EPM May 2020 by EPM Magazine

COVID-19 COVERAGE

BLOCKCHAIN IN PHARMA

COMBATTING COUNTERFEIT DRUGS

May 2020

NA OW

Natoli explains how using tapered dies increases tablet quality and decreases tooling wear for manufacturers.

INTELLIGENT optimized processes with SmartInterface and RFID

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Contents May 2020 | Volume 20 Issue 3 REGULARS 5: EDITOR’S DESK

The questions that need to be asked once the Covid-19 pandemic ends.

6: A SMALL DOSE

A brief round-up of some of the latest developments in the industry.

10: OPINION

ProDPO details the data protection issues facing the pharmaceutical industry.

16: COVER STORY

Natoli explains how using tapered dies increases tablet quality and decreases tooling wear for manufacturers.

21: IN THE NEWS

A short selection of stories from the world of science.

34: TALKING POINTS

Stories to consider and what to look out for in EPM in the coming weeks.

FEATURES 8: PERSPECTIVE ON PHARMA

What blockchain technology offers the pharmaceutical industry

14: IN PROFILE

H.E.L Group speaks to EPM about changes within the industry and the uptake of automated solutions.

18: ANTI-COUNTERFEITING

Interviews and articles examining the steps companies are taking to tackle counterfeit drugs.

25: LYOPHILISATION

Reece Armstrong sits down with Gore to discuss the company’s single-use solution for manufacturers freeze drying APIs.

30: COVID-19

The steps pharmaceutical companies are taking to remove intellectual property rights for key drugs to tackle Covid-19.

Tabletting taken to the next level â&#x20AC;&#x201C; automation not only increases efficiency, but also patient safety. Developing beyond your expectations!

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LESSONS LEARNED?

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Though the Covid-19 pandemic is far from over, countries around the world are beginning to consider steps to ease their lockdown restrictions. With a return to some form of normality in sight, now may be the best time to look at the lessons we should have learned from this crisis.

ovid-19 has exposed our political leaders on grand stages, highlighting their aptitude, vulnerabilities, ineptitudes - not to mention idiocy - on many levels. In the UK at least, it has also exposed our societal weaknesses; our lack of

good quality social care and a devaluing of the NHS which has lasted near to a decade. But lessons can be learned from this crisis, if we ask the right questions now. Going forward, will we be able to anticipate health inequalities? And if so,

EDITOR’S DESK will we consider how the marginalised, the elderly and young, or those is BAME communities might be most at risk? If so, will we adequately support those communities, through better social care, improved standards of living, and equal access to educational and economic opportunities? Will we stop apportioning blame where it is not needed? Take the parallel of HIV and how blame was

apportioned to the LGBT+ community, then compare it to the rise in racism towards those in Asian communities during Covid-19. Do we need to consider that if this was a Western born virus, political leaders in the UK and the US for instance, might have taken it more seriously from the start? Will we look to the future and anticipate other health disasters? Another pandemic is a statistical probability, but the threat of antimicrobial resistance is ever looming, and right now, many health systems across the world may not have the capacity and resources to cope. The life sciences industry can help, and collaboration across sectors has been something of a heartening sight during this pandemic, as companies small and large have announced plans to help tackle Covid-19. But a lack of manufacturing capacity for vaccines; a failure to procure enough testing kits; and a vital mismanagement of PPE, are all areas that require considerable action on the part of our governments. Lastly, will we remove our nationalistic sensibilities and truly co-operate with other global political parties, in order to do the best for the health of our country’s citizens. The UK’s decision not to partake in the EU’s ventilator scheme screams out from the annals of Brexit discourse, playing into a nationalist fantasy that we can do this without the help of others. To some, such actions are noble. To most they are foolhardy and dangerous. Now is the time to learn from our mistakes.

A small dose

QureTech Bio receives grant to fight antibiotic resistance

ife science company QureTech Bio has received a grant of SEK 3 million from a Swedish government backed innovation programme to help it combat antibiotic resistance. The company will use the funding - awarded by the Swelife innovation programme - to advance a project to develop new drugs that either enhance the effect of existing antibiotics or that disarm bacteria instead of killing them – reducing

nternational private equity firm Parabellum Investments has acquired serialisation specialist Advanco with plans for international growth. The acquisition of Advanco marks the first move by Parabellum Investments into the pharmaceutical market.

the development of resistance. QureTech Bio will work with Umeå University and pharmaceutical service provider Malmö-based Magle Chemoswed to take the project to the next phase of development. “We have discovered new opportunities to treat severe infections by making antibioticresistant bacteria susceptible to various antibiotics again. We have already demonstrated that our

substances have an effect in a very difficultto-treat disease model and this money from Swelife makes it possible for us to focus on studies that will help develop a commercial product,” says Fredrik Almqvist, CEO of QureTech Bio. “We are delighted with this collaboration, in which we can combine our in-house developed drug delivery system with the new drug candidates developed by QureTech Bio,” says Peter Schuisky, CSO at Magle Chemoswed.

“Our shared goal is to develop a product that can effectively treat antibiotic-resistant infections and save lives.” Quretech Bio is a Swedish pharmaceutical development company that addresses a significant medical need by developing a new

Equity firm acquires pharma serialisation specialist Parabellum Investment’s CEO Rami Cassis will now become executive chairman of Advanco.

Based in Brussels, Advanco supplies pharmaceutical companies with

software that allows manufacturers to track the serial numbers of every medicine. The company plans to grow internationally and will focus on markets in the US, Russia and Europe initially. Advanco was an early provider of product serialisation software, which is now seen as a critical necessity to stop the increase in counterfeit medicines and pharmaceutical products. Last year, the World Health

class of antibacterial agents that target antimicrobial resistance. Quretech Bio’s aim is to develop first-line medicines to combat infectious diseases and the occurrence of antibiotic resistance, establishing itself as a leading pharmaceutical discovery company in its field.

Organisation estimated that one in 10 medical products is either counterfeit or fake, with the problem being particularly bad in developing countries. “In the near future, almost every product is likely to be serialised. This gives peace of mind of knowing exactly how and where a product was made and, by authenticating sources of raw materials and the manufacturing process, with ethical and environmental applications,” said Rami Cassis, CEO of Parabellum Investments. “Advanco has a proven, resilient and scalable technology on which we plan to build – with acquisitions - in the coming years.”

most inno Switzerla

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AskBio acquires gene therapy company to expand pipeline

linical stage gene therapy company AskBio has acquired a Parisbased gene therapy company to help expand its clinical pipeline for neurodegenerative diseases.

overtaken Germany as that Switzerland has across Europe – and delivery is accelerating innovation in drug highlights that Innovation Index from the Pharmapack Provisional findings shows. market, new research innovative drug delivery as Europe’s most overtaken Germany witzerland has

executives – notably according to industry ‘innovation potential’ Spain) saw increases in UK, France, Italy and (Switzerland, Germany, European markets states. All six major market, the research solutions entering the devices and packaging being driven by new Innovation is largely drug delivery market. Europe’s most innovative

in terms of FDA a remarkable few years Markets, said: “It’s been director at Informa Silvia Forroova, brand overall gains. showing the biggest and Switzerland (10%) United Kingdom (5%) year-on-year, with the has increased by 4% innovation potential leader. On average, States as the world closing on the United

ovative drug delivery market and overtakes Germany as

AskBio has acquired BrainVectis, a Parisbased gene therapy company and French National Institute for Health and Medical Research (INSERM) spin-out. The company has a particular focus on therapies that restore brain cholesterol metabolism as a treatment for

Huntington’s disease and other disorders. BrainVectis has received Orphan Drug Designation (ODD) from the European Commission for its gene therapy candidate BV-CYP01 – which has shown proof-of-concept in various animal models in Huntington’s disease. “We have seen promising preclinical results with BV-CYP01, and combining our programme with gene therapy leader AskBio is ideal as we progress toward clinical studies,” said Dr Nathalie CartierLacave, founder of

BrainVectis. “With its unmatched technology platform, AskBio has the resources to accelerate the development of our gene therapies for patients who desperately need treatment options.”

irreversible disease for which no effective treatments exist. BrainVectis has worldleading knowledge of Huntington’s and other neurodegenerative

diseases and gives us access to a pipeline of candidates for these indications. We’re honoured to have them become part of AskBio.”

