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Volume 11 Issue 1

Peer Reviewed

The Impact of a No-deal Brexit on Pharmaceutical Patents The Main Considerations How Modular Content Delivers Personalised Life Sciences Engagement Overcoming the Challenges of Developing Inhaled Medicine Oral Drug Reconstitution Easier and More Accurate Through Packaging Innovation

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE 08 Pricing Pharmaceuticals in Japan

DIRECTORS: Martin Wright Mark A. Barker BUSINESS DEVELOPMENT: Thomas Kurse EDITORIAL: Virginia Toteva DESIGN DIRECTOR: Jana Sukenikova FINANCE DEPARTMENT: Martin Wright RESEARCH & CIRCULATION: Freya Gavaghan COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications 50 D, City Business Centre London, SE16 2XB United Kingdom Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Summer 2019. ISSN No.International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2019 PHARMA PUBLICATIONS / Volume 11 issue 1 – Spring – 2019

The year 2018 was epic for the Japanese pharmaceutical industry, largely because of the fundamental National Health Insurance (NHI) pricing reforms implemented in April, says Tosh Nagate at e-Projection K.K. The repercussions of this change in policy are yet to be fully felt as of the beginning of 2019; however, some of the cautionary signs can already be seen. For example, some domestic companies exited the market last year because of the unattractive prospects. This was unprecedented, particularly for a full-fledged domestic pharma company and it is difficult to imagine that these will be the only ones, with more moves expected in the coming months. 12 Why Companies Need to Act Now to Guarantee EU Medical Device Regulation Compliance There are just over 12 months to go until the EU Medical Device Regulation (MDR) enforcement deadline of May 2020. This is driving major efforts across the industry to ensure compliance, with initiatives complicated by the fact that not all details of the MDR have yet been finalised. For example, in January 2018 the EU released an update around the format of Unique Device Identification (UDI) codes and how they would be applied to medical devices. How can companies make sure they are ready in time? Seth Goldenberg of Veeva Systems discusses. 14 The Impact of a No-deal Brexit on Pharmaceutical Patents – The Main Considerations In this article, Jim Robertson at Wynne Jones IP discusses how uncertainty surrounding a potential no-deal Brexit has created a deep chasm in opinion in relation to the future of the UK’s lucrative pharmaceutical industry and about the sector’s ability to function effectively post-Brexit. 18 The Manufacturing-regulatory Data Continuum: Forging New Connections It makes no sense that product data exists separately in ERP and RIM systems, compromising any efforts to improve efficiency through tighter inter-function collaboration. A recent panel discussion, hosted by ProductLife Group and featuring industry experts from K2 Consulting, Gens & Associates, LEO Pharma and Lundbeck, debated approaches to bringing down the barriers and reducing manual process repetition. Here, Catherine Gambert, ProductLife Group’s senior consultant for regulatory affairs, summarises the main themes. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 22 Are Your Companion Diagnostic Partners Ready? The new In Vitro Diagnostic Medical Devices Regulation (IVDR), EU 2017/746, was published in the Official Journal of the European Union in May 2017 with full implementation by the date of application, 25th May 2022. It is envisaged that the new regulations will create a robust, regulatory framework which will be internationally recognised to improve clinical safety and improved market access. It appears, however, that the majority of stakeholders are not ready for the increased


Contents challenges of obtaining and maintaining compliance to the new requirements. Seamus Kearney and Maud Smyth from ARC Regulatory reckon that the lack of clarity in some key aspects of the text means that many Rx/CDx sponsors are unsure of how to develop or move forward with their compliance plans. 26 How Modular Content Delivers Personalised Life Sciences Engagement The rise of digital impacts the life sciences industry in multiple ways, says Emma Hyland at VEEVA. When it comes to content, it is fundamentally changing the relationship between the sector and its stakeholders, enabling companies to drive greater engagement by delivering personalised content on their channels of choice.

38 Highly Potent Molecules: Safe, Effective Processing The pharmaceutical landscape continues to evolve, with much R&D focusing on more specialised medicines. As the biological activity and specificity of the API increases, dosage strengths decrease – resulting in increased potency of the APIs in terms of occupational handling for drug product manufacture. Leaders in the development and manufacturing of potent molecules with specialist containment technology provide expertise in the safe and successful management of highly potent active pharmaceutical ingredients (HPAPIs). David O’Connell at PCI Pharma Services shares PCI’s contract development and manufacturing (CDMO) experience. TECHNOLOGY

30 Driving Patient Engagement with Serialisation Data and mHealth

42 Cell Disruption Equipment Selection – Making the Optimal Choice Technically and Financially

Businesses throughout the pharmaceutical supply chain can now develop collaborative solutions that will fundamentally change the way the industry shares information. The potential to provide product information directly to patients has opened a door of opportunity for new approaches to engagement and adherence. Here, Rick Seibert at Sharp, Jean-Marie Aulnette at TraceLink and Nagore Fernandez at Ashfield discuss how mobile health (mHealth) and serialisation data can be used to revolutionise patient engagement and adherence.

There are several methods for achieving cell disruption; however, high-pressure homogenisation (HPH) / microfluidisation is the standard approach for the scale of this client’s microbiological cell harvest application. This technique is therefore the focus of this report by Gary McRobbie at BPE.

CLINICAL AND MEDICAL RESEARCH 32 Comparing Genetic Modification Techniques for Animal Model Generation The first germline transmission-capable transgenic mice were developed in the early 1980s in the laboratories of Frank Ruddle (Yale), Ralph Brinster (University of Pennsylvania), and Richard Palmiter (University of Washington). Since these pioneering experiments, multiple techniques have been developed to generate genetically engineered mice and rats. Each has advantages and drawbacks, making each one more or less appropriate for particular types of model generation projects and study objectives. The following review by Caroline Horizny at Taconic Biosciences will highlight the basics of each genome modification method, as well as outline some of the pros and cons of each.


48 Why Exceptional Devices Are Not the (only) Answer for Inhaled Medicine While historically, inhaled drugs have been used for the treatment of asthma, COPD and other respiratory diseases, inhalation medicines have experienced a recent increase in consideration as an alternative drug administration route for systemic applications such as insulin therapies for diabetes due to their promise of faster pharmacological onset and reduced adverse effects. Delivery to the lungs promises immense benefits to patients and pharmaceutical companies alike. Dr Sarah Zellnitz at the Research Center Pharmaceutical Engineering (RCPE) analyses why the industry has not been able to realise the full potential. 52 Breakthrough Capsule Technology for Tailor-made Solutions Rapidly growing consumer demand for products deemed suitable for vegetarians or vegans means product labels are coming under ever-closer scrutiny. And capsules

Spring 2019 Volume 11 Issue 1

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Contents such as those used in food supplements and over-thecounter medicines are no exception. That’s why, at first sight, hard capsules made from plant-derived cellulose HPMC appear to be an obvious choice for those wishing to avoid animal-derived products and seeking a more ‘natural’ alternative, but are they really all that natural? Dr Holger Becker at GELITA AG analyses. LOGISTICS & SUPPLY CHAIN MANAGEMENT 56 The Role of Smarter Supply Chains in Reducing Drug Shortages within the Healthcare Industry The role of the supply chain in protecting patients from unsafe medical products is crucial, with the transportation and storage of pharmaceuticals having a significant impact on product integrity, and thus end patient welfare. Yet, with the growth of biopharmaceuticals the significance of getting logistics right becomes even more important. The stricter logistic requirements and significant cost are combined with limited supply, meaning that every batch is vital. Ellena Austin of Yusen Logistics considers how supply chains can work smarter to mitigate the risks that cause product failures and better protect end patients. 60 Blockchain in Life Sciences: Moving from Hype to Adoption

PACKAGING 66 Understanding How Serialised Data Can Impact Warehouse Operations The EU Falsified Medicines Directive (FMD) deadline is now days away and all segments of the pharmaceutical supply chain are focused on finalising their solutions to comply with the regulation. It is vital that companies are also prepared for three important exception-based use cases that, if unaccounted for, will mean non-compliance with the FMD. Larry Hall at TraceLink describes each use case and the solution required. 68 Sensitive Medical Packaging: Meeting the Needs of the Pharmaceutical Market The sensitivity of biologics and biosimilars regarding storage and packaging requirements as well as their complexity during administration lead to the demand to meet the highest quality standards, including strict controls at all stages in the manufacturing process. Carina Van Eester at Datwyler explains why, in the field of sensitive biologics and biosimilars, the protection of the active ingredient is of key importance, and companies are constantly seeking new packaging solutions in order to provide the utmost environment for packing and producing the drugs.

Over the last number of years, along with IOT, AI and Big Data, blockchain has emerged as one of the most significant disrupters in the technical industry. Blockchain's association with radical technological and business disruption is related to its decentralised nature. The pharmaceutical industry has a vested interest in the future direction of any interoperable platforms that internal/external stakeholders might adopt. Mark McColgan at Almac Group explains that in the world of blockchain, adopting a solid collaboration strategy through your chosen industry can prove to be just as strong a differentiator. MANUFACTURING 62 Overcoming the Challenges of Developing Inhaled Medicine Drugs formulated for inhalation or nasal delivery have numerous potential advantages over other dosage forms. For example, medicines delivered to the lungs usually have a more rapid onset of action than those that pass through the digestive tract. Similarly, drugs delivered via the nasal mucosa have more direct access to the central nervous system. Aditya R. Das at Recipharm discusses why inhaled medicine has considerable potential for the treatment of neurological disorders. 64 Top Challenges the Medical Device Industry is Facing in the EU The date of implementation of Regulation (EU) 2017/745 of 5 April 2017 on medical devices (MDR) is rapidly approaching, and medical device manufacturers are striving to ensure that they will meet the requirements and obligations imposed by the new rules by 26 May 2020, when the revised legal framework becomes fully applicable. Should the latter not be the case, they would seriously risk being placed out of the market since no grace period is foreseen, as discussed by Vincenzo Salvatore at BonelliErede. 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2019 Volume 11 Issue 1






Editor's Letter Mother nature is telling us that summer is on its way, though it may not feel like that, as the temperature is not very warm outside whilst I am writing this. However, I am certainly hoping for a lot of rain for the environment, as our industry certainly uses a lot of this commodity around the world. At the time of hearing the first words being uttered about Brexit the UK in 2016, the United Kingdom had its first minister for Life Sciences. Now, in 2019, we are still waiting with bated breath to see if the UK will in fact leave the European Union in 2019. Jim Robinson from Wayne Jones IP gives his insights on the impact of a no-deal Brexit on pharmaceutical patents. We hope that our readers who are creating companion diagnostics are Welcome to the Spring 2019 issue of the IPI Journal. This year has certainly started with a turmoil. The mega issue of Brexit is looming over our heads. This uncertainty is a problem for the pharmaceutical industry, where the development of drugs and other products depend heavily on the political and regulatory conditions of a country, and often require planning years in advance. I sincerely hope that this impasse will be resolved as soon as possible so companies can move forward with their agenda to improve drug discovery and patient care. Talking about patient care, in this issue we have a fantastic feature

working well with their partners, to ensure that they are not going to be caught off-guard by the new In Vitro Diagnostic Medical Devices Regulation (IVDR) EU 2017/746. Seamus Kearney and Maud Smyth from ARC Regulator outline in their article what you should be looking for when working with partners. One of my passions about the life sciences sector is to see personalised medicine available to every person on the planet. Emma Hyland at Veeva talks about how the increasing use of digital is impacting the life sciences in multiple ways, changing the relationships between the sector and its stakeholders. The amount of data that the sector has created over its history is huge and there has always been an issue on how to share and collaborate, until now. Rick Seibert at Sharp, Jean-Marie Aulnette at TraceLink and Nagore

Fernandez at Ashfield are talking about driving patient engagement with serialisation data and mHealth, plus how they have developed a collaborative solution that will fundamentally change the way the industry shares the information. One other area that is starting to turn from a buzzword to reality is “blockchain”. Rick Seibert at Sharp, Jean-Marie Aulnette at TraceLink and Nagore Fernandez at Ashfield explain how this is happening. Looking ahead to August, I am looking forward to speaking at the 2nd LSX Nordic Congress being held at Nasdaq in Stockholm, Sweden. I hope you will be able to attend and I look forward to catching up with you then. Lucy Robertshaw Director, Lucy J.Robertshow Consulting

by Gilda D’Incerti, CEO of PQE Group titled, “Emerging Trends in Regulatory Expectations” where he starts by saying that the ULTIMATE TARGET in the Pharmaceutical and Medical Device industries is to ensure Patient Safety within the entire Product Life Cycle, from R&D to Distribution. In 2009, the National Patient Safety Foundation’s Lucian Leape Institute (LLI) published a paper identifying five areas of healthcare that require system-level attention and action to advance patient safety. The authors argued that to truly transform the safety of healthcare, there was a need to address medical education reform; care integration; restoring joy and meaning in work and ensuring the safety of the healthcare workforce; consumer engagement in healthcare and transparency across the continuum of care. In the ensuing years,

the LLI convened a series of expert roundtables to address each concept, look at obstacles to implementation, assess potential for improvement, identify potential implementation partners and issue recommendations for action. Reports of these activities were published between 2010 and 2015. While all five areas have seen encouraging developments, multiple challenges remain.

and Executive Vice President, Vienna School of Clinical Research

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

I hope you enjoy the features we have bought you in this issue, and I look forward to bringing more exciting articles in the Summer issue of IPI.

