continuous flow and is able to incorporate multiple microfluidic chips working in parallel, ensuring that the same method can be used from start to finish. This innovative automated microfluidics set-up has significant potential for removing the common roadblocks to progress in nanoparticle-based therapies, such as time delays and financial limitations, contributing to advances in the clinical development of nanomedicines.

e tremendous success of LNPbased mRNA vaccines during the Covid-19 pandemic has led to rther explosive growth and new opportunities.

MAXIMISING LIMITED DRUG SUBSTANCE TO DEVELOPING OPTIMISED FORMULATIONS

At the beginning of an oral drug delivery development programme, it is not uncommon for the quantity of active pharmaceutical ingredient (API) available to formulation scientists to be limited, which can make it difficult to gather sufficient meaningful data to select the most promising candidates to advance into in vivo studies.

Any formulation ultimately progressed through to clinical studies must demonstrate adequate and consistent drug-to- patient exposure, to collect high quality data. Through an iterative process, numerous prototypes during initial animal pharmacokinetic (PK) studies may be needed to determine the ideal formulation, requiring multiple formulation adjustments that not only take time, but also use greater quantities of API material.

Using in silico modelling, that can predict a compound’s absorption, distribution, metabolism and excretion (ADME) parameters using the molecular structure gives initial information to act as a starting point for formulation studies, and optimise API usage for in vivo studies. Data from these studies can then be fed back into the models to enhance and refine output.

Insights into metabolic susceptibility by human liver CYP450 enzymes can be gained by testing

using liver microsomes and/ or a hepatocyte cell line. Compound solubility in biorelevant media along with an estimation of the intestinal permeability from Caco-2 cells, provide data on oral absorption potential. The biorelevant solubility measurements and predicted permeability can be inputted into the Developability Classification System (DCS) to provide an estimate of oral formulation development risk, and guide formulation development.

The three key factors that determine oral API bioavailability are the molecule’s solubility, metabolism and permeability, and candidates that have the greatest potential to be orally delivered are inherently resistant to hepatic metabolism and/or display high permeability. Solubility is where formulators can be most impactful, and if enhancement is necessary, there are a number of in vitro techniques that can be used on limited quantities of API to ensure the correct formulation for further studies, including small volume dissolution, twostage dissolution, liquid-liquid phase separation, polymer screening studies, film casting, crystallising tendency and flux measurements. Deciding upon the appropriate technique to use may depend on API availability, timescales, and enhancing technologies under evaluation.

SMALL VOLUME DISSOLUTION

Small volume dissolution is useful where kinetic or equilibrium solubility is an issue, for example in micronised materials or amorphous solid dispersions (ASDs) of crystalline drugs. Experimental apparatus is commercially available, and uses small vessels, monitored using fibre optic probes with small amounts of API. The setup measures API concentrations every few seconds rather than minutes during typical full-scale dissolution experiments.

TWO-STAGE DISSOLUTION

The API’s solubility can be very sensitive to pH and the nature of the dissolution media. In the acidic stomach, weakly basic APIs are typically very soluble, but when exposed to the higher pH in the small intestine, can precipitate. Two-stage dissolution experiments can be used to investigate the behaviour of the API during this pH shift. Ideally, an API will remain supersaturated in the small intestine for sufficient time to allow for absorption, but if precipitation occurs at a high pH, follow-up two-stage dissolution experiments should

Author: Lisa Caralli, Science and Technology director, Pharmaceutics, Catalent, discusses the methods that formulation scientists can undertake on small quantities of API to achieve the greatest possible results to progress through drug product development.

Author: LISA CARALLI, Catalent

occurs can be influenced by the biorelevant media used, and the presence/absence of polymers within it. Additional experiments are necessary to identify which polymers can successfully maintain supersaturation of the API, and will need to be incorporated into any final amorphous drug dispersion.

Small volume dissolution apparatus can only be used for polymer screening with small quantities of API, and additional experiments can investigate the optimal API-polymer ratio to provide an estimate of the drug loading feasibility for an ASD formulation.