Commenting on the transaction, Sheila Mikhail, CEO and co-founder of AskBio, said: “Our acquisition of BrainVectis offers us an extraordinary opportunity to work together to potentially transform patients’ lives. Huntington’s disease is a devastating and

WASDELL ACQUIRES PACKAGING SPECIALIST

utsourcing partner Wasdell Group has acquired a specialist packaging supplier to the pharmaceutical and medical device sectors as part of its expansion plans.

The Wasdell Group hopes that its acquisition of Planned Packaging Limited & Planned Packaging Films Limited (PPF) will strengthen and expand its capabilities to be a fully integrated supplier to the life sciences industries.

Vincent Dunne, Wasdell Group CEO commented: “The acquisition of PPF allows the Wasdell Group to vertically integrate into a key commodity area, safeguarding supplies but also expanding our capabilities and product & service offerings”. Planned Packaging supplies companies

within life sciences with an array of premade easy peel pouches, high barrier foil films and semi rigid materials for processing through thermoforming lines. More so, with sustainability on everyone’s minds, the company is introducing new 100% recyclable and biodegradable material options. Martin Tedham, chairman of the Wasdell Group added: “Planned Packaging is a perfect fit due to its synergies within the existing Wasdell operations, a shared customer base,

operating within the same sectors as well as a growing demand for the assembly and packaging of medical devices seen within Wasdell’s outsourced packaging services. “Customers will benefit from expanded services and competitive prices and the integrations of Planned Packaging into our current operations will be a beneficial and advantageous one for all involved. We are pleased to welcome the Planned Packaging team to the Wasdell family and look forward to working alongside them.”

PERSPECTIVE ON PHARMA Blockchain and pharma: lifeline or future vision?

he current health crisis affects all of us: it’s a global struggle that gives companies and producers in the pharmaceutical sector a special responsibility. Product availability, safety and credibility are the critical requirements for doctors, patients and producers of drugs and medical equipment these days. Technology is proving to be an accelerant in the manufacturing and distribution of these products. It has a significant presence in both upstream and downstream manufacturing activities: data analysis and testing, innovation, quality, production, logistics, and administration. As we applaud these activities that will save lives, it is worthwhile to visit how emerging technologies, like blockchain, could add further value. GLOBAL PROCESSES NEED TO BE TRANSPARENT Pharmaceutical supply chains are highly complex with a large number of different suppliers, regulatory agencies, pharmacies, hospitals, insurance agencies, and producers collaborating to manufacture and distribute globally. ARUN SAMUGA, chief technology officer at Elemica, explains how blockchain can add value to the pharmaceutical industry.

As new diseases like Covid-19 occur, this complex chain must be agile and responsive to bring new drugs to market. This means that producers need to be innovative and adapt quickly to the new market need. Suppliers also must comply with additional or new transport regulations.

To do so, a manufacturer needs to secure the quality of each ingredient, ensure that the shipping of goods happens on time and that storage and transport conditions are optimal. In a crisis such as the current one, these challenges are even more important than before: after all, it’s about

timely distribution of life saving agents to protect human life. Technology will help multienterprise business process work more smoothly in many areas. IT STARTS WITH TRUST One promising solution to address the formidable

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challenges within the pharmaceutical supply chain will be blockchain. Blockchain technology is particularly predestined when it no longer involves a partnership of two or three companies, but many partners such as suppliers, producers and so on as part of a network.

Blockchain provides traceability in product lifecycles by relating data, propagating it and sending it through an organisation. This is especially important for highly regulated industries such as pharmaceuticals. This industry requires bringing transparency to activities like clinical trials, control over lot from scale-up, validation, quality assurance till commercialisation of the final approved product.

Experts agree that blockchain could have a revolutionary impact on industries such as pharmaceuticals.

Many pharmaceutical organisations utilise contract manufacturing processes for the co-ordination of sourcing and production processes. Documentation is created and accompanies the products as they travel from raw material through stages until finished goods and delivery. This documentation can include regulatory requirements, ingredient specifications, or contractual information. Blockchain helps to correlate and audit the information, such as packaging components, development evidence, regulatory integrity of all associated commercial content certifications that are created through collaboration with other parties. This results in a need to establish trust among various parties to orchestrate the ﬂow of material, information and finance. There is tremendous amount of time and effort spent on creating and enforcing contracts, auditing payments, reconciliation and legal proceedings. Blockchain technology fundamentally enables a trustless environment with distributed ownership of data. INNOVATION AND PRIVACY It is important for institutions to be able to exchange and expand their knowledge and data globally. Especially when human lives are at stake like in the case of Covid-19. Blockchain

provides the ability to share protected and unalterable data, which allows companies to more easily join forces in the spirit of innovation. By differentiating which persons can access the data from the blockchain, patient data can be sustainably protected. This is important because nobody wants to give up their rights to personal privacy when it comes to healthcare data, not even in the rush to fight this pandemic. However, the general use of patient data is indispensable for the progress of clinical research. This comes into play, for example, in clinical studies: patients must be informed and give their consent at every step of a clinical study. This consent must be appropriately recorded and securely stored, including under current data protection regulations. It is also crucial how such systems handle historical patient data. In this case, the patient should decide what information can be “unlocked”. In addition, only data that are relevant to the disease under investigation should be made available. This differentiation in access authorisations can be implemented using distributed ledger technology. An unlimited number of basically equal copies of the ledger (or transaction and process step) are maintained by different parties. Appropriate measures ensure that new transactions are adopted in all copies of the ledger and that a consensus is reached on the current status of the ledger. Distributed ledgers can be divided into “authorised” or “open” ledgers depending on the access options of the participants in a network. While the latter are openly accessible to everyone, access to the account ledger is regulated in the former.

9 TRACEABILITY OF PRODUCT QUALITY The traceability of process steps plays an important role in pharmaceutical manufacturing and distribution. Goods ﬂows need to be checked from the outset and identified beyond doubt to reduce counterfeit product and quickly execute any recall where the cause of the defective product must be traced. An important added value offered by blockchain are Smart Contracts. These can be automatically attached to deliveries and ensure that the products themselves report a breach of the rules – or re-order replacements if the storage conditions were not appropriate. Trust in the visibility and traceability gained in the supply chain is the basis for the implementation of Smart Contracts. These automatically trigger certain actions at predefined events. Processes that require the agreement of several supply chain actors can be automated. For example, a logistics company’s confirmed proof of delivery can immediately trigger automatic digital invoicing and payments via the banking system. CONCLUSION Currently, many blockchain developments are still pilot projects and implementation across the entire network of suppliers might take a long time. An example of this is the MediLedger Project which formed in 2017 to test a closed blockchain system to track who touched what drug at what time. Experts agree that blockchain could have a revolutionary impact on pharmaceuticals. And the current crisis shows impressively that technology can bring high added value.

Opinion Since the GDPR came into force, individuals have become more aware of their rights over their data.

THE DATA PROTECTION ISSUES FACING THE PHARMACEUTICAL INDUSTRY Author: Elizabeth Kilburn - associate at ProDPO

Two years on from the introduction of the General Data Protection Regulation (GDPR), and the Information Commissioner Office (ICO) is continuing to fine companies who don’t adequately protect their data. Instances within the pharmaceutical industry include companies being fined for failing to secure the security of special category personal data, demonstrating that compliance is still essential. WHY PHARMACEUTICAL COMPANIES NEED TO THINK ABOUT DATA PROTECTION? All pharmaceutical companies hold personal data about individuals. It’s easily recognised that companies which deal with the public, engage in medical research or undertake clinical trials, will process greater amounts of personal data. However, companies which deal only with the non-public facing side of the industry also process personal data; such as those of their staff, customers and suppliers, and need to ensure they’re compliant. The processing of personal data is heavily regulated and, since the GDPR came into force, individuals have become more aware of their rights over