Virginia Toteva Editorial Manager – IPI

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research, Center of MCH, Astana, Kazakhstan Catherine Lund, Vice Chairman, OnQ Consulting

Jagdish Unni, Vice President - Beroe Risk and Industry Delivery Lead - Healthcare, Beroe Inc.

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group

Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma

Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics

Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Stefan Astrom, Founder and CEO of Astrom Research International HB

Maha Al-Farhan, Chair of the GCC Chapter of the ACRP

Steve Heath, Head of EMEA - Medidata Solutions, Inc

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

T S Jaishankar, Managing Director, QUEST Life Sciences

Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2019 Volume 11 Issue 1

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Regulatory & Marketplace

Pricing Pharmaceuticals in Japan Development and pricing strategies to maximise the opportunity in a mature market

Introduction: 2018; A Year of Seismic Shift in the Japanese Market The year 2018 was epic for the Japanese pharmaceutical industry, largely because of the fundamental National Health Insurance (NHI) pricing reforms implemented in April. The repercussions of this change in policy is yet to be fully felt as of the beginning of 2019; however, some of the cautionary signs are already seen, for example some domestic companies exited the market last year because of the unattractive prospects. This was unprecedented, particularly for a full-fledged domestic pharma company such as POLA Pharma or Fujifilm RI Pharma, and it is difficult to imagine that these two will be the only ones and more moves are expected in the coming months.

IQVIA Institute predicts that the compounded annual growth rate of the pharmaceutical spending in Japan, which was at a healthy 2% in the last five years, will drop to somewhere between Δ3% to 0% from 2018 to 20221. Japan is the only market in IQVIA’s “Developed Country” category expected to show either negative or zero growth in this timeframe. Nevertheless, the same report forecasts that Japan will still be the third largest pharmaceutical market in 2022, with its spending between 85 and 89 billion US dollars. Another report by EFPIA also describes that the Japanese share of the new medicines sales will remain at 7.1%2. This suggests that the Japanese market will continue to be open to innovative pharmaceutical products. Various initiatives are taken by the Japanese authorities to encourage innovation within the country, mostly in the form of appraisals reflected in the price of the pharmaceutical product submitted for approval and NHI listing3. Given on the one hand this remaining appreciation to innovation, and on the other the expectedly sluggish growth of the market, leaders of pharmaceutical and biotech companies could face difficulty in making decisions on approaching this market in the Far East. 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

In order to understand the key success factors of a given technology and how the Japanese market appreciates it, it is critical to have the right knowledge about how the value of a drug product will be determined and will be reflected in its price, and how the applicant company can maximise its price potential. In this series of articles, I would like to review the principles of pricing and market access (PMA) in Japan. In this first article, I would like to provide an overview of the Japanese PMA system from the vanishing point of the global pharmaceutical markets. In the future articles, I will discuss the methodology and the underlying concepts (including the political intentions) of how the price of the drugs is determined and may change over time. This will be followed by the discussion about the patient access system in Japan. This may have some implications to the local development strategy of a given pharmaceutical product and the ongoing debate about the implementation of health technology assessment in the PMA process. We will also cover the recent NHI pricing reform and its significance to the industry as a whole. Japan as a “Therapeutic Referencing” Market PMA conditions and structures greatly vary within the global markets and across regions within countries4; each of them has uniquely evolved over time. One of the approaches to deal with this vast diversity is to typify the systems

by using relatively simplified criteria. Schoonveld proposed the following “archetypes” of the payers in order to segment them5. From Table 1 we can see that Japan roughly belongs to the “Therapeutic Referencing” segment because the justification of the valuation of the drugs are largely based on comparison to the values of other available drugs, with adjustments based on the interpretations of the relative therapeutic benefit against the comparator. While this approach is applied in many of the developed markets, there is a wide range of divergence in the way it is implemented. The following are the key characteristics of the Japanese drug valuation system compared to the other “Therapeutic Referencing” markets: •

Reimbursement of any prescription drug is effectively granted upon approval. Reimbursement levels are predetermined and uniform across indications and generally across any patient population. This means that the valuation of the drugs are predominantly reflected in the initial price at approval. Japan’s patient access to new medicines is the best among the developed countries. The median time for approval for a new pharmaceutical product in 2015 was only 311 days in Japan, compared with 422 days in

Table 1. Payer archetypes based on Schoonveld’s classification Spring 2019 Volume 11 Issue 1

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Regulatory & Marketplace

Europe and 333 days in the US6. This is because of the automatic reimbursement in the NHI system which covers the entire population, strict supply obligations, and the great effort to close the “drug lag” by the Pharmaceuticals and Medical Devices Agency (PMDA)7. As of 2019, there are no predetermined cost containment measures which are designed to influence the prescription decision of expensive new drugs, effectively. Cost containment measures such as diagnostic procedure combination (DPC), which is an inpatient prospective payment system similar to diagnostics-related group, puts most of the expensive new drugs out of the basket to allow those drugs to be reimbursed separately. Instead of placing a pre-designed utilisation control scheme, the pricing authorities may cut the NHI price of the pharmaceutical products at a discretional timing and to an arbitrary level when sales have reached a significant level. Japan is the only country in the global market that calculates the official list price of a drug product based on its cost structure. If there is no comparator product available in the domestic market, the applicant company can submit the information regarding the various costs. The authorities will determine the price of the drug by stacking the costs and even allowing a certain level of profit margin. If there is a comparator product available in the Japanese market, prices of new drugs will reference the comparator. Officially, drug price reference only looks for the internal market and if the price gap is large against the average of the three European major markets (i.e. Germany, France and the UK), adjustments will be made. Also to keep in mind is that Japanese drug prices are highly influenced by the prices of the same product in the major European markets. Therefore, European price assumptions, but not US prices, have an important implication in the pricing strategy in Japan. Other than markups on top of the benchmark comparator price, Japanese pricing authorities do not explicitly evaluate the intrinsic


value of a drug. Unlike the other Western countries, neither costeffectiveness analyses nor budget impact analyses are incorporated fully in the valuation process, yet. However, a “trial implementation” is on its way. Key Characteristics of the Market 1. Rapid Pricing Decisions One of the key differences of the Japanese PMA compared to other market authorities is the short lead time for pricing and reimbursement decisions after approval. In Japan, it will typically only take 60 to 90 days to have the NHI price of any new drug that joins the list. For example, compare that to EMA, which approved 47 drugs for 77 solid tumour indications and the median times from the EMA approval to the HTA decision was 188, 209, 384, and 405 days in France, Germany, Scotland, and England, respectively3. Together with the universal coverage and the

diminishing “drug lag”, this continues to offer a great commercial opportunity to the pharmaceutical industry. 2. Powerful Physician Authority Another important aspect is the greater authority given to the individual physicians to choose the medical intervention they offer to their patients. Physicians in Japan have the freedom to prescribe any drug with little limitations. This means that the utilisation of any given drug is difficult to control at a national level. Optimal Clinical Use Guidelines has been recently implemented by the MLHW together with the academic community to try to limit the usage of a newly approved drug to the most appropriate patients. This may become an important role in controlling the level of consumption for expensive new drugs. Such great authority given to physicians not only inhibits utilisation control but also does not allow indirect

Table 2. Comparison of cost control mechanisms among major ‘Therapeutic Referencing’ countries and the US private sector Spring 2019 Volume 11 Issue 1

Regulatory & Marketplace

pricing or reimbursement control, to effectively work as a cost containment measure in Japan. Under the NHI system, almost all of the approved prescription pharmaceuticals are reimbursed at the same percentage against the designated NHI price. Insurers do not have the freedom to alter this percentage. Therefore, insurers in Japan are basically incapacitated and the power balance is largely in favour of the physician. From an industrial perspective, these conditions make Japan an extremely attractive market. The company trying to introduce a product to the Japanese market will basically only have to care about the NHI price of the drug. In other words, development strategies for new drugs in Japan are still quite simple. The most important feature in the target product profile is the clinical benefit of the product. The key to success in Japan is physician preference in prescription decision-making, while in the rest of the developed countries you will also have to understand the payer perspective. 3. Lack of Opportunity to Negotiate As described in Table 2, while the drug prices in France, Germany and the US are determined and evolve through a

continued negotiation process, the window of opportunity to negotiate prices with the Japanese authorities is extremely limited. There are only two formal meetings within the 60 (or 90) day initial pricing process. There is no official hearing from the industry side even when the NHI prices will be significantly cut. The authorities will almost unilaterally determine the prices and in a sense, companies will have to consider drug prices as a given. However, there are some recent cases that the applicant refused the granted NHI price and delayed the launch of the product, which effectively extended the negotiation process. Istodax from Celgene and Taltz from Eli Lilly are among those products. We will discuss the pricing process in detail in the following articles. REFERENCES 1.


2018 and Beyond: Outlook and Turning Points (Mar 2018)," IQVIA Institute of Human Data Science, https://www. The Pharmaceutical Industry in Figures: Key Data 2018," European Federation of Pharmaceutical Industries and Associations, https:// efpia-pharmafigures2018_v07-hq.pdf




Update of Drug Pricing System in Japan," Ministry of Health, Labour and Welfare, content/11123000/000335166.pdf Anand B. Jain, Annette Mollet & Thomas D. Szucs, "Structural and procedural characteristics of international regulatory authorities," Nat Rev Drug Discov. 2017;16:594 PMDA, review-services/drug-reviews/ about-reviews/p-drugs/0013.html

Tosh Nagate Tosh Nagate is a consultant and pharmaceutical pricing, forecasting and valuation expert based in Tokyo, Japan. Currently he is CEO of e-Projection K.K., a consulting firm specialising in commercial assessment and BD support in the Japanese and global markets. Tosh has more than 15 years of experience in the industry with multinational companies including Takeda and Abbvie. Tosh is a PhD in medicine and MBA with honours from University of Chicago Booth School of Business. Email:


Regulatory & Marketplace

Why Companies Need to Act Now to Guarantee EU Medical Device Regulation Compliance There are just over 12 months to go until the EU Medical Device Regulation (MDR) enforcement deadline of May 2020. This is driving major efforts across the industry to ensure compliance, with initiatives complicated by the fact that not all details of the MDR have yet been finalised. For example, in January 2018 the EU released an update around the format of Unique Device Identification (UDI) codes and how they would be applied to medical devices. How can companies make sure they are ready in time?