Figure 1. shows the theoretical dissolution behaviour of a poorly soluble compound as a crystalline drug, an amorphous drug and an ASD. The crystalline drug displays low solubility, whereas the amorphous drug shows peak solubility but quickly drops. The ASD achieves the spring seen with the amorphous drug, and helps maintain supersaturation in solution (parachute effect), improving API encapsulation efficiency. The system is also highly scalable, as it operates in continuous flow and is able to incorporate multiple microfluidic chips working in parallel, ensuring that the same method can be used from start to finish. This innovative automated microfluidics set-up has significant potential for removing the common roadblocks to progress in nanoparticle-based therapies, such as time delays and financial limitations, contributing to advances in the clinical development of nanomedicines.

Figure 1: Spring and parachute concept to achieve high apparent solubility for insoluble drugs.

light microscopy (PLM), differential scanning calorimetry and/or powder X-ray diffraction.

CRYSTALLISING TENDENCY

PLM can also be used to study the crystallising tendency of an API, and this requires little API material. Molecules that exhibit a low crystallisation tendency are often good candidates for ASD formulation.

SMALL VOLUME DISSOLUTION – FLUX MEASUREMENTS

In the small intestine, the jejunum is between the duodenum and the ileum. Permeability across a jejunallike membrane can be studied by measuring the concentration of an API in solution across donor and acceptor compartments. The rate of flux across the membrane can be calculated, and although this does not predict tin vivo PK specifically, formulations can be ranked with respect to their expected in vivo performance. These studies are most useful when investigating complex lipid formulations, where movement across membranes may be more directly impacted by the formulation.

MAXIMISING API RESOURCES

be conducted to screen for polymers that can maintain the API supersaturation following the pH shift.

LIQUID-LIQUID PHASE SEPARATION AND POLYMER SCREENING STUDIES

Liquid-liquid phase separation (LLPS) occurs when the concentration of the API exceeds its amorphous solubility, and is characterised by the formation of drugrich colloidal species within a supersaturated aqueous solution of a poorly soluble API. The concentration at which LLPS

FILM CASTING

Film casting also screens for suitable polymers, and estimates the drug loading for an ASD formulation and the physical stability of API-polymer mixtures. In a typical experiment, the API and potential polymer are dissolved in a solvent and an aliquot of the solution is added onto either a slide, or into wells of a 96-well plate where the solvent evaporates, leaving a film. Phase separation or API crystallisation of the film is then investigated using polarised

Time pressures and the amount of API available for early development programmes mean that formulation scientists need to capture as much data as possible with both careful planning and resource management. In silico tools are invaluable in guiding starting points for development, and advances in rapid experimental techniques that use little API material can mitigate these challenges and yield the information necessary to choose the most promising formulation candidates to move on to in vivo studies.

Author: Allen Jacques, industry thought leader at Kinaxis

OVERCOMING SUPPLY CHAIN IN THE PHARMA INDUSTRY disruption srupti rupt

The pharmaceutical industry fared relatively well through the pandemic, with few manufacturing sites being closed due to infections. Therefore, it may come as some surprise that the sector has recently hit rockier ground. A supply chain shortage has come to light, leaving many patients struggling to access pain relief, oncology medication, anticlotting agents, and other important drugs.

The ramifications of this supply chain issue could be severe. Already, over half (54%) of UK pharmacists surveyed fear that patients have been put at risk in the past six months due to shortages. With the government now urging hospitals to ration stocks of certain drugs, action must be taken to minimise the impact on end consumers needing medicines.

However, the picture is not all bleak. The pharma industry is robust enough to heal its supply chains – if it leverages the right tools. By using technology to improve supply chain visibility and transparency, companies can plan for volatility and identify potential disruption before it occurs, thereby restoring consumer wellbeing and trust.

WHAT IS FUELLING THE SUPPLY CHAIN SHORTAGE?