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OPINION

their data. In addition, data protection regulators have become increasingly active, with the UK data protection authority, the ICO, being one of the most active regulators in Europe. Even without fines, there is a reputationally damaging element of a regulatory enforcement action which, in many respects, is unquantifiable from a costs’ perspective. ESTABLISHING A LAWFUL BASIS Before companies process personal data, they must establish a lawful basis to undertake such processing. Pharma companies whose most significant processing activities relate to their staff will not usually have trouble in establishing a lawful basis. The processing is generally necessary for performing the employment contract with that staff member. However, pharma companies which process special categories of data, through research and clinical trials etc., must establish a separate lawful basis to process this type of data. The GDPR has established a number of lawful bases. However, careful analysis must be undertaken to ensure the organisation is relying on the correct lawful basis. In addition, local legislation may need to be considered, whether this be local data protection law, such as the UK Data Protection Act 2018, or laws or regulations applicable only to the pharmaceutical industry. WHY IS DATA PROTECTION ESPECIALLY SIGNIFICANT FOR THE PHARMACEUTICAL INDUSTRY? The pharmaceutical industry covers a myriad of different types of organisations which each have their own distinctive data protection considerations. For example, companies undertaking medical research are a fundamental part of the pharmaceutical industry. Whilst medical research companies may be able to establish a lawful basis for processing health data, such companies should also consider whether they need to process identifiable data, or whether anonymous data can be used. The advantage of anonymised data is that, provided it is truly anonymous and does not directly or indirectly identify a living person, it will not be subject to the GDPR. Conversely, companies undertaking clinical trials are, on the whole, not able to consider anonymising data. Such companies must consider the requirement for informed consent under the Clinical Trials Regulation (CTR) and how this interacts with consent under the GDPR. The European Data Protection Board (EDPB), the pan-European data protection advisory board, published an opinion which clarified that ‘informed consent’ under the CTR is different to ‘explicit consent’ under the GDPR. The EDPB went on to warn that relying on explicit consent to process health data for clinical trials may be difficult, due to the imbalance of power between the sponsor/investigator and the participants. Assessment

of other available legal bases is therefore required. Therefore, here are a number of issues which are key to ensuring compliance. 1. The requirement to appoint a data protection officer. The GDPR requires companies which process large amounts of special categories of personal data to appoint a data protection officer. This can either mean recruiting a new employee, or appointing an outsourced data protection officer. The options will depend upon experience, levels of complexity or perceived risk and resource availability. 2. How to respond and effectively deal with subject access requests. One effect of the GDPR has been to significantly increase individuals’ awareness of their rights over their personal data. Not only are these individuals increasingly utilising their rights, and in particular the right of access, but companies have been established to serve hundreds, if not thousands, of subject access requests on controllers. Pharmaceutical companies need processes that allow these requests to be dealt with in an efficient way. 3. Ensuring contracts with service providers have sufficient protections in place to protect personal data processed, particularly where any special category data is processed on behalf of the pharma company. The GDPR requires controllers to implement a written contract with their processors. These cannot be contested by processors, however apportioning liability for risks involved with data processing is heavily argued, with many controllers seeking uncapped indemnities for data protection breaches. 4. To the extent pharma companies process special categories of personal data, the risk of suffering a data breach becomes more significant. Companies need to ensure they have stress-tested their processes to identify any weaknesses and be able to react to a data breach immediately. 5. Data transfers. Operators in the pharma industry are often multinational companies with a presence in a number of jurisdictions. This means that personal data is often transferred around the world, which adds an extra layer of complexity to data protection considerations. This issue is likely to only become more complex with the Brexit transitional period coming to an end at the end of this year. Whilst many pharma companies completed their ‘GDPRreadiness’ projects two years ago, it is clear that the pharmaceutical industry has its own unique complexities which mean data protection considerations may not have been fully tackled yet. In addition, the GDPR requires constant evaluation and monitoring of personal data processing activities, and therefore no company can ever really say it is ‘100% compliant’. It is imperative that organisations document their steps and decisions made with respect to personal data.

14 In Profile with H.E.L Group’s Paul Orange & Joe Willmot EPM sits down with H.E.L Group to discuss the company’s customer legacy and how the pharma market has changed since its formation over 30 years ago.

What’s the biggest change you’ve experienced in pharma since the formation of H.E.L? As H.E.L has been in business for over 30 years, picking just one change is a tough question. However, we have seen the rise of biotherapeutics from an almost zero base. What is an interesting observation, is that the predicted death of small molecule drugs has not taken place. Instead, we see that biopharmaceuticals are finding their own therapeutic

Authors: Paul Orange - chief marketing officer at H.E.L Group & Joe Willmot, application leader at H.E.L Group

niches. These niches are evolving alongside the continued growth of small molecule therapies. And how have changing trends in the industry impacted H.E.L as a company? Taking our customer base as a whole, 30 years ago we could not have predicted the importance and speed of battery technology development that we see today. Nor could we have predicted the level of activity in the white biotechnology sector - in particular trying to solve some of the more challenging climate change issues that we face. For us, these changes have meant that our product portfolio has continuously developed to support the changing market. Thinking specifically about changes in the pharmaceutical industry, we see that R&D is significantly pared down compared to when we started as a business. Commensurately, the use of automation has become incredibly important to maintain the productivity of those R&D departments. Therefore, ensuring that we are fully compatible with automation approaches is something that we have to guarantee. What’s the uptake of automated solutions been like in pharma and biotech? As per the previous response, the uptake of automation has been huge in the pharma industry.

Although the profile of how automation is applied has changed over time, we believe we will see the continued evolution of what automation is used for and how it is applied. It’s fair to say that automation continues to evolve beyond the simple act of putting a robotics platform into a laboratory and doing the physical experimentation through that mechanism. The use of machine learning and artificial intelligence-like approaches are themselves driving the creation and design of those experiments. Looking into the crystal ball, the future of automation will rely ever more on this interface between robotics, that can do very accurate or difficult experiments with high accuracy, and systematised data collection and interrogation. We also see that this data interrogation is able to pose questions and find patterns in data that humans cannot realistically do. Thinking specifically about the biotech segment for a moment. There is a significant proportion of biotech companies that have started due to the fact that the founders were working for a pharmaceutical company which either closed, or downsized, the R&D department where they were working. This push caused the founders to think about starting up their own business, quite often buying the automation systems from the pharmaceutical company

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P R O F I L E

Historically, the UK has been very good at punching above its weight in terms of R&D and innovation. at a very attractive price. This means at the heart of a great number of biotech companies is a very solid technology platform, and that technology platform is quite often heavily reliant upon automation. We therefore see a very synergistic relationship between intelligent, accessible automation and the growth of the biotech industry over the past few years. How do you expand as a company whilst safeguarding H.E.Lâ&#x20AC;&#x2122;s legacy and existing customer base? The important part of this question is about supporting our customer base. As a company that has put significant focus historically into developing custom solutions for our customers, we are in the position of having strong customer connection and focus as part of our DNA and our operating system. We fully intend to maintain that strong customer connection as a business and use that as a mechanism to expand. The bottom line is if you understand the problems your customers are trying to solve, and you think a little bit beyond those immediate needs to see how they fit into the wider market needs and trends, then that gives you the platform to grow as a business. We also look at expansion of our business in a very considered and logical manner. We see the gaps in our operations where we feel we can add additional resources that will allow us to better support our customers. Ultimately, this gives us

the basis to grow and scale as a business. Do you think R&D in the UK and Europe has enough support via government schemes and funding? Unfortunately, our answer is inherently no. We donâ&#x20AC;&#x2122;t believe that this is just the UK and Europe either - I would extend that to the US as well. Many of our staff come from either scientific backgrounds or have worked in scientific companies, so we feel very passionately about the positive impact that science and engineering can have on society as a whole. At an almost instinctive level, we would all like to see more of our public funding go to R&D. Historically, the UK has been very good at punching above its weight in terms of R&D and innovation, and this is clearly a national skill set that we could expand and exploit more if there were more resources put into it. For the UK in particular, there is a lot of uncertainty about how funding will continue to be provided once the UK fully leaves the European Union. If Brexit leads to a decrease in the amount of funding for R&D, it could have a very significant effect on the innovation output from the UK. Clearly one huge uncertainty that we all face at the moment is the Covid-19 pandemic. It is difficult to fully comprehend what impact this will have on our R&D funding in the future. On one hand, we may see greater willingness from governments to fund R&D that will

help future pandemics. However, on the ďŹ&#x201A;ipside, given the massive public spending that is taking place to prop up economies during the crisis, we find ourselves in uncharted territory in understanding what that means for public spending once this crisis is over.