The MDR has been introduced in response to demand from the public for increased transparency, following safety concerns around products such as some breast implants and metal-onmetal hip replacements. Under the MDR, companies will be responsible for ensuring that all their products meet general safety and performance requirements, and the regulation will be expanded to include cosmetic devices and medical device software. Transforming the Regulatory Approach It is becoming clear that the MDR requires a totally new way of ensuring compliance. Clinical evaluations will be at the heart of this approach, with greater transparency and traceability across both the device lifecycle and the entire supply chain. It will also require a shift from passive management of regulatory files, based around specific milestones such as device changes or audit dates, to active management of all files, requiring constant monitoring and updates. Given the short timescale and complexity of the MDR, simply adding more people to compliance teams will not be enough to meet the regulation cost-effectively. There are not enough trained QA and regulatory people available to meet demand. This means software and systems will be vital to ensure compliance, 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and organisations need to act now to understand the legislation, evaluate what it means for their businesses, and take steps to meet it. Failure to be ready by May 2020 leaves companies open to potential compliance risks. That means they should look to put appropriate measures in place to guarantee business continuity and minimise issues, as well as ensure they have all data and documentation in place to achieve compliance across their products. Focus on Data and Ongoing Compliance The MDR takes an evidence-based regulatory approach, which means companies will need to demonstrate clinical evidence regarding the safety of every Class III device in their portfolios, irrespective of when these were introduced. This “no grandfathering” clause will have particular impact on older devices. These may not have required clinical information when they were introduced, which means manufacturers may not have data to hand to share with regulators. At the same time, a greater number of products are expected to be designated as Class III under the MDR, and this will add to the workloads of already-overstretched compliance teams. Manufacturers also need to take an ongoing, continuous approach to compliance. Rather than simply achieving certification through single submissions, the MDR mandates that companies maintain systems and documentation in permanent compliance throughout device lifecycles. This new approach is likely to change internal processes and require greater collaboration between multiple departments, such as risk management, clinical evaluation, post-market surveillance, and clinical studies. Using Technology for Business Transformation Technology is key to meeting the

requirements of the MDR. However, in many cases the existing systems and processes that medical device manufacturers rely on won’t provide the support they need in the post-MDR world. Essentially, medical device companies in the sector face a similar dilemma to that of pharmaceutical companies five to 10 years ago. To successfully navigate changing market conditions, pharma businesses transformed their approaches to technology, moving away from homegrown, on-premise, or legacy systems to embrace best-of-breed and cloudbased solutions. The MDR provides a similar opportunity for medical device manufacturers to use technology to transform their systems and how they use technology within their businesses. With just over a year until the enforcement deadline, here are three steps companies should be taking now to improve how they track clinical documentation and ensure MDR compliance: 1. Invest in understanding what the MDR means to your business. Whatever the size, the MDR will disrupt every medical device business operating in Europe. While time is short, the first step should be to invest in fully understanding the regulation and its impact. Compliance will require a significant amount of documentation, and much of this will need to be freshly created. This is because previously there was no requirement to run trials in Europe for every new product – manufacturers just had to provide clinical evidence that new devices used similar materials to those already on the market, or delivered the same levels of effectiveness as competitors’ products. This approach is no longer compliant under the MDR, as every product will require real-world clinical evidence. Spring 2019 Volume 11 Issue 1

Regulatory & Marketplace 2. Review your entire portfolio. Medical device manufacturers must ensure that every device they are selling is compliant under the MDR – they will not be able to “grandfather” in legacy devices that were introduced many years ago, or did not require clinical evidence at those times. Many companies have expanded rapidly, and their portfolios have grown quickly. This makes assessing all products a time-consuming but vital step. Companies must check that supporting data and documents, such as post-market surveillance plans and reports, post-market clinical follow-up reports, periodic safety update reports, and summaries of safety and clinical performance are all in place.

Given the MDR’s focus on clinical evaluation requirements, companies must collate and maintain real-world clinical data. Additionally, in some cases, devices may need to be reclassified, which may require additional data, documentation and, inevitably, scarce time and resources. Completing their portfolio reviews will enable companies to highlight any gaps in the evidence required for MDR compliance. They will then need to perform informed cost-benefit analyses for those devices that don’t have the supporting clinical evidence. Does the device generate sufficient revenue and profit to justify the expense of running a fresh clinical study to gather the necessary evidence? How can I efficiently generate and disseminate clinical data to regulators, patients, and providers?

3. Use technology to enable compliance. The MDR means medical device businesses will need to collect and share much larger amounts of clinical evidence. They will need to invest more in trials, as well as ensure that this information is stored and shared in ways that make demonstrating compliance simple and straightforward. Essentially, they will need to

redesign their processes and evaluate their outsourcing strategies and the overall designs of their organisations. Technology is essential – there are simply not enough trained QA and regulatory people available to achieve cost-effective compliance by May 2020.

Medical device businesses need to begin by assessing their current systems and processes. Can they support clinical, quality, and regulatory requirements across their organisations? Do they provide platforms for improved compliance to reduce risk and increase visibility, transparency, and collaboration?

The Benefits of System Modernisation Historically, most medical device manufacturers did not need to invest heavily in technology. This means many still operate through inflexible on-premise legacy systems, Excel spreadsheets, file sharing, and email for information sharing. This will not be enough to ensure MDR compliance. The approaching MDR deadline should therefore act as a catalyst for these companies to update legacy systems and processes and transform their technology landscapes by moving to more modern, effective, cloud-based technology. Adopting these modern systems delivers benefits well beyond MDR compliance. They provide the framework for more collaborative and transparent document and data management across all functions. They help break down departmental silos, increasing transparency into workflows and document lifecycles. Switching from internal systems to cloud technology makes collaboration with external organisations, such as regulators and outsourcing partners, easier. Adopting new technology underpins easier regulatory compliance. Companies can quickly establish audit trails as tasks are documented through the entire product lifecycle, while monitoring statuses through automatic, dashboard-based updates. Reporting is simpler with the ability to drill down into data to provide

insight that understands and improves performance. Removing paper and paper-based processes optimises employee time, improves efficiency, and streamlines operations. Preparing for a Post-MDR World The clock is ticking towards the MDR enforcement deadline, and medical device manufacturers need to transform how they operate if they are to be compliant by May 2020. Existing technology and processes will hinder, rather than help, efforts to be ready. Now is therefore the time to act – investing in flexible, cloud-based technology will make MDR compliance more straightforward, as well as transform wider operations, increasing competitiveness in the future.

Seth J. Goldenberg Seth J. Goldenberg is responsible for the Veeva Vault strategy in the medical device and diagnostic industry, including customer engagement, market adoption, and product development. Seth has nearly 20 years of experience helping medical device and diagnostics companies navigate complex regulations and improve market access.


Regulatory & Marketplace

The Impact of a No-deal Brexit on Pharmaceutical Patents – The Main Considerations Uncertainty surrounding a potential no-deal Brexit has created a deep chasm in opinion in relation to the future of the UK’s lucrative pharmaceutical industry.

Despite the UK’s exit from the European Union advancing at an alarming rate with a meaningful deal yet to be reached, a growing division has emerged between the confidence demonstrated by international investors who continue to plough millions into the UK pharmaceutical industry, and the nationwide concern from industry leaders about the sector’s ability to function effectively post-Brexit. Concern around pharmaceuticals has understandably increased as many across the business and medicinal landscape have questioned the impact that a no-deal Brexit could have on the pharmaceutical sector’s fundamental operating needs and abilities. Much emphasis has been placed on the potential implications to the industry, due to its particular dependency on the seamless operations of effective political and regulatory systems in order to continue the development, manufacture, and trade of drugs and other pharmaceutical products. Fears surrounding free movement of pharmaceutical workers across the UK and EU, and ultimately the impact this could have on patients, have also grown as government negotiations have become increasingly unstable in recent months. This growing trepidation is unsurprising given the industry’s substantial global value of $934.8 billion (£756.4 billion) in 2017, a recent report by The Business Research Company showed. According to a report from PwC, the sector employs more than 73,000 people across Britain, with exports to the EU valued at $15 billion (over £11 billion), and pharmaceutical 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

products being one of the top five most imported and exported across the Channel. Yet despite this inevitable worry and growing unease, pharmaceutical giants GSK and Astra Zeneca invested £6 billion and £5.4 billion respectively in R&D spending in the UK last year, according to a report from PwC. Data published by the ABPI also revealed that the pharmaceutical industry spent £370.9 million in supporting UK healthcare professionals (HCPs) and organisations (HCOs) relating to research and development activities in the UK during 2017. Much of the value of the pharmaceutical industry is inherently linked to the individual financial monopoly afforded to unique drugs and technology when they reach the market. To ensure a product is marketable, companies routinely invest significant sums into research and development to ensure they have created an effective product, which fills a niche in the pharmaceutical world. This initial R&D investment, and the consequent products created as a result, are protected when they become commercialised, thanks to patents. With patents playing such a vital role to the ongoing growth and success of the UK’s thriving pharmaceutical industry, it is perhaps significant to explore how a no-deal Brexit could impact the current patent system. Understanding the impact a UK withdrawal without a deal could have on pharmaceutical patents, could help to address the contradicting beliefs expressed by pharmaceutical giants and UK business leaders, and ultimately could help to guide their focus towards how to ensure success in the UK’s pharmaceutical industry before and after March 29th. Leading patent attorney and partner at intellectual property firm Wynne Jones IP, Jim Robertson, explores

the implications of a no-deal Brexit on pharmaceutical patents, and advises companies on the crucial considerations they should undertake before and after the impending withdrawal. How Would a No-deal Brexit Affect Pharmaceutical Patents? Firstly, how would a no-deal Brexit affect pharmaceutical patents? Mr Robertson, a specialist in the protection of biotechnology, pharmaceuticals, diagnostics and medical devices, reassures companies that in terms of obtaining a granted patent, there is unlikely to be an impact. He explains: “Patents in force in the UK are either granted by the UK Intellectual Property Office (UK IPO) or by the European Patent Office (EPO). In terms of those granted by the UKIPO there will understandably be no change. As for those granted by the European Patent Office, the EPO is not a European Union (EU) institution. Instead, it was established by a separate international convention (the European Patent Convention) and has many non-EU member states such as Norway, Switzerland, and Turkey. Therefore, a no-deal Brexit would have no impact upon patents in the UK. On a more global basis, there would similarly be no effect – the international patents system is completely separate from the EU.” With the prospect of a no-deal Brexit looking increasingly more likely, due to an impasse in negotiations within the Government and the EU, pharmaceutical companies are highly likely to have explored contingency plans to protect their patents, should the UK leave without a deal. Supplementary Protection Certificates (SPCs) Mr Robertson said that the main consideration for pharmaceutical companies in the event of a no-deal Brexit is Supplementary Protection Certificates (SPCs). Spring 2019 Volume 11 Issue 1

Regulatory & Marketplace The IP specialist added: “These SPCs provide up to five years of additional monopoly protection for marketed medicinal products when the basic patent has run its full term. The law that underlies SPCs is an EU regulation, although individual SPCs are granted on a national (country-bycountry) basis – in the UK, this is done by the UK IPO. This means that for existing SPCs, i.e. SPCs that have been granted before Brexit, there should be no change and SPC owners should not need to do anything extra. For SPCs that have not yet been granted and SPC applications that have not yet been filed, there will not be any immediate change. However, there is likely to be change in the medium- to long-term.” Court of Justice of the European Union Rulings He cautioned that the biggest impact in respect of changes to EU law will be seen in rulings made by the Court of Justice of the European Union (CJEU) on the day of, or after Brexit. The European Union (Withdrawal)

Act 2018, which was enacted in June 2018, states that direct EU legislation, including EU regulations, forms part of domestic UK law on and after exit day. This means that when Brexit occurs, the EU SPC regulation will form part of domestic UK law. “However, in the event of a no-deal Brexit, this retained EU law will not include case law from the CJEU made on or after Brexit day, and new EU law will not have effect in the UK,” Mr Robertson said. “Similarly, if there is a Brexit deal, which enables the UK and EU to enter into a withdrawal agreement, then after the end of the transition period (running until 31st December 2020), new EU law will not have effect in the UK. Additionally, case law from the CJEU in legal proceedings instituted after the end of the transition period will have no effect.” In respect of inevitable changes following the implementation of Brexit, it is “crucial” that pharmaceutical manufacturers engage with industry bodies and the Government to ensure

that changes to UK law work in their favour, and that they are not left disadvantaged by changes in EU law, Mr Robertson said. Divergence in EU and UK Rulings Another fundamental difference in relation to CJEU rulings post-Brexit will be the potential divergence in opinion and rulings, when the UK courts inevitably take over. Currently, where the UK courts have doubts about the interpretation of SPC law, they are required to refer questions to the CJEU – this ensures that EU law is properly (and consistently) applied. However, when the UK exits the European Union these referrals will cease. Mr Robertson said: “After Brexit, those questions will have to be answered by the UK courts themselves, with binding precedent coming from the UK Supreme Court. Although CJEU decisions may be persuasive for the UK courts when they make their decisions, there is a very strong likelihood that UK and EU law on SPCs will diverge.”