Supply chain shortages have been a recurring problem over recent months, but for pharma, certain factors have combined to create a unique challenge. Firstly, demand for hormone

replacement therapy has doubled over the last five years – largely due to increased awareness of the menopause – while capacity has failed to keep up. Seasonal demand for certain hay fever medications was similarly left unmet recently, this time due to shortages in stocks of chlorphenamine maleate.

Current trade tensions have only exacerbated the issue. Raw materials and active pharmaceutical ingredients sourced from countries like China can be caught in logjams due to international disputes. Meanwhile, some believe that Brexit has created importation complexity, significantly slowing down the entry of externally sourced drugs.

Inevitably, questions of profitability can also come into play. Pharma companies often prioritise patent protected drugs, where profit margins are high, over drugs with generic competition, where profit margins are much lower. This does little to help tackle shortages of non-patented painkillers, blood pressure pills, and antidepressants.

TECHNOLOGY: AN ANTIDOTE TO THE SUPPLY CHAIN CRUNCH

Of course, some factors – like Brexit and geopolitical trade tensions – are outside of the pharmaceutical industry’s control. But the time has come for companies to focus on what they can control – and they can do this by bolstering the resiliency of their supply chains.

The pharma supply chains that are in the best current shape are those that can see and assess events quickly and drive actions to

ruptmitigate any ensuing disruption. This involves having consistent visibility and transparency, not only internally but also into suppliers, contract manufacturers, and downstream distribution. While this may initially sound complex, innovations in technology mean that companies can now work from a single platform to intuitively manage, link, and collaborate with data insights across the supply chain network.

Having this capability allows companies to respond much more quickly to potential disruptions in the pharma supply chain. For example, the visibility provided by data analytics will help the industry to anticipate and pre-empt changes in consumer demand, so that a targeted, timely response can be put into motion. Technology can also facilitate better planning for factors such as manufacturing problems, late supply of raw materials and components, and compliance issues.

Everybody benefits from greater supply chain visibility, transparency, and resilience. For pharma companies, the agility to make fast, confident decisions across the entire supply chain will undoubtedly drive business growth and help to protect revenues. But even more importantly, it ensures that end consumers can get the medicines they need, with zero delay. The implementation of technology means the pharma industry can futureproof its supply chains to better serve the needs of companies, healthcare providers, and the public at large.

Optimising data collection and synthesis in compliance e orts

Punya Abbhi, COO at Celegence, explains how the adoption of digital technologies enables companies to manage their regulatory compliance requirements in a more efficient and reliable manner.

Compliance at pharmaceutical companies is often perceived solely as an enabling function – it needs to be executed to required standards but can be a burdensome task with little opportunity to create additional value.

However, compliance does need specialised expertise, collaboration between departments within an organisation and, traditionally, several well-established manual processes. This means that compliance programs may only ever be as powerful as the skills and number of people involved.

This is where digital technologies can make it possible to keep up with the growing amount of data. Organisations must explore how to optimise data collection, remediation, syncing, and submission to external authorities to streamline compliance efforts.

LEVERAGING ROBOTIC PROCESS AUTOMATION TECHNOLOGY

RPA is software that seeks to mimic human capabilities to increase efficiency and reliability in certain, well-defined, and repeatable tasks.

There is a significant opportunity to use RPA across the healthcare industry, with the potential to employ the software in managing electronic records and data sharing, appointment scheduling, data analytics and diagnostics, and in regulatory operations, among others. The ability to automate the copy and pasting of data entries for regulatory information management for instance, allows for the more efficient creation of content and data reuse. As the software is automated, it

can perform these tasks faster, more consistently, and for longer periods of time when compared to humans.

A Pegasystems survey of decision-makers employing RPA solutions found that 63% stated it was a ‘major component’ of their overall digital transformation.

STREAMLINING THE PROCESS

To best harness digital technologies’ capabilities, companies can identify where tasks are executed according to clear, harmonised, and defined requirements. RPA can provide a solution and offer a better alternative when these tasks are resource-draining or inefficient.