COVER STORY

Natoli explains how using tapered dies increases tablet quality and decreases tooling wear for manufacturers.

U ABOVE: An example of a tapered die, per TSM standards. BELOW: A common tablet defect is a scorched belly band.

tilising tapered dies is beneficial for both increasing tablet quality and decreasing tooling wear. Standard dies have straight bores throughout their entire height. Taper is an optional feature that increases the bore dimension at the top of the die, then tapers inward until reaching the nominal bore size. Tapered die bores offer a multitude of benefits, which include reducing tablet defects, such as capping and lamination.

enters the die at the beginning of the compression cycle. Tapered dies are also effective in combating capping and lamination when pre-compression isn’t available or is insufficient to solve the issue. A tapered die bore allows air to be exhausted at a faster rate when compared to a die bore without taper. The taper effectively increases the clearance around the upper punch tip, which provides a wider pathway for the air to escape.

CAPPING & LAMINATION Capping occurs when the upper or lower cup portion of a tablet separates horizontally from the main body of the tablet. It can partially or completely separate to form a “cap.” Lamination is the separation of a tablet horizontally into two or more layers. One of the most common causes of capping and lamination is the compression of low-density formulations.

Decompression/expansion related stress is a critical factor in capping and lamination defects. The taper allows the tablet to expand gradually throughout the ejection cycle instead of the rapid expansion that would take place in a tablet that is ejected from a straight-bore die. This gradual expansion reduces internal stresses within the tablet that are frequently associated with capping and lamination defects.

A tapered die bore provides additional space for air contained within low density formulations to exhaust as the upper tip first

While tapered dies were designed as a solution for capping and lamination, they can also be used

to prevent other common tablet defects. EXCESSIVE EJECTION FORCE As the compression force is removed, tablets begin to expand. This expansion results in the tablet exerting pressure on the die walls. Taper aids in tablet ejection by allowing the tablet to expand gradually throughout the ejection cycle. This reduces the kinetic friction between the band of the tablet and die wall, thus lowering the force necessary to move the tablet through and out of the die bore. In general, tablet expansion is proportional to tablet size. Larger tablets tend to expand more than smaller tablets, so the amount of taper can be customised based on the size of the tablet. As the ejection cycle begins, a break-away force will be needed to overcome the static friction caused by expansion. This initial break-away force is greater than the force needed to continue to eject the tablet. Taper depth can

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also be customised based on band thickness and upper punch penetration to help minimise this break-away force.

LEFT: Lower punch head with extreme ejection cam wear.

SCORCHED BELLY BAND A scorched belly band of a tablet is identified by vertical striations or dark spots on the band of the tablet. A scorched, or slightly burned, tablet belly band is typically caused by high ejection forces related to a marginal formulation. Friction generated during ejection results in heat generation. One or more formulation components that have a low melting point may be subject to discolouration caused by the high temperatures generated during ejection. These discoloured particles can adhere to the die wall, then ﬂake off during subsequent filling and compression cycles and can then be observed as dark spots on and within later compressed tablets. Ejecting the tablet through the taper reduces friction and heat associated with this phase, which helps reduce the occurrence of these dark visual defects as well. TOOLING WEAR High ejection force may cause excessive wear on the lower punch head and the ejection cam of the press. However, tapering the die bore can help reduce ejection forces and therefore, the associated tooling wear. After compression takes place, tablets begin to undergo elastic recovery (expansion). Die taper allows the tablet to begin expanding gradually as soon as the ejection cycle begins, which reduces the related forces the tablet is exerting on the die wall. Therefore, reduced ejection force will equate to less wear to lower punch heads and the ejection cam.

Die taper is a frequently used tooling option to address common tableting defects and excessive tool wear Die bore taper can also be used to correct some minor turret wearrelated alignment issues. Wear in punch guides and die pockets can cause slight misalignment between the punch tips and die bores. The taper can act as a “funnel” to help guide the upper tip into the die bore possibly preventing some of the misalignment related damage such as j-hook on the upper punches, which is a contributing cause of capping and lamination. TAPER ATTRIBUTES The TSM (Tableting Specification Manual, 7th ed.) standard taper amount is 0.003” (0.08mm) wide by .188” (4.76mm) deep, which is considered to be suitable for the majority of tableting situations.

However, as mentioned above, the taper dimensions can be customised for specific situations or formulations. Dies with a tapered bore can be one-sided or tapered on both sides. Two-sided taper can prolong the working life of the die due to the ability to ﬂip the die over for use on both sides. One-sided taper is recommended to compare the efficacy of taper vs non-tapered die bores in R&D applications. Die taper is a frequently used tooling option to address common tableting defects and excessive tool wear. Consult with your tooling vendor for additional advice and guidance regarding the benefits of tapered dies.

ABOVE: Example of a tablet capping defect. BELOW Lamination defect

ANTI-COUNTERFEITING

Author: LU RAHMAN, head of content, life sciences

FAKE NEWS What the role of drug serialisation is in anti-counterfeiting and why an expert partnership, plus technology, can be the route to success.

he threat that counterfeit medicines pose to the global pharmaceutical sector is immense. From fake formulations to issues in the manufacturing process, some industry figures believe we could be looking at revenue losses up to as much as 27 billion euros in Europe alone.

and protecting consumers and manufacturers.

Ensuring integrity of products can be a challenge for many pharmaceutical businesses. There are European and US regulations to adhere to as well as additional global regulations. Business models and supply chain operations can differ from one contract manufacturing organisation (CMO) to another, adding an extra layer of complexity to the issue of adherence. However, we know that supply chain security is crucial in the fight against fake products

According to the guidance from Gov.uk, these safety features are “a unique identifier (a 2D matrix code and human readable information) which will be placed on medical products that can be scanned at fixed points along the supply chain” and anti-tampering technology on the pack.

An expert’s view

LR: How big an issue is counterfeiting for the pharmaceutical sector in terms of danger to the public and lost revenue to business?

But the billions in lost revenue pales in comparison with the lives lost as a result of fake medicine.

Lu Rahman asks Scott McDougall, cofounder of The Independent Pharmacy, about the threat that counterfeit medicines pose within the supply chain

From last year, the EU Falsified Medicines Directive (EU FMD) Safety Features Delegated Regulation, made the serialisation of licensed drugs in Europe a legal requirement.

The unique identifier is a “a product code which allows the identification of at least the name of the medicine, the common name, the pharmaceutical form,

SM: In terms of revenue, the impact of counterfeiting is enormous. Collectively, pharmaceutical businesses lose billions of pounds to counterfeit medication every year. But the billions in lost revenue pales in comparison with the lives lost as a result of fake medicine.

the strength, the pack size, and the pack type; a serial number which is a numeric or alphanumeric sequence of a maximum of 20 characters randomly generated; a batch number and an expiry date”. In The US, the Drug Supply Chain Security Act (DSCSA) had a compliance cut-off point in 2018. Despite Brexit, it looks as though FMD is here to stay, in the short term at least, so adherence is vital if you want to sell your products in Europe. IMPLICATIONS FOR PHARMA MANUFACTURING These changes have had implications for pharmaceutical manufacturing - financial, as well as organisational. The two-part process of FMD for example, means that pharmaceutical companies must send serialisation

While Western countries are not immune to this risk, most deaths occur in countries with poor quality control, scant regulatory inspections, and a high demand for medicines (such as anti-malarial drugs in Africa). LR: Where do you see most of the fake products coming from and what can the industry do about it? SM: Most fake products are produced in countries like (but not exclusively) India and China. A

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data back to Europe via a barcode system as well as place a tamperproof seal on every package. The impact of this on businesses has been immense, requiring a re-think of major elements within an organisation - financial, manufacturing operational, IT, regulatory, for example. The scale of data integration required should not be under-estimated either, particularly for those businesses where IT infrastructure has not been a key priority. THE BENEFIT OF PARTNERSHIP The key to successful serialisation can often be found in partnership with a company that has industry expertise, longevity and drug serialisation expertise. Contract development & manufacturing organisations (CDMOs) understand the challenges facing clients and have the knowledge to help them deal with the issues that come when working within global regulatory frameworks. CDMOs understand the need for supply chain transparency and how damaging fake goods are to the global pharmaceutical market. When choosing a serialisation partner, it’s important that they understand your exact needs. It’s

combination of poor regulations, inadequate laboratory facilities, and fewer industry inspectors makes these countries hotbeds for the production of counterfeit medication. It is up to the industry as a whole to place greater pressure on those country’s regulatory bodies to conduct more stringent checks on manufacturers. Similarly, the supply chains that operate between these countries and Europe need to face greater scrutiny by industry bodies.

not a ‘one-size fits all’ approach that you want but a tailored solution that works well for your business and one which can accommodate changes to your global reach should that be required and understands European, US or other regional regulations. It’s also a good idea to examine your potential partner’s approach and preparation. One of the requirements of the EU FMD is that serialisation data is submitted to the European Hub of

LR: How has the False Medicines Directive helped? SM: While the FMD has huge potential for the industry, very few counterfeit medicines enter the supply chain of registered pharmacies. In reality, the biggest purchasers of fake products are by oblivious consumers from illicit online pharmacies that exist outside the established supply chain. However, Brexit has somewhat hampered the impact of the FMD.