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Regulatory & Marketplace SPC Manufacturing Waivers Another change to the SPC is the introduction of the SPC Manufacturing Waiver which has been proposed by the European Commission. This will enable EU-based companies to manufacture generic or biosimilar versions of protected medicines for export outside of the European Union and beyond IP-protected areas. While this is indeed a positive step for EU-based manufacturers, it could potentially be catastrophic for UK pharmaceutical companies, which could be suddenly faced with limitless competition from identical products in the marketplace. Not only could this significantly impact their financial monopoly, but it could ultimately decimate their ability to continue developing and producing life-saving medicines. Mr Robertson said: “If there is a no-deal Brexit, the EU's proposed SPC Manufacturing Waiver could have a significant impact upon UK pharma manufacturers. Under this new law, SPCs will not prevent EU companies from manufacturing products for the exclusive purpose of export to third countries such as the UK. Although an SPC for the product may also exist in the UK, the end result of this will be that EU companies will be able to manufacture and stockpile product for export and sale in the UK from the moment that the UK SPC expires. In contrast, the retained SPC regulation will mean that UK pharma manufacturers would not enjoy the same rights. “At the moment, there is no indication that the EU SPC Manufacturing Waiver will come into force before 29 March 2019, and similarly there is no indication that UK SPC law will be amended immediately upon a no-deal Brexit. Therefore, there is no reason to delay filing SPC applications to take advantage of changes in the law.” The issue could be rectified by the UK Government passing new legislation to modify the UK SPC law, according to Mr Robertson. However, this would probably require Parliament to pass new primary legislation, which would be after Brexit occurs. Mr Robertson added: “The current draft of the proposed new EU law has 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

its own problems and limitations, which new UK law could resolve. Similarly, basic issues with the retained SPC law, such as the marketing authorisation which should be used as the basis for the SPC, could also be resolved. "The Rt Hon Lord Henley, Parliamentary Under-Secretary of State at the Department for Business, Energy and Industrial Strategy, stated in a House of Lords debate on 6 February 2019 that ‘The Government have said that they will review the data and market exclusivity arrangements within two years of a no-deal exit’. However, that is distinct from introducing a manufacturing waiver, and the timescale for this (let alone getting legislation enacted) may simply be too long to avoid harm to UK businesses. “Pharma companies and their trade organisations should look to lobby Government to ensure that new UK law addressing these problems with SPCs is enacted as soon as possible.” Being Proactive The intellectual property expert said it was crucial that pharmaceutical companies took an increasingly proactive role in being more vigilant and proactive in monitoring developments in relation to SPCs, and SPC Manufacturing Waivers, and urged them to engage with industry bodies and Government to ensure a beneficial outcome for the UK. He said: “If made quickly, changes in UK SPC law to introduce an SPC Manufacturing Waiver could give a real competitive advantage to UK businesses. If changes lag behind those made to EU law, UK businesses could be at a significant disadvantage.” Conclusion Pharmaceutical patents in the UK are undeniably set to undergo a period of sustained upheaval, which could result in both positive and negative factors for the UK overall. In the process of splitting from the European Union and the rule of the CJEU, there is understandable uncertainty and concern surrounding the pharmaceutical industry’s ability to continue developing, manufacturing, and trading multimillion-pound medicines and technology. Alongside this, the legal ramifications for the UK pharmaceutical industry outside

of the EU, in a system which has not yet established how it will necessarily be governed and how rulings will be decided, is also a cause for significant worry. However, it is always tempting to be endlessly bleak when approaching discussions around Brexit. If the UK is able to establish sound legal and IP systems quickly and efficiently, the UK could see itself in a stronger, more independent position. While a no-deal outcome does undeniably raise additional considerations surrounding an already incredibly complicated exit process, swift action by the Government and industry bodies to create a more robust UK SPC system could be incredibly advantageous for the UK’s pharmaceutical industry going forwards.

Jim Robertson Jim Robertson is a leading patent attorney and partner at nationwide intellectual property firm Wynne Jones IP. His primary technical fields are in life sciences – biotechnology, pharmaceuticals, diagnostics and medical devices. He is also a member of the CIPA life sciences committee.

Spring 2019 Volume 11 Issue 1

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Regulatory & Marketplace

The Manufacturing-regulatory Data Continuum: Forging New Connections It makes no sense that product data exists separately in ERP and RIM systems, compromising any efforts to improve efficiency through tighter inter-function collaboration. A recent panel discussion, hosted by ProductLife Group and featuring industry experts from K2 Consulting, Gens & Associates, LEO Pharma and Lundbeck, debated approaches to bringing down the barriers and reducing manual process repetition. Here, Catherine Gambert, ProductLife Group’s senior consultant for regulatory affairs, summarises the main themes.

As long as each organisational department has its own systems, processes and priorities for capturing and managing product data, information preparation will be subject to repetition and risk and processes will take longer than they need to. And currently this is the situation that persists with product-related data, between manufacturing and regulatory affairs. A recent roundtable debate, between a panel of frontline life sciences industry experts, delved into this issue and looked at workable solutions, including those being piloted by companies involved in the discussion. On the panel were Steve Gens, managing partner at Gens & Associates; Kelly Hnat, principal at K2 Consulting, Jesper Kihl, VP for global regulatory affairs at LEO Pharma; Jan VindbergLarsen, senior director and head of global regulatory affairs at Lundbeck; Erick Gaussens, PhD, chief scientific officer at ProductLife Group (PLG); Catherine Gambert, senior consultant for regulatory affairs and regulatory information at ProductLife Group (PLG); and Loetitia Jabri, regulatory and pharmaceutical platforms associate director at PLG. Recognising that product and regulatory information has an ever greater role to play in the efficiency and strategic direction of life sciences 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

businesses, the panel considered how companies could make more of this. Getting Product Data in Order: A Rising Priority Steve Gens noted that, in his firm’s latest market research into companies’ regulatory information management (RIM) activities1, the improvement of data management and connections to other functional areas is now a major priority for life sciences firms of all sizes. Yet, although some firms are making good progress, others are held back by the scale of change to processes and systems that are be involved – and the senior organisation involvement that will be needed to effect a shift towards more routine collaborative working. But change they must. Currently, only 14 per cent of companies have connected RIM and enterprise resource planning (ERP) systems, according to Gens & Associates’ findings. This means most information gathering and verification is being conducted manually, creating a huge data management burden, not to mention considerable scope for business risk. When information that exists across RIM and ERP systems is inconsistent, and the respective systems aren’t set up to communicate with one another, this can create complexity and vulnerability – from compliance challenges to losses of sales based on a failure to get products to market in a timely fashion. If information about a change control process doesn’t flow between regulatory and manufacturing, meanwhile, it can cause hold-ups in international markets. As PLG’s Catherine Gambert cautioned, “When a product gets stuck at the border because the information printed on the box isn’t the same as that in the regulatory documents, it becomes a serious issue – and this can arise because the supply chain doesn’t have access to the information in the RIM system.”

Swelling Data Volumes as Health Goes Digital It isn’t just the pharmaceutical sector that is facing practical issues because of faltering data exchange and poor visibility. The medical device sector shares many of the same challenges, and these will prove increasingly critical as regulators impose stricter regulations around device traceability. But effective data exchange isn’t just a compliance challenge in this sector either. As the digital health movement gathers momentum, the importance of having robust data trails will only grow. “Data integrity will be a major challenge – especially when it comes to connected medical devices involving remote measurements of physiological functions,” PLG’s Loetitia Jabri explained. One of the growing issues for all life sciences organisations is the speed and frequency with which data can change and need to be updated across all departments and systems. Fragmented data chains and system silos create points of risk. “The objective is to make sure we all use the same source of data,” Jesper Kihl of LEO Pharma said. “We recognise the potential benefit of having more integration.” Over the last year, LEO Pharma has updated its labelling practices, for instance, so that there is more end-to-end visibility and a seamless data flow. Having seen the positive impact this can have, the company is now looking at how to apply the same treatment to other parts of the business.

Lundbeck’s Jan Vindberg-Larsen noted that his regulatory affairs organisation has developed an effective infrastructure for collaborating more readily with production, allowing the two parties to share information more effectively. An SAP system is used for assessing all changes to products, including business cases; these are evaluated by Spring 2019 Volume 11 Issue 1


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Regulatory & Marketplace commercial, regulatory and production teams before implementation. The ability to work from the same data is also prompting broader collaboration. “We’ve also established a product committee for our marketed products,” he said. “The committee governs any major cross-functional activities and ensures alignment between regulatory affairs, production, and commercial operations on goals and priorities.” It helps that modern software systems are now being built to be more open, in support of easier data exchange and process traceability. Kelly Hnat of K2 Consulting noted that today’s RIM systems are very good at tracking changes to each change to a set of registered particulars about a product, the associated variation’s filing, and the approval status of that particular variation filing. “So you can see all of the changes to each registered data point in a RIM system if it’s managed properly,” she explained. In the Gens 2018 survey, two-thirds of respondents said their companies expected to start to automate the regulatory-clinical connection over the next two years, while just over half said they would start to connect and automate regulatory supply release and product change control processes. Investing in a Single Source of Product Truth Connecting disparate systems isn’t always straightforward, however, especially if those respective systems have their own descriptors for products. Not having a common vocabulary means it’s hard to identify data elements in one system and connect them to elements in the other. It’s here that the prospect of master data management – building and maintaining a single, definitive version of the product truth – offers to transform things. As Steve Gens noted, “One of the initiatives for the connection of information is the standardisation of terminology, so that once systems are connected they 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

can share information seamlessly. Typically, that’s the most difficult job – the handling of terminology – rather than the connection of systems.” “It’s not just about the differences in controlled vocabularies, but also about how data is stored, what it’s stored for, when it changes, and how it changes,” Kelly Hnat added. “Regulatory and quality teams use their systems for different purposes, and they’re tracking information at different points in the process. One of the things companies have to be cautious about when implementing master data management is not only the importance of finding out who owns the data but also the purpose of the data, when it was updated, etc.” Although data captured for IDMP regulatory purposes focuses on what’s registered, it doesn’t necessarily cater for what the manufacturing site is doing,” she noted. So master data approaches need to extend beyond specific use cases. PLG’s Erick Gaussens suggested that an effective approach to keeping all of the fuller data sources and supporting documents aligned can be to layer the RIM system on top of the ERP system, maintaining control of the metadata. Whatever the broader opportunities, it is typically the intensifying regulatory demands that continue to drive improvements and free up the necessary budget. Companies are aware that initiatives such as IDMP and the Falsified Medicines Directive mean data must become more integrated, so functions have become more willing to spend time and resources on building bridges and establishing interfaces. But it’s those organisations that have also identified the wider business benefits of more streamlined data management that have seen the greatest scope to modernise and innovate. At LEO Pharma, Jesper Kihl explained how his team has used IDMP to highlight the broader potential for greater efficiencies and closer connection between functions. He hopes that IDMP implementation timelines will be brought back on track by regulators soon, when a

higher sense of urgency will help drive through the benefits. When a company treats data as a corporate asset and maintains it in the form of definitive master data, the whole organisation stands to benefit from an environment in which data can be trusted as being a high-quality record of the latest truth, the panel agreed. Ultimately, this makes everyone’s life easier, makes processes slicker, and drives out cost and risk, while supporting greater market agility: desirable aims for any business in 2019. REFERENCES 1.