For example, RPA can be used in management of data in RIMS (Regulatory Information Management Systems) that may require data elements to be verified against documents before being entered into the system. These data elements might even need to be added in more than one screen in the system, and verification that the correct data was submitted to the system can be time consuming. By utilising bots for this type of work, regulatory associates are free to focus on QC activities and process improvements.

RPA technology can also support scheduling activities by programming the software to understand when a document is due to be updated or submitted. At this point, it can assign the work and resource allocation to the correct individuals and initiate those projects.

A SUPPLEMENT, NOT A REPLACEMENT

It is important to point out that RPA software cannot replace human medical writers, nor will it decrease the demand for their work. Instead, it allows medical writers to focus on the work of understanding and articulating data to create a convincing scientific narrative. There are also limits to what the software can help with. RPA is limited by its programming – if it does not have the correct instruction to identify and copy certain data, no action will be taken.

However, in specific use cases, the automation enabled by RPA can accelerate the generation and harmonisation of data across multiple documents. Just as importantly, the software can reduce human input errors on manual data entry tasks. This improves the overall efficiency and quality of medical writing, whilst also providing regulatory affairs team updates of project status throughout the entire process.

Author: PUNYA ABBHI, COO at Celegence.

Not only does the 505(b)(2) support developers, but it also allows patients to have access to more treatment options. However, formulating drug products for these targets can still present challenges related to poor water solubility and/or bioavailability.

STRATEGIES FOR SOLUBILITY

Excipients have always played an important role in the formulation and manufacturing of pharma dosages, aiding product functionality as fillers, binders, or coatings. For oral dosage forms, these include substances such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and polyvinyl pyrrolidone (PVP).

In parenteral formulations, modified cyclodextrins, polyethylene glycol (PEG), polysorbate 20, and polysorbate 80 have been used in many approved drug products over the years.

Alongside the use of excipients, formulators investigating oral solid or parenteral forms for low soluble APIs may also consider utilising formulation techniques, including:

• Physical Modification: amorphous dispersions, milling, co-crystals

• Chemical Modification: pH modification, salt formation, PEGylation

• Encapsulation Techniques: micelles, liposomes, lipid/polymer-based encapsulation

• Inclusion Complexes: cyclodextrins, serum albumin

Leveraging the right excipient technology is important for these formulation techniques,

as they provide a tool to stabilise APIs and increase solubilisation. But, when it comes to selecting the best method for your drug formulation, factors such as properties of the API, intended final dosage form, and even commercialisation factors such as cost of scale-up and IP protection, need to be considered.

Furthermore, leveraging traditional approaches alone for poorly soluble drugs may not be able to enhance the solubility up to the desired level. As such, finding the right approach for each project requires investigating combinations of various polymers and formulation techniques.

NEW TECHNOLOGIES, COLLABORATIVE SOLUTIONS

Novel excipients can open new paths of opportunity for drug developers and are becoming an increasingly attractive option to improve the solubility of hydrophobic APIs.

However, as new, complex, and multifaceted NCEs and 505(b)(2) opportunities continue to move through the pipeline, formulators will need to leverage new tools to ensure more of these drugs make it to market. Polymeric excipients are one of the main areas gaining traction, such as Apinovex and Apisolex, which can support oral solid and parenteral dosage forms, respectively.

Furthermore, novel excipients play a major role in optimising established formulation techniques and efficacy and IP protection are the most prevalent reasons as to why.

The indicative new IP protection from the novel

excipient means that there is a long patent life ahead for drug developers and marketers to utilise. New chemical entities can generally rely on their own IP; however, novel excipient IP may be useful for older clinical candidates that had been previously shelved due to solubility issues.

Despite this, there has been hesitancy within the industry to apply them in development programs due to perceived regulatory and scale-up challenges. However, an experienced and reliable excipient supplier can mitigate the risk associated with novel excipients by establishing robust processing under GMP guidelines, providing safety and toxicity data, and creating Drug Master Files (DMFs).