European Medicines Verification Organisation (EMVO). How far down the line with that process are they and what expertise have they drawn upon to ensure complete success? We know that some companies are still in the pilot stage of submission to the EU Hub. Compliance is a crucial aspect of the pharmaceutical supply chain. Choosing the right serialisation expertise and working with a valued and well-organised partner can make a huge difference to your overall experience.

If the UK has a no-deal exit from the EU, we would lose access to European Medicines Verification System (EMVS), a crucial database used to inform the FMD. LR: How is technology helping address the problems of fake medicines and drugs, and how have you made use of it? SM: There is an array of technological application helping the industry in the fight against fake drugs: packaging identification features such as

ANTI-COUNTERFEITING

Compliance is a crucial aspect. THE ROLE OF ANTICOUNTERFEITING TECHNOLOGY The International Hologram Manufacturers Association (IHMA), is a good source of expertise in this field and highlights an industry report that indicates continued growth for anti-counterfeiting packaging technologies. According to the IHMA, the ‘Anticounterfeiting, Authentication

and Verification Technologies’ report signals the added expertise holography brings to the authentication of packaging products. Coming at a time when international business is struggling with the impact of the coronavirus pandemic, the trade body says the report offers reassurance that the market for packaging authentication technologies will remain strong for the next few years. The worldwide market for holograms is expected to grow by an estimated 27% over the next five years, at a time when

the global anti-counterfeiting packaging market is expected to reach US$ 133720 million by the end of 2026. Companies looking to protect their products against brand piracy and reduce the levels of counterfeiting are adopting advanced authentication and verification technologies. And technological innovation within the anti-counterfeiting, authentication and verification technologies market is a major factor contributing to the growth of the market, says the IHMA. Commenting on the report, IHMA chair Dr Paul Dunn stated: "As brand owners face a range of threats, suppliers are developing and adopting integrated platforms that allow brands to comprehensively address physical retail, supply-chain and online threats."

An expert’s view continued

“Digital solutions are a clear and growing addition to authentication solutions, sometimes in isolation, but within the holographic industry it’s the combination with packaging track and trace systems among other solutions, that’s seen as the foreseeable future. In doing so, the opportunities for holograms to be at the forefront will drive sector growth.”

holograms, guilloches, and colourchanging inks, for instance. At The Independent Pharmacy, we use these unique ID features (in line with other precautions) for spot checks and to ensure our supply chain remains safe and uncompromised. Other techniques used throughout the supply chain include spectrometers to detect the chemical composition of drugs and radio-frequency identification

(RFID) to create digital records of when a product was created, like a barcode but far more secure. Blockchain also plays an important role. As a product moves through the supply chain, blockchain technology gives each drug a timestamp at each stage. This provides accountability at every stage of the supply chain.”

IN THE NEWS

CPHI AWARDS 2020 OPEN FOR ENTRIES

ntries for this year’s CPhI Pharma Awards are now open, event organiser Informa Pharma Intelligence has announced.

The 17th Annual CPhI Pharma Awards are set to take place at CPhI Worldwide later this year, and will recognise the innovations occurring throughout the industry. Categories echo the event’s commitment to honouring “Excellence in Pharma” and include a wide range of industry activities, including bioprocessing and manufacturing, supply chain, logistics and distribution, digital innovation, and sustainability. “Each year we look forward to hosting these awards and to recognising the exciting, innovative and life-changing work that is being carried out across the pharmaceutical industry”, said Tara Dougal, senior content producer, Informa Markets. “The previous years’ entries have all been great examples of the dedication and commitment that these industries demonstrate every day, so I’m really looking forward to seeing this year’s entries.”

Global supply chain essential to running of NHS T he Covid-19 pandemic has proved why robust global supply chains are essential to the running of the NHS, according to the chief executive of the Association of the British Pharmaceutical Industry (ABPI). Speaking to the International Trade Committee, the ABPI’s chief executive Dr Richard Torbett explained why having medicine supply and manufacturing spread out across the globe allows manufacturers to adjust capacity as needed. In regard to the NHS, Dr Torbett said: “With around 12,000 medicines used by the NHS it would be

impossible for the UK to be in a position to manufacture all of the medicines it needs.

“No country operates in this way for good reason. Robust global supply chains are fundamental for ensuring the NHS continues to get the medicines it needs, and we need to make sure this continues. Coronavirus has shown us that they cope incredibly well in the face of a crisis, but we must be vigilant.” Dr Torbett also called on future government policy to ensure that the UK is an attractive place for those

innovating within the manufacturing supply chain.

“While the UK must continue to be a voice for global co-operation and the fair distribution of medicines, it’s also vital for the UK life sciences and the economy that we

continue to maintain and grow our medicines and health technology manufacturing capability here. “Protectionist measures only undermine the supply chain resilience that has been so vital during this pandemic,” he added.

Did you know?

The UK has banned There are over 2,900 Between 2018-2019, the exports of 80 medicines products in the NHS to NHS saved £294 million to help prevent support patients in the by focusing on best shortages in the NHS intensive care unit (ICU). value medicines. during the pandemic.

The arthritis drug adalimumab was responsible for £110 million in savings after coming oﬀ patent.

ANTI-COUNTERFEITING

EPM speaks to Rami Cassis, executive chairman of pharmaceutical serialisation company Advanco and CEO of Parabellum Investments about the rise in counterfeit medicines during the Covid-19 pandemic.

When supply does not meet the demand, it creates an environment where poorer quality or fake medicines will try to meet those needs. from the current situation through a combination of exploiting people’s desperation to have a Covid-19 cure and, at the same time, established supply chains are breaking due to current circumstances.

Quick questions with Rami Cassis EPM: Has there been a rise in counterfeit medicines during the Covid-19 pandemic? Cassis: It certainly seems so. The World Health Organisation has recently warned against a surge in fake medicines, notably in the developing world, and Interpol’s global pharmaceutical crime ﬁghting unit has reportedly made 121 arrests across 90 countries in just seven days, resulting in the seizure of dangerous pharmaceuticals worth over $14m (£11m). EPM: How are criminals exploiting the crisis to sell/distribute fake medicines? Cassis: Criminals and counterfeiters are able to proﬁt

EPM: Are people at risk more because of scams/counterfeit schemes due to the pandemic? Cassis: Yes, because, as the WHO has warned, when supply does not meet the demand, it creates an environment where poorer quality or fake medicines will try to meet those needs – and we are already seeing that happening in many countries. By consuming fake medications posturing as a Covid-19 cure or as a fake alleged Covid-19 treating drug (eg; Chloroquine). Many people are obviously being put at risk. EPM: How is serialisation helping the pharmaceutical industry track medicines throughout the supply chain? Cassis: Medicines are tracked right from the shop ﬂoor all the way through the supply chain and ultimately to dispensation, so it is possible to trace each batch number and ensure the authenticity and source of supply. This gives peace of mind and also enables medicines to be veriﬁed. EPM: What kinds of serialisation software are in place within the industry? Cassis: For more than a decade now, GS1 Standard solutions have

been implemented by over 80 countries EPM: Is enough being done via regulation to ensure pharmaceuticals are properly tracked and to fight counterfeiting? Cassis: The technology is there but the adoption and speed of implementation is slow in certain regions / countries. As a result of the current situation, things may accelerate – let’s hope so. EPM: Does more need to be done currently to fight a rise in fake medicines during the pandemic? Cassis: Serialisation as a process is mandated in many parts of the globe but the policies and speed of implementation greatly varies. Robust tech solutions like that from Advanco can help, but ultimately their eﬀectiveness is dependent on a number of moving parts working together. EPM: In regards to the pharma supply chain, what can we learn from Covid-19? Cassis: The largest new thing after Covid-19 will be de-globalisation of the supply chain with serialisation used more widely across pharmaceutical medicines and products. We believe that as a result of this pandemic, many manufacturers will look to pull back from China, and establish local or regional production capacity, which will eﬀectively reduce the dependence of the West on China and strengthen the US and European economies.