World Class Regulatory Information Management Whitepaper: Connections to Supply Release, Product Change and QMS, Gens & Associates’ 2018 (a study of RIM priorities and status in 69 companies globally): http://gens-associates. com/wordpress/wp-content/ uploads/2018/10/GensAssociates_ ExecutiveWorldClass_RIM_Whitepaper_ Fall2018_Edition_101218.pdf

Catherine Gambert Catherine Gambert is senior consultant for regulatory affairs and regulatory information at ProductLife Group. Web:

Spring 2019 Volume 11 Issue 1

Product News

Sartorius Stedim Biotech Introduces BIOSTAT® RM TX with Flexsafe® RM TX for Producing Consistent Quality Cellular Products Sartorius Stedim Biotech (SSB), a leading international supplier for the biopharmaceutical industry have launched the BIOSTAT® RM TX single-use bioreactor, a new wave mixed system developed specifically for closed, automated expansion of consistent quality cell products such as ex vivo cellular immunotherapies. This new GMP platform, which combines SSB’s established singleuse Flexsafe® bag technology with the company’s expertise in biopharmaceutical automation, was introduced at Phacilitate Leaders World 2019 in Miami, USA. SSB’s new bioreactor is designed for scale-out expansion of cells including patient-specific T cells and is a closed system, consisting of an automated control unit and a up to two rocking platforms to gently agitate single-use Flexsafe® RM TX bags (up to 5L working volume). The bag is the core of the system and built on SSB’s Flexsafe® film, which is already well-established from clinical development to GMP manufacturing of vaccines and biologics by major global biopharma companies. The film formulation is developed to minimize leachables and extractables, guaranteeing consistent batch-to-batch culture performance of even sensitive cell types, such as genetically modified T cells. The proprietary Flexsafe® RM TX bag is designed with a special port for hands-free gravity harvesting. In combination with the innovative Flexsafe® RM TX Harvest Device it reduces the contamination risks from manual handling, maintaining cell integrity and cell viability. Unlike other

BIOSTAT® RM TX automated twin system for culturing of consistent quality cells.

cell therapy expansion systems which use pumps for cell recovery, this unique gravity harvest concept reduces the risk of shear stress on these delicate cells, to maximize cell number recovery. A benefit of using the BIOSTAT® RM TX bioreactor in combination with the Flexsafe® RM TX bag for cell culture is the possibility for walk-away monitoring and culture control. The bags include single-use sensors for pH, DO and viable biomass. These sensors are integrated in the BIOSTAT® B control unit, and the system’s sophisticated software is set-up for fully automated process control of gases, flow rate, filling volume and substrate addition. With culture volumes greater than 500 mL, on-line analysis of viable biomass is also possible by connecting the single-use BioPAT® ViaMass sensor. These sensors make the system suitable for running continuously in fed-batch or perfusion modes, saving labor, time and effort with manual sampling and also minimizing contamination risks to precious patient cells. Utilizing this bioreactor system, manufacturers can attach a second rocking platform and Flexsafe® RM TX bag to each BIOSTAT® B control unit to scale-out their production. The system

also provides a standard interface to common Supervisory Control and Data Acquisition as well as Distributed Control Systems such as BioPAT® MFCS and DeltaV™. “Combining single-use technology with advanced automation for the expansion of cell products ensures control of process variability and enables safe, robust and affordable cell production,” explained Dr. Franziska Faulstich, Global Product Manager Regenerative Medicine and RM Bioreactors at Sartorius Stedim Biotech. “Working extensively with leaders in the cellular immunotherapy field, we have identified the right technologies and best practice workflows, which we have incorporated into our new BIOSTAT® RM TX bioreactor,” she added. Cell product developers using this cleverly designed system can help improve their process performance, and as a result the integrity and consistency of their promising cell therapies in development. BIOSTAT® RM TX and Flexsafe® RM TX bags are for research and further manufacturing use only – not for use in therapeutic or diagnostic procedures. They are not CE marked for in vitro diagnostic use nor are they medical devices. Drug manufacturers and clinicians are responsible for obtaining the appropriate IND | BLA | NDA approvals for clinical applications. Contact: Sartorius Stedim Biotech Phone: 0049(0)551.308.0,

Flexsafe® RM TX Harvest Device for hands-free gravity harvest of the cell culture with maximum recovery.

Flexsafe® RM 2L TX bag with single-use BioPAT® ViaMass, Sartopore® Air vent filters and patented perfusion filter.


Drug Discovery, Development & Delivery

Are your Companion Diagnostic Partners Ready?

The new In Vitro Diagnostic Medical Devices Regulation (IVDR) EU 2017/746, was published in the Official Journal of the European Union in May 20171 with full implementation by the date of application, 25th May 2022. It is envisaged that the new regulations will create a robust, regulatory framework which will be internationally recognised to improve clinical safety and improved market access. It appears, however, that the majority of stakeholders are not ready for the increased challenges of obtaining and maintaining compliance to the new requirements. The IVDR will have significant impact on the regulation of companion diagnostics (CDx) and manufacturers of CDx devices are facing some of the greatest regulatory challenges in order to become compliant by the date of application. While the IVDR uses the same basic regulatory processes as the current In vitro Diagnostic (medical device) Directive (IVDD), including the continued need for technical documentation to demonstrate device performance, there is now a requirement for considerably more detail. The Essential Requirements remain but have been renamed to the General Safety and Performance Requirements and updated to include new requirements as well as additional requirements for clinical evidence. Existing requirements for Post Market Surveillance have been reinforced and expanded.

The lack of clarity in some key aspects of the text; the associated difficulty in uniform interpretation; along with an apparent lack of understanding or consideration of the global companion diagnostic clinical validation paradigm already established in the US, Japan and S. Korea, means that many Rx/CDx sponsors are unsure of how to develop or move forward with their compliance plans. In this whitepaper, we will provide an overview of the transitional activities required under the IVDR and their status, as well as examine the most 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

significant new requirements and assess their impact on companion diagnostic manufacturers and their pharma collaborators. While preparations should now be well advanced to ensure compliance with the new requirements, the reality may be otherwise, particularly for smaller companies and laboratory test providers with limited resources. We will outline the steps that the manufacturers of targeted therapies who rely on CDx availability in the EU to select patients for whom their therapy is safe and effective, should take now to ensure that their CDx vendors are as prepared as possible for the new regulatory paradigm and that their CDx devices are available for use at clinical laboratories by the date of application. Transitional Provisions In order to prepare for the new regulatory model in the EU, many changes must be implemented by the EU Commission and National Competent Authorities to ensure that the systems are ready to submit and assess the conformity of existing and new medical devices being placed on the EU market (both for clinical use and for clinical research) by the date of application. Through the work of the Medical Devices Coordination Group (MDCG), whose members are drawn from representatives of member state competent authorities and who provide input to the commissions programme of implementation of the new regulations, these transitional provisions for in vitro diagnostics include the following; • • • • • • •

Scope & Designation of Notified Bodies EUDAMED (European Databank on Medical Devices) UDI (Unique Device Identification) Implementing Acts (including Common Specifications for Class D IVDs) EU Reference Laboratories (for class D IVD devices) Establishment of Expert Panels Development of Guidance Documents

As of the end of 2018, progress has been made in some of the transitional areas above, however this progress has been slow, and fears are growing that key provisions will not be in place in time for the date of application of the MDR in May 2020. As a result of the size of the medical device sector, the focus of attention at Commission/ MDCG level has been largely confined to working to ensure that the needs of the general medical device sector are met on time, albeit some of these provisions will equally apply for in vitro diagnostic medical devices. In relation to designation of Notified Bodies, only 7 (out of an existing 22 designated under the directive) applications have been received for designation under the new IVDR. This figure includes Notified Bodies who have applied for designation in more than one member state. Since Companion Diagnostics shall require the involvement of a Notified Body in the Assessment of Conformity, the capacity of the Notified Bodies to review and approve (CE mark) CDx device technical documentation will be seriously constrained. Given that around 85% of IVD devices will require approval by a notified Body, this represents a serious risk to the availability of CDx devices, approved for their intended use, by the date of application. It is currently unknow by industry whether there are additional Notified Bodies who intend to apply for designation under the IVDR. Another transitional provision permits the continued placing on the market of IVD devices that have a valid CE certificate issued by a Notified Body under the current directive at the date of application. These devices can be supplied until this certificate expires or until May 27th, 2024 whichever comes first. Since CDx devices CE-marked in compliance with the directive are self-certified (i.e. no Notified Body involvement in the CE-marking and therefore no CE-mark certificate), this provision will not apply to Companion Diagnostics.

Spring 2019 Volume 11 Issue 1

Drug Discovery, Development & Delivery Additionally, the commission has agreed to a ‘sell-off’ provision, permitting devices that are in the supply chain (already placed on the market) on the date of application to be used by their final user up to 26 May 2025. Devices must, however, have been transferred outside of the manufacturers’ ownership by the date of application. This provision is clearly of limited utility to IVD manufacturers resulting from manufacturing capacity and device stability constraints. Overview of the Conformity Assessment Process for Companion Diagnostic to the requirements of IVDR The introduction of the IVDR brings with it many changes for manufacturers of Companion Diagnostics. In addition to meeting the applicable general safety and performance requirements in Annex I of the regulation, Companion Diagnostic devices must additionally follow a conformity assessment process in compliance with Annex IX or Annex X combined with Annex XI. The requirements of Annex IX are based around implementing a robust quality management system that will control development, manufacturing and release of the IVD device with additional requirements detailed in Annex IX section 5.2, specific for Companion Diagnostics including consultation by the Notified Body with the EMA or National Competent Authority for Medicines in the country where the Diagnostic manufacturer has a registered place of business. In combination with the numerous changes to the way in which the performance testing of the Companion Diagnostic device is planned, conducted, along with the remaining uncertainties in the text and many areas requiring further clarification for CDx stakeholders, the procedures for conformity assessment represent a significantly increased burden on manufacturers and Notified Bodies. IVDR Effects on the Development and Validation of Companion Diagnostics As outlined earlier, the changes in the IVDR represent a challenge to many CDx stakeholders to ensure;

• • •

The continued availability of devices for patients in the EU at the date of application and; The level and nature of device performance data is adequate That current and ongoing development programmes are considering and meeting the requirements of the new regulation.

Below, we consider the most significant changes between the existing directive and the regulation affecting companion diagnostics, their direct impact and explore the ‘known unknowns’ that will affect the development and approval of CDx devices in the EU.

Figure 2 indicates that there are substantially more activities to be carried out under the IVDR to plan and conduct a performance evaluation. The performance evaluation process per Annex XIII, is a continuous process throughout the life-cycle of the device (documented in the Post-Market Performance Follow-up), carried out according to the Performance Evaluation Plan and presented in a Performance Evaluation Report. The Performance Evaluation must be developed and planned such that it generates adequate evidence that demonstrates Scientific Validity, Analytical Performance and Clinical Performance based on a Clinical Performance Study Plan (CPSP).

1. Companion Diagnostic Classification

Figure 1: Impact of IVDR on CDx Device Classification

As shown in Figure 1 above, one significant aspect of the new regulation is the introduction of a risk-based classification system based on the IMDRF (formerly GHTF) system of device classification. This, in combination with a specific definition for Companion Diagnostics, results in a change in the classification from self-certified general IVD devices to high risk class C devices. CDx devices will require conformity assessment by a Notified body in consultation with the European Medicines Agency (EMA) or Member State Competent Authority for Medicines.

The CPSP contains twenty-six specific elements, any considered not appropriate for inclusion in the CPSP due to chosen study design (e.g. use of left over samples versus interventional clinical performance studies) must be justified. The Clinical Performance documented in the Clinical Performance Study Report should be transparent, free of bias and clinically relevant. As a general rule Clinical evidence should be sourced from performance studies under the responsibility of the study sponsor (manufacturer).