SOLUTIONS WHICH SUPPORT THE WHOLE MARKET

Patient centricity is often a concern in the formulation of novel therapeutics. With a growing, ageing population, patients need efficacious therapeutics that can be delivered efficiently and with minimal discomfort. An API that exhibits poor solubility will need a higher dosing or more frequent administration to achieve the desired therapeutic effect, which can increase the incidence of side effects.

The amount of API that can be included in a dose of a drug product is often impacted by the excipients used. In oral solid dosage forms, inefficient drug loading in a tablet means that a patient may need to take a difficult-to-swallow tablet or multiple tablets throughout the day to achieve the desired dose. Similarly, for parenteral therapeutics, patients may need to receive longer IV infusions or multiple injections to achieve the recommended dosage.

Some novel excipients can

address these difficult-toadminister challenges, allowing for more efficient drug loading or encapsulation than traditional options.

Formulations that utilise complexing excipients usually require high amounts of polymer to solubilise drugs. This limits the drug loading and increases the potential risk of polymer side effects. Efficient, novel excipients, such as the polyamino acid-based polymers developed by Lubrizol, have been designed for low usage levels, minimising the risk of side effects. And from a compositional perspective, polymers made from naturally occurring amino acids, such as sarcosine, offer an inert replacement to polymers like PEG and polyvinyl alcohol (PVA).

Novel excipient development has helped solubilise BCS Class II and IV APIs, not only easing the pain points for developers, but helping to create better and more effective therapeutics for patients that have a lower risk of adverse side effects.

SOLUBILISING THE FUTURE, TODAY

As more poorly soluble molecules enter the pipeline and more pharma companies seek ways to utilise the 505(b) (2) regulatory pathway, excipient technologies and manufacturing techniques provide the tools to carry out more efficient and effective drug development.

However, selecting the best excipients requires a balance between time and cost efficiencies as well as anticipated product performance. Looking to the future, collaboration between pharma companies and innovative excipient suppliers continue to play an important role in providing higher quality drug products.

ENSURING FINANCIALLY SUSTAINABLE EUROPEAN GENERICS MANUFACTURING

The global pharmaceutical generics market is currently going through a very difficult time as a result of the pandemic and the war in Ukraine. Pharmaceutical companies are trying to find a way to reduce supply chain dependencies and diversify risks[1], against the backdrop of the highest industry inflation in many years[2]. The European Union Producer Price index indicates a clear pattern of rapidly rising manufacturing costs[3]. The prices for certain APIs, excipients and packaging materials went up by multiples[4], signalling the need for immediate discussions amongst stakeholders in the pharmaceutical value chain to ensure product supply continuity. In addition to these challenges, Europe is witnessing an unprecedented call for energy rationing, including for medicines production[5], which has the potential to complicate and harm the generic pricing. Generics manufacturing in Europe is critical to ensure patient access to affordable, high-quality medicines.

MATERIAL PRICES CLIMBING

The manufacturing costing structure for different pharmaceutical forms and formulations can vary significantly depending on the process. Some products are labour intensive, with stable labour rates and materials price fluctuations do not have a significant impact on the costs. Others are almost entirely material driven, especially in finished product manufacturing. It is

not uncommon for materials to account for 95-96% of the cost (API, excipients and packaging components). They are often supplied from external sources, and when purchasing prices skyrocket, there is no other way but to transfer the increases through the value chain. This is particularly valid for APIs. They are registered in the dossiers and diversifications require substantial investment in validation and stability studies, as well as time for marketing authorisation updates. Second sources for excipients and packaging materials should be investigated based on the yearly volumes used by a company. In certain circumstances, establishing a second source results in reduced MOQs and, thus, higher pricing. Therefore, to mitigate supply risk and ensure competitive prices, we may end up raising costs.