WHAT'S

TRENDING

Author: DR LEFTERIS TEPERIKIDIS - freelance medical writer at Kolabtree

IBUPROFEN AND COVID-19: To use or not to use

Exploring the research for using ibuprofen when treating Covid-19 patients.

ince the original Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV) 2 outbreak in Wuhan, China last December, a large body of evidence on Covid-19 has been published. However, the urgent need for scientific information relating to the virus has led to a lot of the usual safeguards of literature reporting, such as the peer-review process, being bypassed on several occasions.

whose condition worsened after ibuprofen administration, created reasonable concern regarding the use of NSAIDs in Covid-19 patients. Additionally, a letter to the editor describing potential mechanisms that put patients with diabetes and hypertension at higher risk of Covid-19 complications came to add to the ongoing speculation. This resulted in a recommendation to avoid ibuprofen by the World Health Organisation (WHO).

As a result, an unprecedented number of publications have emerged, leading to a vast amount of available information. In fact, a simple Pubmed search using the term “Covid”, including only results from 1 December 2019 up to 16 April 2020, yielded an astonishing 4,090 reports. While some of these articles are reports on actual clinical data related to Covid-19, there are also a large number of editorials and expert opinions on various different topics.

It should be stated that the evidence to support such a claim is virtually non-existent. In pre-Covid-19 times this type of evidence would be considered anecdotal, if considered at all. There is a complete lack of scientific data and everything is based on a theory, and an unpublished report of four patients. The journey from theory to practice can be a very long one, regardless of how viable the theory actually sounds. In fact, this was taken into

One issue that came to mobilise a worldwide debate was the use of non-steroidal anti-inﬂammatory drugs (NSAIDs) and their potential to cause more severe illness in Covid-19 patients. This theory originated when the Angiotensinconverting enzyme (ACE)2 receptor was described as the SARS-CoV-2 receptor, binding to which the virus gains entry to the host cell via phagocytosis. Furthermore, an unpublished report of an infectious disease specialist from France, describing four cases of children with Covid-19

consideration by WHO when they retracted their original statement about the use of ibuprofen. Similarly, other authorities, such as the European Medicines Agency, have also made official statements that the data is insufficient to make specific recommendations. So, what do we do? Do we use ibuprofen or not? The answer is simple as stated by all authorities who have issued statements on the subject. While their evidence is nowhere near sufficient to recommend against the use of NSAIDs in Covid-19 patients, the theory behind this debate is potentially viable. Consequently, medications such as ibuprofen should be avoided and acetaminophen (aka paracetamol) should be used instead as an anti-pyretic. If acetaminophen is ineffective, then ibuprofen may be considered. Hopefully more reliable data will emerge soon.

A CLEARER VIEW OF ANNEX 1

Ecolab remains at the forefront of industry regulations, providing insight into the Annex 1 updates. With the latest draft* making more exacting demands around cleaning and disinfection for pharmaceutical manufacturers, Ecolab can help your compliance with: A range of product formats which are sterile and ready-to-use as well as Hydrogen Peroxide Vapor (H2O2) technology that provides an aseptic processing environment Validation expertise through our Validex program Service excellence from our Technical Consultants to provide guidance around interpretation and implementation of the regulations To help guide you through Annex 1, speak to your Ecolab account manager today, or visit our dedicated web page at

10316.4_EPM

ecolablifesciences.com/annex1

LYOPHILISATION

EPM sits down with SCOTT ROSS, global product specialist for the GORE LYOGUARD Freeze-Drying Trays, to learn about lyophilsation in API manufacturing and the beneﬁts of single-use products.

SAFETY FIRST Author: REECE ARMSTRONG - editor, European Pharmaceutical Manufactuer

hilst Gore may be best known for its GORE-TEX brand of outerwear fabric, the company has a rich portfolio of products that span multiple industries; from ELIXIR branded guitar strings to implantable medical devices – Gore even helped make the roof at Wimbledon stadium so matches can be held in the rain. Nearly 20 years ago, Gore developed a single-use tray for pharmaceutical manufacturers who need to lyophilise an active pharmaceutical ingredient (API) in bulk. The GORE LYOGUARD Freeze-Drying Tray is a singleuse disposable product with an integrated top barrier of ePTFE membrane that enables high vapour transmission or mass transfer during lyophilisation in an enclosed container. Ross tells me how the company designed the product to address a range of problems that manufacturers faced when lyophilising potentially unstable APIs like polypeptides and oligonucleotides, in bulk. Of particular concern to producers are risk of operator exposure to drug product and the cost of cleaning and validating stainless steel trays after processing. When describing the bulk lyophilisation process, Ross explains how operators can be exposed to the API throughout many stages of manufacturing.

“There are opportunities along the way for the operator to be exposed to API. That can present challenges depending on whether it’s a highly potent API or what the occupational exposure band of that material is,” Ross says. When it developed the tray, Gore’s goal was to create a product to help customers reduce exposure to API by keeping drug product contained while still enabling lyophilisation. And it seems to have been accomplished – at least according to customer reports.

One customer went so far as to describe LYOGUARD tray as an additional level of personal protective equipment (PPE).

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When discussing the value of the product, Ross explains how the number one response to the question of why our customers use the tray, is around operator safety. One customer went so far as to describe LYOGUARD tray as an additional level of personal protective equipment (PPE). The Gore product keeps operator exposure to API to a minimum in several ways. Before lyophilisation, liquid API is filled into trays. These trays are transported to the lyophilisation chamber and loaded, presenting the potential for spills and product loss, especially when using open stainless steel trays. Each spill is potentially dangerous and could be costly to the manufacturer. Once in the freeze-dryer, API tends to aerosolise and ﬂy-out or be ejected from an open tray, and possibly contaminating surfaces inside the equipment. After processing, both the freeze-dryer and the tray must be thoroughly cleaned and re-validated before they can be used again. These cleaning procedures expose workers to drug product again and can add significant time and additional costs. In particular, the process of washing a stainless-steel tray which has held an API isn’t a simple one. It requires a chemical cleaning process and after washing, assays must be used to ensure the cleaning was effective. By contrast, the GORE LYOGUARD Tray is a single-use disposable solution so no tray cleaning is required. Of course, developing a singleuse disposable product raises the question of whether it’s

sustainable or not. Ross believes that the trend towards single-use in pharma answers the question of sustainability and refers to the complex requirements customers have on a case-by-base basis. “The entire pharma industry has been moving en masse to disposable single-use manufacturing,” Ross explains. “This has been going on now for nearly 25 years in the industry and it continues.” "Certainly, understanding which model is going to work, reusable or single-use technologies, has to be determined by the customer based on their process requirements, cost concerns, analysis of the risk to operators and sustainability goals. Ross continues, “At one point, people predicted that the industry would move entirely to single-use, but people have backed off that prediction and have envisioned something of a hybrid model where you have some combination of disposable and stainless steel in the facility.”

At one point, people predicted that the industry would move entirely to single-use."

CASE STUDY

Who: Richard Shook, director, Drug Product Technical Services and Business Integration at Cambrex What: Looks at the benefits of combining multiple APIs into a single fixed dose combination (FDC) product.