2. Performance Evaluation and Clinical Evidence

Figure 2: Performance Evaluations and Clinical Evidence under the IVDR INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Drug Discovery, Development & Delivery 3. Requirements for Performance Studies

Figure 3: Comparison of Requirements for Performance Evaluations conducted under the IVDD and IVDR

As shown in Figure 3, there are significantly increased requirements to demonstrate the performance of companion diagnostic devices requiring a performance evaluation study to be conducted. The definition of a performance study includes both analytical and clinical performance studies. Requirements for planning, executing and reporting on the studies is dependant only on the nature of the study design (observational/interventional/etc.) and whether surgically invasive sample-taking is done only for the purpose of the performance study. For all performance studies involving companion diagnostics, excluding those that use exclusively left-over samples, sponsors must meet the additional requirements for performance studies detailed in Article 58, Articles 59–77 and Annex XIV. These studies are subject to authorisation by the member state competent authority and approval by an ethical committee in accordance with national law. In addition, clinical performance studies carried out in accordance with the applicable sections of Annex XIII must be conducted unless it is duly justified to rely on other sources of clinical performance data. For companion diagnostic devices already cleared through the PMA process or by Japan’s PMDA and where the clinical performance data has been gathered in a central testing laboratory that does not represent the normal conditions of use, questions remain over the validity of this data under the IVDR.

4. Health Institution Exemption

Figure 4: IVDR Requirements for In-house Tests Developed & Used Within a Health Institution

As shown in Figure 4, requirements for Health Institutions are now included in the IVDR, requiring manufacturers of in-house assays (that meet the definition of the Health Institution in the exemption) to, inter alia, provide justification for use of their tests and a declaration of compliance to the General Safety and Performance Requirements. Any changes to the manufacturers’ specification by a Health Institution will make them the manufacturer of the modified device and subject to the requirements in Article 5(5). In addition, laboratories

are required to compile a product dossier for class D devices and to have this available for review by member state competent authorities. Competent Authorities are free to apply this requirement to laboratories who manufacture class A, B and/or C device which will include devices used as companion diagnostics. Figure 5 shows the involvement of the medicines agencies in the approval of companion diagnostics, which represents an additional layer of scrutiny as well as an additional

5. EMA/Medicines Competent Authority Review

Figure 5: Requirement for Medicines Authority Review 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Spring 2019 Volume 11 Issue 1

Drug Discovery, Development & Delivery

• challenge to the sponsors of the new drug and companion diagnostic. In addition to the lack of any clear picture on how the alignment of the multiple stakeholders might occur, there are concerns as to the capacity and technical capability of the agencies to adequately review the information provided. The lack of any performance criteria related to the device efficacy relevant to the treated patient outcome in Annex I of the IVDR present a further challenge and does the need to demonstrate clinical benefit address this. Conclusion Is your diagnostic partner ready? While many areas remain unclear, there are activities that CDx sponsors/ manufacturers should already have started and be progressing throughout the transition period. Many drug development programmes run to and beyond the date of application, meaning that by the time the drug is being submitted, the companion should also have all of the data requirements under the IVDR in place for review and approval. Some of the questions you should now ask of your CDx development partner(s) include; • Have they reviewed and confirmed, based on the intended use, that the device meets the definition of a Companion Diagnostic under the IVDR? • Do they already have a Notified Body identified for CE marking and has this Notified Body confirmed their intent to or their completion of an application for designation

under the IVDR that includes Companion Diagnostics? Have they conducted an assessment of the gaps in their clinical evidence for the device? Have they discussed this with their Notified Body and considered a plan as to how those gaps might be filled? Have they confirmed the need for a clinical performance study to generate the clinical performance element of clinical evidence and discussed this with their Notified Body? Are they able to leverage any clinical performance data already gathered through studies conducted for other market approvals? Do they have the necessary processes and systems in place to manage a clinical performance study that assures valid, robust, verifiable clinical data and protects the health, safety and welfare of patients? Do they have adequate liability protections in place for defective devices both in commercial distribution and in interventional clinical performance studies? Do they have the necessary resource capacity and expertise in place to meet the requirements of the new regulation? It is clear that the introduction of the IVDR represents a challenging shift in the regulation of Companion Diagnostics in the EU. It should be advised however, that for many CDx devices already cleared in, for example, the US or Japan, much of the clinical evidence will already exist from studies undertaken for these submissions and might be leveraged to meet the clinical evidence required for CE marking under the Regulation. The clinical use of the CDx device and feedback from clinicians regarding patient reported results and outcome data is another important source of real-life clinical evidence that can be leveraged towards CE marking for existing marketed CDx devices.

REFERENCES 1. &uri=CELEX:32017R0746

Seamus Kearney Seamus Kearney BEng MSc; CEO ARC Regulatory has been working in the medical device industry for almost 20 years. After graduating from The Queen’s University of Belfast with a BEng Honours Degree and a Master Degree, also in Engineering, he started his career as a design engineer for the US-based medical device company. He has held various roles of increasing seniority in device development from Project Management, Design Quality and Risk Management to Regulatory and Clinical affairs. Seamus founded ARC Regulatory in 2010 and has focused on the in vitro diagnostic sector working with many leading names in the global IVD and CDx industry and their partner companies to bring targeted therapeutics to the US, EU and global markets.

Maud Smyth Maud Smyth PhD has over 20 years of experience in the global IVD industry. Maud graduated with an honours degree in Biological Sciences from the University of Ulster and was later awarded a D.Phil in 1995 from the same institution for her research in scanning force and correlative microscopy in the study of epithelial cells. Maud’s early career was spent as an R&D scientist in immunoassay development, later moving in to a global regulatory role gaining global regulatory market access for a broad range of IVDs. Maud has spent the last 5 years working in the area of companion diagnostics development, aligning with various stakeholders and US FDA through the Q-Sub programme, developing and submitting PMA’s as well as Regulatory Authority approvals in other markets.


Drug Discovery, Development & Delivery

How Modular Content Delivers Personalised Life Sciences Engagement The rise of digital impacts the life sciences industry in multiple ways. When it comes to content, it is fundamentally changing the relationship between the sector and its stakeholders, enabling companies to drive greater engagement by delivering personalised content on their channels of choice. At the same time, audiences want more – healthcare professionals, key opinion leaders and patients expect life sciences companies to provide content that is varied, personalised, and locally relevant, at a much faster speed than in the analogue age.

The issue for life sciences companies is that successfully delivering digital content requires a fundamental change in approach. Traditionally, they’ve adopted a centralised strategy, in which entire assets (such as an advert, article, or presentation) are created, translated as necessary, approved centrally, and then distributed to every country. This ensures conformity, brand consistency, and universality. However, this traditional process can be slow, expensive, and disconnected from individual market needs, which makes it ill-suited for today’s requirements. The combination of rising expectations and exponentially increasing volume of content means that a universal approach is no longer fast enough or able to provide the personalisation that is required. Whether it is an article, video, or tweet, or a presentation given to a healthcare professional by a sales rep, content must be timely, tailored, and delivered through the recipient’s channel of choice to drive greater and more productive engagement. How can life sciences companies achieve this, while still ensuring compliance and control? Implementing an agile modular content approach for content and breaking it into smaller components that can then be approved and assembled into larger pieces can make the process simpler and more efficient. This brings down the time needed to create new content and makes it much easier to personalise it to healthcare professionals’ 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

(HCPs’) preferred channels and local requirements, which results in more effective and productive engagement. Creating a Compliant, Effective Digital Content Supply Chain To operate effectively, life sciences companies must ensure that their digital content strategies deliver on three vital requirements: streamlining the end-to-end process, increasing efficiency, and enabling compliance, all while making personalisation and localisation simple and straightforward. The key is to start small and build from there. By breaking down content into small components – such as an image or product claim – and making these available through a single, cloud-based digital asset management system, life sciences companies can balance compliance, localisation, and speed while meeting the needs of their audiences. Companies can “templatise” their core channel layouts, pre-approve content components, and make both available globally through one system. Essentially, this approach means local brand managers have access to a library of pre-approved content. To create tailored campaigns, they simply pick specific content and bring it together in the right form to meet their market needs. All stored content is therefore consistent with brand values and approved at corporate level, requiring minimal local review to ensure compliance. The end result is that more convincing, tailored content is delivered to local markets more rapidly, reducing resources, time, and cost while driving greater engagement. The need for compliance doesn’t end when content is published. Life sciences companies often have to withdraw previously approved content after it has been released. This is both difficult and time-consuming for those relying on traditional processes, as they have to manually track down and remove every piece of content, with the risk that some mentions may be missed. Adopting a single, worldwide digital asset management system

makes it simpler to meet compliance requirements. Particular items of information can be withdrawn, quickly and simply, across every property and channel. Thanks to the modular content approach, life sciences companies don’t need to withdraw whole pieces – just replace individual components as required. Adopting the modular content approach transforms life sciences content strategies in three key ways – streamlining the process, increasing efficiency, and enabling compliance. 1. Streamlining the End-to-End Process With traditional methods, creating and sharing digital content is complex, cumbersome, and resource- and time-intensive. Content is created and assembled manually into different formats, such as an advert, an article, or presentation. This process involves multiple internal and agency authors, with medical, legal, and review teams then checking to ensure that every claim can be satisfactorily substantiated. If everyone involved is using a range of disconnected, independent systems it makes it difficult or even impossible to create a seamless, end-to-end process. This leads to duplication of effort and time, overly complex approval processes, and growth of regional silos of information as local teams store content on their own systems. To deliver content effectively, life sciences companies need to cut through this complexity by switching to worldwide digital asset management systems. Adopting a single, cloud-based solution that contains all components and content pieces in one location that is accessible to all streamlines the process and removes duplication and complexity. Teams can simply download approved content whenever they require it, safe in the knowledge that it is compliant and meets brand guidelines. Life sciences companies have specific compliance and audit Spring 2019 Volume 11 Issue 1

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Drug Discovery, Development & Delivery requirements, which means the off-theshelf content management systems that are used by other sectors cannot match these needs. Instead, they should look to adopt purpose-built systems with compliant cores built around understanding of the industry, while still providing functionality and flexibility. 2. Increasing Efficiency and Reducing Costs The complexity within traditional processes increases the time and resources required to create content. While this was a problem in the analog age, it becomes a much more serious issue in today’s digital era, when speed to market is crucial and the volume of content is continually increasing. Life sciences companies need to be able to do more with less and create more compelling content, more efficiently. Traditional content creation and distribution approaches are inefficient and resource-heavy. They are also cumbersome when it comes to removing non-compliant content. Implementing a unified, end-to-end modular content approach drives much greater efficiency. By replacing a mix of systems and processes with a single digital asset management solution, a life sciences company reduces complexity, saving cost and time. New content can be bulk published, updated, or withdrawn if required, wherever it appears. As marketers have a library of approved content to work with, they can rework minor details (such as resizing an image or changing the format of a leaflet from portrait to landscape) themselves. This approach reduces costs, increases efficiency, and removes bureaucracy. Essentially, teams can focus their time on creating and sharing engaging content, rather than administration. 3. Enabling Compliance While Delivering True Localisation The majority of life sciences companies operate globally but face a balancing act between ensuring compliance and brand consistency and meeting the local needs of individual countries and regions. This focus on compliance means that under the traditional process, a small number of content pieces are created, translated as necessary, and approved before being 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

provided to each country. Life sciences companies can then be certain that all their content is compliant, and full audit trails are available to show where content has been distributed. However, this approach limits effectiveness. Audiences in every country have different needs and expectations when it comes to content. They want to interact with life sciences companies in a range of ways, and can be looking for very different information from their peers around the world. Consequently, creating a single article centrally and pushing it out globally in a one format is unlikely to deliver an optimal result in each country. Translation is an obvious change, but localisation needs to go much further if it is to be personalised and relevant, while remaining compliant and consistent with overall product messaging. Beyond Efficiency – The Deeper Benefits of Modular Content Moving to a unified modular content approach saves time and money, underpinning greater efficiency and enabling localisation while still ensuring compliance. However, the benefits go much deeper, enabling life sciences companies to take a data-driven approach to content and how it is received by audiences. By storing content in one place, life sciences companies can track its usage and gain much deeper insight into its efficacy. They can see which assets are being used most frequently, which channels are most effective, and even which component assets within specific assets are resonating most with different audiences. Fundamentally, they can now drill down and measure the impact of content on engagement, gauging its effectiveness. For example, teams can easily see which content is being used by reps in the field or whether a piece of content actually changes a doctor’s prescribing behaviour. They can understand which content types work best in specific markets and channels – and how approaches need to be adjusted to meet changing needs. They can even measure the ROI of specific pieces of content, as all the usage data is in one system, accessible to all. Shire has halved the 1500 agencies it used globally by implementing a unified digital asset management

solution. The company has also reduced local content approval time by 60%. All content, from press releases to multimedia assets, is now available through a single, global system, which gives local managers a “one-stop shop” for content that they can download and combine quickly and easily. This reduces cost and bureaucracy while improving quality. Adopting a single, cloud-based digital asset management solution also provides the opportunity to break down the traditional silos between marketing, sales and medical, ensuring that they work together more closely. With all content in one place, everyone can collaborate more easily, whether around a major launch or an ongoing campaign. The rise of digital provides life sciences companies with the chance to radically change how they engage with their audiences through content. They can deliver a more personalised, localised approach, through the right channel for each individual or group. Digital also brings challenges – the increasing volume of content required across multiple formats threatens to overwhelm traditional, centralised strategies, and requires a new approach that balances control with flexibility. Adopting a modular content approach with a single digital asset management system for creation, distribution, and localisation of digital content overcomes these challenges, enabling life sciences companies to balance control with flexibility, while meeting local needs and delivering a faster, more efficient end-to-end content process.