PRICE PRESSURE AND THE IMPACT OF INCREASINGLY STRINGENT REGULATIONS Securing supply of lifesaving medicines is the highest priority for both the pharmaceutical manufacturers and local governments. The rising material and utility costs call for an immediate conversation on adjusting the market ceiling prices for less expensive and extensively regulated generic products. The industry cannot absorb the current cost increases entirely. Some of these increases must be passed further in the value chain in order to ensure supply continuity. The generic RX market in Europe is characterised by exceptionally

Author: YULIYANA MANOLOVA, director Business Development Contract Manufacturing at Acino

low prices. In Germany, the tender business lacks transparency and has fixed financial contract terms for years ahead[6]. If all stakeholders do not come to a common understanding of the situation and do not take swift and meaningful measures in response to the recent cost changes, suppliers will likely incur temporary losses and eventually will be forced to discontinue products or even go out of business. With fewer suppliers on the market, costs will rise in the long run, which is not in the best interests of patients or healthcare systems. Therefore, in order to secure better prices in the long-term, the shortterm solution is to immediately adjust the current prices to match rising costs. There is an obvious need for proofing the pharmaceutical supply chain by enacting legislation to provide financial assistance to manufacturers and healthcare systems in the event of pandemic or war[7]. The German Ministry of Health, for example, should reconsider their plans to drive down generic prices by requesting further rebates[8], since such actions would raise the risks of product discontinuation in the current economic context.

ENERGY RATIONING

Production of pharmaceutical products, unlike other goods, is subject to rigid monitoring, which allows no production flexibility. Rationing energy is not an option for pharmaceutical manufacturing plants as it may permanently disrupt and damage the product. If the manufacturing process is interrupted for any reason, there is a risk that the product will no longer comply with its analytical specifications and it will have to be scrapped. This would increase the manufacturing output, possibly delay supply to market, and add additional expenses to the already heavily burdened generics producers. The continuous supply of gas and electricity is critical for both supply continuity and financial sustainability of generics manufacturers.

To ensure product supply continuity, it is critical to maintain an open dialogue with all stakeholders in the pharmaceutical value chain. Immediate actions on price adjustments for affordable generic products are required. Actions towards tax breaks, direct financial assistance, rebates removal and elimination of energy rationing for the sectors might help stabilise the situation. The industry is facing challenging times, and we must find a way to better navigate the current market environment. This is an opportunity for a transparent dialogue, fast decisionmaking and collaborative partnerships that may serve as a model for avoiding a crisis.

[1] https://www.fiercepharma.com/manufacturing/fierce-jpm-week-5industry-execs-discuss-pandemic-supply-chain-issues-solutions

https://www.worldbank.org/en/research/brief/inflation-database

https://www.statista.com/statistics/1287467/produce-price-index-eu/

https://www.raps.org/news-and-articles/news-articles/2022/6/euro-

https://ec.europa.eu/commission/presscorner/detail/en/IP_22_4608

https://www.bundesgesundheitsministerium.de/arzneimittelpreise.

https://www.medicinesforeurope.com/wp-content/uploads/2022/06/ New-pricing-models-for-generic-medicines.pdf

https://www.bundesgesundheitsministerium.de/arzneimittelpreise.html

CPhI Europe – 1st – 3rd November, Frankfurt

In 2022, CPhI Worldwide will become CPHI Frankfurt: a 3-day event that will take place in person and online. This hybrid model will fuse the best elements of our traditional show with interactive online features to help you get the most out of your CPHI experience!

In addition to the dates in Frankfurt, this format will see our event take place online over an extended period of time, allowing you the flexibility to connect, network, learn and do business – when and how it suits you.

Adare Pharma Solutions is a global technology-driven CDMO providing end-to-end integrated services, from product development through commercial manufacturing and packaging, with expertise in complex oral formulations. Our specialised technology platforms provide taste masking, controlled release, solubility enhancement, and patient-centric dosing solutions. We have developed and manufactures more than 45 products sold by customers worldwide.