Case study

How: By examining two case studies related to FDCs

A COMBINED EFFORT I

t is no secret that drug product development can be a challenging endeavour. In addition to the need to find efficacious, safe molecules that can be formulated into medicines, there are a multitude of global regulatory challenges to meet along the way. From clinical to commercial phases, each step of the process presents unique obstacles to overcome. And even when an effective molecule or combination of molecules is targeted, understanding how to deliver them to the intended patient population without compromising the dosing integrity can be one of the most challenging steps in bringing a drug to market. This challenge is escalated when multiple drug products are being combined into one dosage form. THE MANY BENEFITS OF FDC There are many FDCs currently on the market due to the benefits they provide to both the manufacturer and the end user, including: Combining previously approved molecules eliminates additional molecule development safety and efficacy, expediting the go-to-market strategy. A 505(b)(2) pathway is commonly used for these approvals, which delivers shorter development programme times and additional IP protection, thereby extending market value. Manufacturing cost can be lowered due to the production of one drug product versus two or three separate drug products. The treatment regimen is simplified for the patient, often resulting in better adherence and compliance through combination. Healthcare costs are reduced through fewer co-payments. 



CONSIDERATIONS FOR DEVELOPING FDCS While there are many benefits to FDCs, key considerations must be addressed during their development. Most importantly, drugto-drug interactions are a critical component of FDC manufacturing. Drug interaction at the targeted dose level may impact safety and limit formulation potential. Compatibility studies can evaluate drug-to-drug and excipient interaction to ensure a stable formulation of two or more APIs. In addition, the posology and ratio of API strengths of the FDC drug product need to be established based on the existing marketed dosing regimen. This is exceedingly important when administered APIs have a cooperative

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therapeutic treatment. The target dissolution release profile of each API from individual dosage forms must be appropriately evaluated and integrated into the formulation development of the FDC. These studies can also play an important role in overcoming any regulatory challenges to successfully bring an FDC drug to market. THE RIGHT FORMULATION FOR THE PATIENT In addition to taking into consideration the formulation elements, the patient population plays a critical role in FDC solutions. While many people in the general population assume that formulations can be used across the full spectrum of patients, this is not accurate. There are different considerations for paediatric, adult and geriatric patient doses. For paediatric and geriatric patients, swallowing or dosing ability, taste preferences, and the release of the drug become more critical than with the standard adult population. Depending on the full profile of the drug, accommodations must be made to ensure that the end user is treated safely and does not risk under or overdosing through the FDC product they are presented with.

A TALE OF TWO COMPANIES Two companies came to Cambrex with requests to create FDC formulations containing multiple drug substances that would be presented in a single solid patient dose. The first customer was looking to combine three drug substances into an FDC product suitable for both adult and paediatric dosing. This required combining three different APIs into one formulation, which is challenging in itself. However, the bigger issue was that one of the APIs was not compatible with the other two, necessitating an FDC design that ensured API segregation to avoid potential interactions. The second case involved a customer that was looking to take two APIs with different release profiles and administer them as one FDC drug product.

A CLOSER LOOK AT THE CASES CASE STUDY 1

n the first case, three APIs needed to be combined while addressing the incompatibility between them. The customer also required two FDC drug products, one adult and one paediatric, requiring different formulations to meet the dosage needs. The design of the adult FDC drug product involved combining the two compatible APIs into a single tablet and coating it with a polymer. The resulting tablet was then coated with the third API, where the polymer coating was used to segregate the third API from the first two. The newly formed three-API multilayer tablet was then polymer-coated, resulting in one dosage form. For the paediatric indication, mini tablets were the ideal solution since they could be sprinkled from a sachet. To meet the compatibility requirement in this FDC formulations, the two compatible APIs were compressed into one mini-tablet. The third API was then manufactured in a separate mini tablet. For dosing, the two mini tablets were then polymer coated and brought together into an FDC product.

CASE STUDY 2

n the second case, the customer needed to formulate an FDC drug product that contained two APIs with different release profiles. One API was targeted for release in the duodenum, the first part of the intestine which is located immediately after the drug exits the stomach. The second API was intended to release further along in the intestinal tract. To address the challenge, an innovative formulation was developed by coating individual batches of multi-particulates with the first and the second API. Each batch of multi-particulates was then coated with a polymer specifically selected for its controlled-release properties targeting different pH levels, resulting in release of the APIs in different specific areas of the intestinal tract.

Patient population plays a crucial role in FDC solutions.

ANALYTICAL SUPPORT These are just two examples of the unique challenges that can arise when working with FDC products. However, there are other important considerations. To arrive at a final successful solution, analytical methods must be developed and validated for each FDC product. In particular, when there are multiple APIs with various strengths that will make it to the finished dosage form, characterisation becomes paramount to finding the right FDC solid dose solution.

COVID-19

Waiving the way TO DRUG DISCOVERY

n the global race to find new drugs and tests for use in the treatment of Covid-19, pharmaceutical companies are taking the unprecedented step of forgoing their intellectual property rights. Without the promise of commercial gains that accompany

such exclusivity rights, these companies could be seen to be effectively putting cause before profits. A series of pharmaceutical companies have already taken action voluntarily, although it is fair

AS THE COVID-19 PANDEMIC CONTINUES, PHARMACEUTICAL COMPANIES ARE TAKING GENEROUS STEPS AND REMOVING INTELLECTUAL PROPERTY RIGHTS FOR MANY KEY DRUGS WHICH COULD HELP FIGHT THE VIRUS.

to say that in some cases there has been a certain amount of external pressure for them to do so. Even so, the industry-wide response is impressive and heart-warming. Among them, Gilead Sciences is currently supporting clinical trials of its antiviral drug, Remdesivir. Previously developed for use in the treatment of Ebola, the drug has been shown to have benefits in the treatment of other diseases, including SARS. If the trials are successful, regulatory approval will follow, and the company could

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be first to market, which would give them a significant commercial advantage. However, in a recent statement, Gilead Sciences has indicated that it will provide around 1.5 million individual doses of Remdesivir for free. Furthermore, Gilead Sciences previously applied for and obtained ‘orphan’ drug status for the use of Remdesivir - giving them access to an extra layer of protection due to their involvement in developing a treatment for a ‘rare’ disease. Having faced some criticism for this action, the company has since decided to waive its ‘orphan’ rights. In another example of voluntary action, Abbvie has announced that it will not enforce its intellectual property rights on trials involving the use of Kaletra, a combination drug which is approved for use in the treatment of HIV. This means pharmaceutical and biotech firms around the world are free to make Kaletra and use it in clinical trials for Covid-19, without needing to secure a licence and pay royalties. As

the first firm to secure regulatory approval to produce a generic of Kaletra, Mylan has also waived its exclusive rights in the US to distribute Kaletra. A similar causal response is evident in the search for diagnostic tests for Covid-19. Labrador Diagnostics has recently announced that it will grant royalty-free licences to third parties to use its patented diagnostic technologies for use in tests directed to Covid-19. Swiss pharmaceutical company, Roche, has also recently released details of a formulation used in testing kits for the virus, following a plea from the Dutch government. Underlining the importance of removing barriers to Covid-19related research and development activity, Francis Curry, director general of the World Intellectual Property Office (WIPO), has urged the pharmaceutical and biotech industry to do the right thing. Speaking at a UN-led discussion last week he warned that ‘extra measures’ might be needed if companies don’t respond appropriately and suggested that compulsory licensing orders could be employed at jurisdictional level where necessary. To avoid this scenario, he added that a ‘nonlegislative mechanism would be a great way forward’. The threat of multiple compulsory licence orders, which are generally only granted to address a national emergency, is real. In the current pandemic, the only example so far is in Israel where Abbvie had been forced to allow trials for Covid-19

treatments using their patented technologies to go ahead without a licence. Governments in the US, Germany, Canada and Chile have indicated a willingness to impose compulsory licence orders where necessary and the UK government has previously discussed such action. To avoid such adversarial action from governments around the world, an industry-wide response is now urgently needed to find an alternative mechanism to support the search for Covid-19 treatments and tests. The Costa Rican government has recently put forward a proposal, backed by the World Health Organisation (WHO), for the industry to establish a ‘patent pool’ to support research and development activity directed to Covid-19. Patent pools are typically used to help make treatments for life-threatening diseases available in low-income countries. In this case, the creation of a patent pool would level the playing field globally, allowing any new tests and treatments for Covid-19 to be made available to as many people as possible, as quickly as possible. With hopes raised of finding a vaccine or antiviral drug quickly, it is important that efficacy and safety tests are not compromised. The pharmaceutical and biotech industry has an important role to play in helping to protect and save lives, but there is also an opportunity to generate significant goodwill by demonstrating a willingness to collaborate and to be ﬂexible with respect to intellectual property rights.