Emma Hyland Emma leads Veeva’s market strategy and key customer and partner collaborations, advancing life sciences in content strategy and digital transformation. She has worked in life sciences for 15 years, including roles at Zinc Ahead Ltd, Ketchum, and Affiniti. She holds a Bachelor of Science in Biochemistry and Biomedical Physics from the University of Nottingham.

Spring 2019 Volume 11 Issue 1

Patient-focused drug delivery devices Drug Delivery Devices Innovative developments Customized solutions GMP customer IP manufacturing Phone: +33 (0)4 74 94 06 54


Drug Discovery, Development & Delivery

Driving Patient Engagement with Serialisation Data and mHealth Global serialisation regulations have digitised information-sharing models throughout the pharmaceutical industry. As the US Drug Supply Chain Security Act (DSCSA) and Falsified Medicines Directive (FMD) compliance deadlines pass, the industry is presented with the opportunity to move from compliance-driven needs to improving the efficiency of healthcare systems globally.

Businesses throughout the pharmaceutical supply chain can now develop collaborative solutions that will fundamentally change the way the industry shares information. Moreover, digitised information-sharing will revolutionise the way the collective life science industry, healthcare providers (HCPs) and patients engage with each other. The potential to provide product information directly to patients has opened a door of opportunity for new approaches to engagement and adherence. Here, Rick Seibert, senior vice president of innovation and technology services at Sharp, Jean-Marie Aulnette, vice president of Europe, the Middle East and Africa (EMEA) sales at TraceLink, and Nagore Fernandez, Head of Clinical Services for Europe at Ashfield discuss how mobile health (mHealth) and serialisation data can be used to revolutionise patient engagement and adherence. From Compliance to Leveraging Outcomes With a foundation of compliance, we are able to unequivocally identify a product as it moves through the supply chain. The opportunity for improving care arises when we connect this information to the patient – for example, linking medicines to individual patients can prevent prescription errors in hospitals. The NHS is currently trialling such a system – ‘Scan4Safety’ – six sites are implementing GS1 standards and using barcodes (either on wristbands, 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

name tags or products) to identify every person, product and place. This gives administrators the ability to digitally verify who administered what to whom, where and when. Moreover, the approach involves scanning the barcodes of each patient and products used on a patient at the point of care, giving healthcare providers product information such as expiry data and batch/lot number. This enables hospitals and healthcare systems to digitise healthcare and hence become more efficient – the Scan4Safety trial sites have already saved millions of pounds. In the longer term, the entire eco-system of stakeholders involved in providing care will – potentially – be in a position to analyse outcomes based on patient treatment patterns and deduce the best course of therapy for a patient of a given profile. Serialisation and mHealth In conjunction with the adoption of serialisation and the digitisation of the supply chain, patients have been moving away from traditional face-toface interactions towards mobile or mHealth management. Mobile technology and health apps are increasingly used by patients to engage with and manage their own wellbeing. Patients can take their own blood pressure, body temperature, blood oxygen levels and glucose levels and record this data. There are even smartphone-controlled patches that provide electrical neuromuscular stimulation to manage pain. The appetite for more tailored and patient-led health management is clear. A recent survey of adult social media users with health conditions conducted by PatientsLikeMe1 shows that 94% would be willing to share health data to help doctors improve care and 84% would be willing to share information with drug companies to help them make safer products.

The challenge now, for all stakeholders, is to collaborate and create an environment where information is freely exchanged between patients, caregivers and pharma companies to improve everything from care to research and supply development. The tools and applications currently being developed are leveraging the technical infrastructure and connectivity established in response to serialisation regulations. With all medicines in the marketplace now serialised, they can be leveraged to offer connectivity between pharmacists, doctors, and other HCPs and ultimately, to the patients. Better Patient Outcomes – Improving Adherence Applications that leverage serialised data will enable patients to securely opt in to receiving real-time information from participating pharmaceutical manufacturers, hospitals, pharmacies and regulatory bodies. More direct access to information from manufacturers leads to a greater feeling of involvement among patients and ensuring that they are properly educated about medicine use cases leads to better informed regimens and improved adherence rates. Even simple engagement tools can lead to better adherence. A study conducted by the National Community Pharmacists Association (NCPA) and the Arkansas Pharmacists Association (APA) shows that the use of appointment-based medication synchronisation (ABMS) made patients 2.57 times more likely to stay adherent to their medications.2 ABMS involves scheduling an encounter between a pharmacist and a patient (or caregiver) where a review is performed in addition to coordinating medications to be refilled. During the review, medications are assessed for safety and effectiveness and any patient queries or concerns can be resolved. The potential then of an applicationbased approach to improve adherence Spring 2019 Volume 11 Issue 1

Drug Discovery, Development & Delivery

Rick Seibert Rick has over 20 years’ experience and is Sharp’s senior vice president of project management and technology services. He joined Sharp in 2004 after holding senior roles at B. Braun Medical. Rick has a Bachelor of Arts in Applied Sciences, a Bachelor of Science in Industrial Engineering, a Master of Science in Manufacturing System Engineering, a Master of Business Administration in Management, a post-Master of Business Administration Graduate Certificate in Pharmaceutical Marketing and a Graduate Certificate in Pharmaceutical Manufacturing Practices.

when comprehensive information on a medication is available immediately is incredible. At the point of medicine consumption, patients can learn about product quality, including any pending recalls or expiry notices, or report adverse reactions. The increased level of support and reassurance this provides will likely increase patient adherence in a wide range of scenarios. If we imagine the anxiety around administering an injectable medication to an infant in a home environment – a caregiver could scan the drug’s data matrix and be assured that it is safe to administer. Information on whether the vial has had any cold-chain excursions or even needs to be recalled could be offered instantly. Manufacturers can also securely share more sophisticated educational materials with patients. Product descriptions, administration instructions, photos, videos and medicine disposition details (information on absorption, distribution, metabolism, and excretion – {ADME}) could easily be made available. Conclusion The pharma industry’s investment in serialisation compliance has laid a foundation of connectivity and 31 INTERNATIONAL PHARMACEUTICAL INDUSTRY

information-sharing. Stakeholders are now looking for opportunities to capture additional business value through digital tools and solutions. At the same time, patients are wanting to better engage with their care and the entire eco-system of stakeholders involved in providing that care. They increasingly want to do so digitally and are more receptive than ever to sharing and receiving information that will not only improve their own care, but that of others as well. Without serialisation data, mHealth may have reached an unsatisfactory zenith, but by creating digital information-sharing networks and enabling patients to access some of this and contribute their own data – every stakeholder, from manufacturer to patient, will benefit greatly. Ultimately, it should be the shared mission of the entire healthcare space to empower patients to use products more effectively and enjoy optimal health outcomes. REFERENCES 1.

2. press-release/patientslikeme-surveyshows-vast-majority-people-healthconditions-are-willing-share-t

Jean-Marie Aulnette With over 20 years’ experience in international sales, Jean-Marie is responsible for building and leading the company’s EMEA business. He also has extensive experience in enterprise SaaS applications. His main focus at TraceLink is to deliver track and trace solutions across EMEA pharmaceutical markets to ensure visibility, traceability, and compliance throughout the supply chain. Jean Marie joined TraceLink in 2014 and has previous experience of developing enterprise solutions to help improve business processes.

Nagore Fernandez With over 15 years’ experience in the pharmaceutical and health industry, Nagore Fernandez is responsible for building and executing the strategy for the Patient Solutions division in Ashfield for Europe and Canada. Nagore completed her Masters degree in Pharmacy at the University ofthe Basque Country and her clinical post-graduate diploma in De Montfort University in the United Kingdom. She holds a Ma degree in Clinical Research by Cardiff University.

Spring 2019 Volume 11 Issue 1

Clinical and Medical Research

Comparing Genetic Modification Techniques for Animal Model Generation The first germline transmission-capable transgenic mice were developed in the early 1980s in the laboratories of Frank Ruddle (Yale), Ralph Brinster (University of Pennsylvania), and Richard Palmiter (University of Washington). Since these pioneering experiments, multiple techniques have been developed to generate genetically engineered mice and rats. Each has advantages and drawbacks, making each one more or less appropriate for particular types of model generation projects and study objectives. The following review will highlight the basics of each genome modification method as well as outline some of the pros and cons of each.

In a groundbreaking set of experiments some 45 years ago, Rudolph Jaenisch and Beatrice Mintz microinjected DNA from the SV40 retrovirus into mouse blastocyststage embryos and confirmed that a substantial amount of viral DNA persisted in forty per cent of the resulting adult mice. These animals represented the first geneticallymodified mammals in history.1 However, their applicability was limited due to the fact that the transgenic mice did not transmit the foreign DNA to their offspring. In 1981, Frank Ruddle, Ralph Brinster and Richard Palmiter (among others) published on the viral infection of mouse embryos and the resulting successful germline transmission to subsequent generations.2,3 Since then, a number of genetic modification techniques have been developed and used successfully in rodent models. Random and targeted transgenesis are commonly used today to study the effects of incorporating exogenous DNA for the purposes of expressing proteins not normally present in mice and rats, while RNA interference (RNAi) has been used to silence specific genes without deletion from the genome. The "gold standard" technique for incorporating long, complex sequences utilises homologous recombination in embryonic stem cells. Newer technologies, like CRISPR/Cas9 and Easi-CRISPR, induce genetic 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

modifications with much faster timelines than traditional methods. Random and Targeted Transgenesis While the term "transgenic mouse" is generally used as catch-all for any genetically-modified mouse, there are two specific techniques commonly used to incorporate foreign DNA into the mouse genome that fall into this category. Random transgenesis refers to the introduction of exogenous DNA into a random location in the genome, while targeted transgenesis is the introduction of DNA into a specific, known genomic locus. Random transgenesis is achieved by the pronuclear injection of a DNA fragment into zygotes. Zygotes – egg cells that have been fertilised by sperm – are collected at the single-cell stage and the DNA fragment is microinjected into each one. The zygote at this stage contains two pronuclei – one from each donor cell – and the transgene is microinjected into the pronucleus. Once the injection is complete, the zygote is implanted into pseudopregnant foster females. Depending on the success of the DNA incorporation, usually 10–20% of the offspring will contain the transgene.4 Random transgenesis has been especially useful when studying the effects of over-expressing a specific gene, for example, the ERBB2 gene in overly-aggressive forms of breast cancer.5 Complex neurological diseases that may result from copy number variations, such as autism and schizophrenia, could potentially be studied utilising the over-expression of transgenes in mice.6,7 However, introduction of the DNA fragment into a random site in the genome could cause unwanted mutations. Additionally, this random insertion could cause the genes flanking the insertion site to be silenced unpredictably and the transgene itself could be silenced due to the insertion site or over time by methylation. Targeted transgenesis offers multiple benefits over random transgenesis – the most significant being the integration of the transgene into a defined genomic location, usually a genomic safe harbour