We have the expertise and proven track record to guide projects from clinical research stages through optimisation, validation, and approval. We operate seven facilities in the US and Europe, equipped to facilitate efficient drug product development and manufacturing, maintaining excellent environmental conditions compliant with US and EU cGMP regulations.

Adare has dedicated, engineered high potent GMP manufacturing and development areas. Our in-house regulatory and quality teams have a proven global track record, assuring our clients that products we manufacture are provided with the highest relevant standards for patient care.

Hall 9, Stand #90F70

As a Swiss pharmaceutical manufacturer, Acino can look back on to a long history in producing oral solid dosage forms for major generic companies at the highest quality possible. Having developed profound know-how within this field, Acino has a well-known track record in manufacturing complex modified release formulation such as MUPS (Multi Unit Pellet System). Some of the service we offer are dry, wet and melt granulation, extrusion/spheronisation, pellet layering in fluidised bed and coating.

Acino understands well the customer needs and has a manufacturing and packaging sites in Switzerland, Estonia and Ukraine. This allows flexible and customised offering for clients with various project requirements. We can handle high volume products as well as smaller volume SKUs as a result of carefully considered cost structure. We operate under highest industry standards and we offer EU batch release.

Last but not least, Acino is always thriving to achieve the highest customer satisfaction.

Come and visit us at Hall 9.1 Stand H63

From developing a fit-for-purpose formulation for FIH trials, to scaling up for late phase trials, registration and ultimately ongoing commercial supply, Almac Pharma Services’ solid oral dose pharmaceutical development and manufacturing solutions are tailored to meet your needs.

Almac operates from state-of-the-art non-GMP and GMP facilities, allowing seamless transition between formulation and process development, and clinical trial material manufacturing. Our development facilities have complementary equipment trains and integrated technical teams to facilitate technology transfer.

Our development and commercial teams work side-by-side, together with our experienced project management teams, to ensure a smooth transition of our clients’ products from development into our extensive commercial manufacture and pack network.

We will offer you the most appropriate, effective, and timely solution to develop your clinical candidate into an optimum formulation as well as supporting manufacture for all phases of your clinical trial programmes.

Visit our team at booth 90F20 to discuss your pharmaceutical development needs.

FORMULATION CONSIDERATIONS

FOR PAEDIATRIC POPULATIONS: FINDING THE RIGHT DOSAGE FORM FOR BETTER ADHERENCE

To address the challenges of paediatric formulations, specialised technology platforms are often needed to provide ease of application and improve patient outcomes.

Paediatric populations represent the most diverse patient groups in all of medicine. Factors such as individual preferences, physiology, and dosage considerations all serve to complicate drug formulation aimed at paediatric care. Drug formulation for children has become increasingly important as the healthcare field recognises the huge impact that strict patient adherence can have on a treatment’s efficacy.

By partnering with a contract development and manufacturing organisation (CDMO) with experience in paediatric formulation, pharmaceutical companies can increase acceptability of their drugs among paediatric patients.

FACTORS THAT INFLUENCE TREATMENT ADHERENCE IN CHILDREN

Eating and swallowing are complex behaviours, involving more than 30 muscles and nerves. These behaviours differ in young children compared to adults, owing to changes in the pharynx that occur with maturation. Consequently, developers and manufacturers should understand the impacts of physiology when formulating a drug for paediatric populations.

Author: Luigi Boltri, PH.D., senior director, Pharmaceutical Sciences, Adare Pharma Solutions

Texture and taste have an impact on the acceptability of a drug formulation, particularly for paediatric patients; the most acceptable textures are a combination of mild flavours and smooth textures, For older children, overall palatability is arguably more important than any other factor in deciding on a formulation approach.

PARTNERING FOR BETTER PAEDIATRIC PATIENT OUTCOMES

The cost and timelines associated with developing alternative dosage forms for paediatrics can result in a reluctance to invest. But finding a manufacturing partner with the experience, expertise, and facilities needed to pursue a range of formulation options can help expedite the development process.