Without the promise of commercial gains that accompany such exclusivity rights, these companies could be seen to be effectively putting cause before profits.

Author: ADRIAN TOMBLING – partner and patent attorney at Withers & Rogers

WHAT'S

TRENDING

Rahul Thakar, technical key account manager at Datwyler Pharma, discusses the rise of injectables, quality control measures, and personalisation.

Author: RAHUL THAKAR, technical key account manager at Datwyler Pharma.

RISE ON UP

s of May 2019, the global drug delivery systems market was expected to reach US$ 2,302.2 billion in 2027 from US $1,243.1 billion in 2018 with a CAGR of 7.2% from 2019-20271. That was prior to the Covid-19 outbreak and it is unknown exactly how the virus will impact the global market. Up until recently, much of the growth could be attributed to a range of developments over recent years - particularly innovations and advancements in healthcare for the modern patient. The growth of injectables, personalised medicines, and customised drug delivery solutions are just a few trends that have emerged to address industry challenges. CHRONIC DISEASE AND KEY ADVANCEMENTS PROPEL INJECTABLES Increased prevalence of chronic diseases is a significant factor driving demand for injectable biologics2. Others include the enhanced convenience, ease of use, and reduced pain of today’s injections, which add to the merits

of injectable biologics. However, the growing use of injectables pose certain challenges to drug manufacturers. Compared to oral medications, injectable biologics are less stable molecules and difficult to manufacture. Injectable biologics can also have high viscosity, necessitating unique functionality specifications on parenteral packaging components. QUALITY TAKES CONTROL Since injectable biologics also present a higher immunogenicity risk to patients, authorities’ expectations for quality control are escalating. As such, manufacturing environments must meet the more stringent regulatory and quality demands placed on the primary packaging solutions for these applications. Implementing 100% camera inspection minimises the accidental use of defective components and utilising vacuum sealed bags for Ready-to-Use (RTU) components add a layer of security by indicating - through the absence of vacuum - if a bag may have been compromised in transport. VALUE-BASED CARE DRIVES PERSONALISATION Personalised medicine requires unique delivery designs and functionalities. It can take medical device manufacturers two to seven years to commercialise a customised design for prefilled syringes or autoinjectors, depending on the complexity of the design as well as resources, time and equipment. Moreover, these products would come in

much smaller batch sizes than standard drugs, which also requires ﬂexible manufacturing. Though this move from standardisation seems daunting, personalised medicine comes with a myriad of benefits. Most importantly, companies will be able to better engage with patients to ensure that drugs are being delivered in more effective ways. Beyond that, personalised medicine offers product differentiation for better brand recognition in the market. This opens the door for patented products and better equips manufacturers guard against ‘copy-cats.’ DRUG DELIVERY INNOVATION RESTS ON THE DETAILS With these emerging drug delivery trends, companies need to be equipped to catch up or stay ahead of the curve. Companies can implement superior primary packaging and streamline their production processes in cleanroom environments. This allows manufacturers to mitigate contamination threats and even improve personalisation and customisation capabilities. Careful consideration of what materials and processes are used to develop components like plungers and stoppers, make advancement in syringes, autoinjectors, and other medical devices possible. REFERENCES

1 https://www.marketstudyreport.com/ reports/drug-delivery-systems-market-to2027-global-analysis 2 https://www.marketsandmarkets.com/ Market-Reports/injectable-drug-deliverymarket-150.html

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The role AI can play in drug discovery and development is well documented, but the recent global pandemic has highlighted the growing importance this technology has in the ﬁght against disease.

Why we need to take AI in drug discovery seriously Author: LU RAHMAN, head of content, life sciences

ever has the world been more aware of the time and cost involved in the development of new drugs and vaccines. The global hunt is on for a vaccine for Covid-19, a process that usually takes 10-15 years. And while the pharmaceutical sector seeks treatments for the virus, this comes at a cost – a huge one. According to a study by the Tufts Center for the Study of Drug Development, it costs around $2.6 billion to develop a new prescription drug.

Earlier this year, UCL Innovation & Enterprise and Causaly began exploring the potential of collaboration. With the escalation of Covid-19, they saw the opportunity to bring their expertise together. UCL has been working on a number of Covid-19 related research projects, including the development and delivery of a low-cost breathing aid trials of a potential anti-viral, and rapid genome sequencing to better understand the spread of the disease.

When the race is on to find treatment and prevention, the need to do things differently is clear. The luxury of time doesn’t exist when hundreds of thousands are dying, and this is where AI and machine learning are coming into their own. Companies such as Sanofi, Pfizer and Genentech, have already shown their interest and support for this technology, but in 2020, its ability to accelerate drug discovery and development has never been more crucial.

Healx, is an AI-powered, patientinspired biotech specialising in rare diseases. It is using its AI platform to develop drug combinations from approved drugs to find treatments for Covid-19. This requires analysis of the eight million possible pairs and 10.5 billion drug triples stemming from the 4,000 approved drugs already on the market. Healx’s AI platform, Healnet, overcomes this challenge by analysing data to predict combination therapies most likely to succeed in the clinic.

Academics at UCL have partnered with AI specialist Causaly in the hope of speeding up coronavirus research. Causaly uses AI techniques to rapidly read and interpret databases of biomedical knowledge. It pulls together evidence from 30 million biomedical publications in seconds, enabling researchers to map epidemiology data, biomarker genes, molecular targets and identify potential treatment options.

Dr David Brown, Healx chairman, said: “Healx’s data-driven AI platform is able to predict, within weeks, which known drugs can be repurposed to treat other conditions such as Covid-19. This approach significantly shortens discovery-to-clinic timelines. Our AI is able to combine two to three existing drugs to formulate the most effective treatment. This approach ensures that any potential treatments we identify

can be used by clinicians to help patients very quickly.” The FDA has shown its support for AI in the healthcare sector. Yet the technology is not without its concerns. Alix Lacoste, BenevolentAI, outlined this in Statnews.com last year: “Despite the potential of artificial intelligence to identify new targets for disease faster, at lower cost, and with lower failure rates, adoption of this technology is still low. Trust has a significant role to play in that.” Lacoste outlined that BenevolentAI, “is to date the first drug-discovery company that has embedded artificial intelligence from early discovery through clinical trials. Yet even we face challenges in the adoption of this technology by our own experts. And not without reason: Sometimes the algorithm gets it wrong.”

The luxury of time doesn’t exist when hundreds of thousands are dying, and this is where AI and machine learning are coming into their own.

UK launches country-wide Covid-19 survey

he UK government has launched a country-wide Covid-19 survey to try and work out how many people have the virus - even if they’re not aware they have had it. The Covid-19 Infection Survey (CIS) will collect 25,000 patient samples in its first phase, with plans to ramp up collection to 300,000 over the next 12 months. Volunteers wanting to take part in the survey have three options, including; one visit; one visit every week for one month; or one visit every month for one year. The government is hoping that results from the study can help it to manage the pandemic better and to understand how to keep the NHS from being overwhelmed.

TALKING POINTS

Talking points WHY ANYONE WITH A COMPUTER CAN HELP COVID-19 EFFORTS

to better understand protein behaviour in diseases.

The Washington University School of Medicine’s Folding@ home project will utilise supercomputers at the Science and Technology Facilities Council (STFC) Hartree Centre

The project is calling on anyone with a personal computer to help out, as they can lend any unused background capacity to help power simulations into protein behaviour. The scientists hope that by running simulations which show how proteins behave in diseases, they can identify the most effective drugs to target Covid-19.

nyone with a computer is being urged to sign up to a global project that is using supercomputers to help scientists find the best existing anti-viral drugs that are most effective for treating for Covid-19.

OUTSIDE EPM

eb content editor Ian Bolland sits down with Bernard Ross, CEO of Sky Medical to discuss the company’s wearable device which can help patients’ blood circulation.

Make sure to read the full article on med-technews.com

COMING UP ON EPM

ditor Reece Armstrong speaks to Derek Wang, CEO of technology company Stratifyd about how artificial intelligence (AI) could help identify and potentially control the growth of viruses. Derek Wang previously worked with the US government on an infectious disease surveillance programme designed to understand how diseases such as Avian Inﬂuenza and Zika spread throughout populations.

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