Adare Pharma Solutions, a multinational CDMO providing product development through commercial manufacturing expertise, has long focused on oral dosage forms that address the unique needs of paediatric populations. Their expertise helps them address complexities that are challenging for companies new to pursuing patientcentered development. Adare’s portfolio consistently focuses on important paediatric considerations like taste masking and product acceptability.

Adare’s taste masking capabilities include commercially feasible physical barrier technologies, such as Microcaps and Optimμm, that boast an array of delivery formats such as powders, liquid suspensions, orally disintegrating and dispersible tablets.

Adare’s Parvulet dosage form, which approximates the texture of easy-to-swallow soft foods, can be an important aspect of a paediatric formulation. Parvulet initially takes the form of a granule/powder or tablet. Once placed in a spoon along with a few milliliters of water, the solid dosage form is converted in less than a minute into a food-like product with the consistency of applesauce.

By partnering with a CDMO like Adare, companies can help ensure that their drug’s paediatric formulations are the best fit for its youngest patients, and improves therapy outcomes through better patient adherence.

Rare fatal blood clots after Covid-19 vaccines unaffected by sex or age, says new study

Rare fatal blood clots after Covid-19 vaccines do not appear to be affected by sex or age, according to a new study by the UK’s independent Drug Safety Research Unit (DSRU).

Unusual clotting with concurrent low platelets, known as thrombosis with thrombocytopenia syndrome (TTS), after adenoviral vector vaccines - including the AstraZeneca vaccine - was first reported in March 2021, when it was thought younger women may be at increased risk. Now, researchers at the DSRU have analysed all UK cases of TSS that were reported to the MHRA via the Yellow Card scheme and they have calculated case fatality rates by age and sex.

Researchers analysed data reported between May 2021 and May 2022 when a total of 443 cases of TTS were recorded. Of these, 81 cases were fatal (18.28%) and case fatality remained stable throughout observation at 17-18%. The study found no trends in deaths by age or by sex, though they did observe that events more frequently occurred following someone’s first dose of the vaccine.

Read the full article at: www. pharmaceuticalmanufacturer. media

Talking points

ICR CRITICISES NICE REJECTION OF OLAPARIB FOR ADVANCED PROSTATE CANCER

Findings from the PROfound trial, led by researchers at the ICR and The Royal Marsden NHS Foundation Trust, showed that giving olaparib to men with tumours with faulty DNA repair genes blocked prostate cancer growth more effectively than the modern hormone treatments enzalutamide and abiraterone – it improved survival and delayed disease progression.

The findings led to olaparib being licensed in the US and Europe for the treatment of some men with advanced prostate cancer. But NICE has judged that the drug is not sufficiently cost-effective to be used on the NHS – apparently in part because of the cost of the accompanying genetic testing.

The Institute of Cancer Research, London, has expressed disappointment that NICE has confirmed its decision not to recommend olaparib for previously treated, hormonerelapsed metastatic prostate cancer.

NICE’s recent decision puts the NHS in England and Wales out of step with Scotland, where olaparib was approved last year for the treatment of prostate cancers with faulty DNA repair genes, like BRCA1 or BRCA2, which have not responded to prior treatment

with the hormone therapies enzalutamide or abiraterone.

The Institute of Cancer Research (ICR) is especially concerned that olaparib appears to have been judged too expensive in part because of the cost of genetic testing to tailor the drug for patients.

Olaparib, which was initially developed to treat women with ovarian and breast cancer, is part of a family of drugs called PARP inhibitors that target and kill cancer cells with faulty DNA repair machinery.

The ICR is now urging NICE to work with the manufacturer to make olaparib available –including by showing flexibility on the cost of genetic testing.

Read the full article at: www. pharmaceuticalmanufacturer. media

OUTSIDE EPM

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

BE SURE TO LISTEN TO

The latest episode of The MedTalk Podcast features Charlie Ramping from Kudos - a discussion about making academic information clear for the public and manufacturers to understand to act upon them.

IT’S TIME FOR A CHANGE

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