locus. A safe harbour locus is a specific site identified in the genome that is able to accommodate the integration of DNA sequences without inducing potentiallyharmful alterations of the genome and is permissive for transgene expression. The ROSA26 locus is a well-established safe harbour locus utilised frequently in genetic engineering. Advantages of this technique include the certainty that the inserted gene will be present at one, predicted location in the genome. In addition, the chances of mutation and silencing by methylation are much less than when using random integration transgenesis. RNA Interference RNA interference is the general term which refers to a natural process of degrading messenger RNAs (mRNAs) through complementary RNA-RNA binding events. In order to utilise this endogenous system for research purposes, a DNA construct is designed encoding the desired short hairpin RNA (shRNA) or microRNA (miRNA) sequence. Often, expression is controlled using an inducible promoter such as those from the tet system. The transgene is then introduced into the genome using either a random integration or targeted transgenic approach. Once incorporated, an antibiotic such as doxycycline can be added to the animal's water supply to control the expression of the RNAs. Once this binding event occurs, the target mRNAs are subject to degradation. Withdrawal of the antibiotic results in inability to transcribe the shRNA/miRNA and thus antibiotic-inducible systems allow for this method of genetic engineering to be inducible and reversible. These properties could be useful in mimicking a drug's effects on a specific gene, and in evaluating a potential dosage regimen in order to silence the gene. Because the gene of interest is not itself being modified, this technique is used for knockdowns (suppressing activity of a gene) instead of knockouts (removing the gene). This is therefore the preferred method for analysing the effects of downregulating a gene Spring 2019 Volume 11 Issue 1

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Clinical and Medical Research without permanently deleting it. One disadvantage of this method is the possibility of off-target effects, as well as incomplete knockdowns of the gene, due to the sequence and quality of miRNA/shRNA.8 Homologous Recombination in Embryonic Stem Cells Homologous recombination is a natural cellular process that occurs to repair double-stranded breaks in DNA and during meiosis. Capecchi, Evans and Smithies – recipients of the 2007 Nobel Prize in Physiology or Medicine – first hijacked this naturallyoccurring process to introduce foreign DNA into a mouse in the 1980s.9–11 To incorporate foreign DNA, embryonic stem cells (ESCs) are isolated from the inner cell mass of a blastocyst and exogenous DNA is transfected into them.12 Post-transfection, the ESCs that have successfully incorporated the foreign DNA undergo positive selection through the addition of an antibiotic to the culture medium. There is a chance that some of the surviving cells incorporated the DNA, but at a random locus, in which case, negative selection via an antiviral can kill off the cells that still contain the viral gene from the original targeting vector. In order to confirm that the ESCs incorporated the gene at the correct locus, multiple molecular validation tecniques must be used. Polymerase chain reaction (PCR) is first used to screen the ESCs and detect which cells contain the inserted gene.13 A second technique called Southern blotting is then used to confirm that the inserted gene is intact and properly located in the genome. Throughout these experiments, the ESCs must be maintained in in vitro culture. Sometimes, after multiple cell divisions, chromosomal abnormalities may arise. The ESCs should therefore be karyotyped to determine if their chromosomes remained intact over the course of the validation experiments. This entire process can take up to two months in order to carry out the necessary QC for proper validation. The ESCs that pass all validation tests are injected into donor blastocysts which are transferred into the uterus of pseudopregnant foster mothers. Offspring produced from this process are known as chimeras, meaning that 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the resultant mouse contains a mix of ESC-derived and host blastocystderived cells.14,15 Traditionally, the contribution of the modified ESCs to the tissues of the animal is evaluated by assessing the coat colour of these chimeras as a surrogate or indirect measure. For example, if ESCs derived from a strain with a black coat colour are injected in blastocysts derived from a strain with a white coat colour, the resulting animals will have different levels of black versus white fur depending on the contribution of the modified ESCs to the dermal tissue. Coat colour can then be assessed to estimate the chimera’s germline transmission (GLT) potential16 under the assumption that the percentage of ESC contribution to the coat will predict the percentage of ESC contribution to the germ cells.15 The chimeras with the highest GLT potential are then selected for breeding with wild type mice to generate offspring that are heterozygous for the target modification. The disadvantages of utilising HR for generating modified animals are few and well-documented. This method is well-established, has low potential for off-target mutations, and allows researchers to introduce very complex modifications; something that is not possible with alternate techniques. However, this process is inherently a lengthy time commitment. Typical vector generation can take two months, subsequent ESC targeting and validation another two months, and thus once chimeras are born and able to generate the next generation, 10 months have already passed. The cohort present at this time contains heterozygotes that must be intercrossed to generate

homozygous animals, which produces a colony that needs to be expanded prior to delivery to the customer. This overall process typically takes anywhere from 16–18 months. CRISPR/Cas9 The programmable CRISPR/Cas9 system has garnered immense press and interest since its discovery. Recently, He Jiankui, a Chinese biophysicist, claimed to have used the CRISPR/ Cas9 system to genetically engineer two human babies.17 While the debate about genetically engineering humans will continue for quite some time, CRISPR is commonly and frequently used in the genetic modification of animal models for research purposes. Due to CRISPR's speed and efficiency, this method is an attractive technique to generate an animal model of interest. To understand why CRISPR is better suited for certain genome modifications than others, one needs to understand the basics of the CRISPR/Cas9 system. This system was originally discovered in bacteria and archaea, which utilise endogenous versions of these RNAs and proteins to defend themselves against foreign viral DNA.18 CRISPR (clustered regularly interspaced short palindromic repeats) refers to a family of DNA sequences found within the genomes of these prokaryotic organisms. The Cas9 molecule refers to a CRISPR-associated protein 9, which is a nuclease that cleaves both DNA and RNA. Endogenous CRISPR sequences are remnants of viral DNA that have previously infected the prokaryotic organism and attempted integration into the genome. These sequences are referenced by the Cas9 nuclease, which attempts to destroy future foreign viral

Spring 2019 Volume 11 Issue 1


Clinical and Medical Research DNA based on sequence similarity with the CRISPR sequences. Much like the utilisation of RNAi for gene editing, researchers have been able to customise the CRISPR/Cas9 system for use in laboratory animals in vivo. In order to target the correct genomic location, CRISPR RNAs (crRNAs) and trans-activating RNAs (tracrRNAs) are designed and complexed with the Cas9 protein. In some cases, a single-guide RNA (sgRNA) is used instead of the combination of two RNAs to achieve the same end goal. The resulting sgRNA-Cas9 or crRNA-tracrRNA-Cas9 complexes are then microinjected into zygotes. Among the resulting offspring are founder animals which carry the target gene modification. Possibly the most significant advantage of this technology is the ability to bypass the labour-intensive processes of complex gene targeting vector design and generation, and ESC manipulation described previously. This reduction in steps decreases the time and cost of model generation greatly. When compared to HR in ESCs, utilising the CRISPR toolset for model generation projects usually results in a concept to colony timeline of 12 months, at least four to six months less than traditional projects. Additionally, CRISPR/Cas9 is not limited to rodents of a specific strain or genetic background because ESCs are not needed. While many researchers are eager to use this technology, it is unfortunately currently not suited for all genomic modification. Perhaps the "worst issue" with the CRISPR/Cas9 system is the potential for off-target mutations in the genome. Additionally, while generation of gene knockouts is fairly straightforward, reliable and predictable gene knock-ins are restricted to certain lengths. Longer, more complex sequences can be inserted using the CRISPR/Cas9 system, but with low efficiency and high error rate. Easi-CRISPR As described previously, the CRISPR/ Cas9 system does not perform well when attempting to insert large, complex DNA sequences or replace existing genomic sequences. However, the advent of Easi-CRISPR (efficient additions with ssDNA inserts-CRISPR) in 2017 addressed this issue by utilising 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

long ssDNA donors for genomic insertion and deletion. These donor sequences can range from about 500 nt – 2 kb and have been shown to deliver targeted insertion with higher efficiency.19 An advantage of Easi-CRISPR is the fact that the long ssDNA donor sequences do not randomly integrate into the genome, as has been seen with short dsDNA sequences. While Easi-CRISPR is an improvement to the base CRISPR technology, ensuring that the long ssDNA sequence is of high quality and fidelity is a must. Obviously, insertion of mutant DNA sequences would be undesired and the presence of contaminating dsDNA can be an issue. When generating a rodent model for a study, it is essential that one carefully and thoughtfully considers which genome modification technology to employ, weighing the objectives of the study and the advantages and disadvantages of each available technology. It is helpful to work closely with a provider that is experienced in custom model generation and has a wide range of genome modification capabilities, to ensure that the resulting model is well suited to supporting the goals and objectives of the study.





12. 13.

14. 15.









Jaenisch, R. & Mintz, B. Simian Virus 40 DNA Sequences in DNA of Healthy Adult Mice Derived from Preimplantation Blastocysts Injected with Viral DNA. 71, 1250–1254 (1974). Brinster, R. L. et al. Somatic expression of herpes thymidine kinase in mice following injection of a fusion gene into eggs. Cell 27, 223–231 (1981). J. Gordon, F. R. Integration and Stable Germ Line Transmission of Genes Injected into Mouse Pronuclei. Science. 214, 1244–1246 (1981). Cho, A., Haruyama, N. & Kulkarni, A. B. Generation of transgenic mice. Curr. Protoc. Cell Biol. (2009). doi:10.1002/0471143030 Vernimmen, D., Gueders, M., Pisvin, S., Delvenne, P. & Winkler, R. Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers. Br. J. Cancer 89, 899–906 (2003). Conrad, D. F. et al. Origins and functional impact of copy number variation in the human genome The WTCCC collaborated on array design. Validation experiments were performed by Europe PMC Funders Group. Nature 464, 704–712 (2010). Zhang, F., Gu, W., Hurles, M. E. & Lupski, J. R. Copy Number Variation in Human

17. 18.


Health, Disease, and Evolution. Annu. Rev. 10, 451–481 (2009). Kathrin Schmitt. Overcoming Drawbacks of Gene Silencing with RNAi. Genetic Engineering and Biotechnology News (2012). Thomas, K. R., Folger, K. R. & Capecchi, M. R. High frequency targeting of genes to specific sites in the mammalian genome. Cell 44, 419–428 (1986). Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981). Smithies, O., Gregg, R. G., Boggs, S. S., Koralewski, M. A. & Kucherlapati, R. S. Insertion of DNA sequences into the human chromosomal β-globin locus by homologous recombination. Nature 317, 230–234 (1985). Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–7 (1998). Lay, J. M., Friis-Hansen, L., Gillespie, P. J. & Samuelson, L. C. Rapid confirmation of gene targeting in embryonic stem cells using two long-range PCR techniques. Transgenic Res. 7, 135–140 (1998). Koller, B. H. & Smithies, O. Altering Genes in Animals by Gene Targeting. Annu. Rev. Immunol. 10, 705–730 (1992). Bradley, A., Evans, M., Kaufman, M. H. & Robertson, E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature 309, 255–6 (1984). Schuster-Gossler, K. et al. Use of Coisogenic Host Blastocysts for Efficient Establishment of Germline Chimeras with C57BL/6J ES Cell Lines. Biotechniques 31, 1022–1026 (2001). Gina Kolata, P. B. Why Are Scientists So Upset About the First Crispr Babies? The New York Times (2018). Barrangou, R. et al. CRISPR provides acquired resistance against viruses in prokaryotes. Science (80-. ). 315, 1709–1712 (2007). Quadros, R. M. et al. Easi-CRISPR: A robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins. Genome Biol. 18, 1–15 (2017).

Caroline Horizny Caroline Horizny, PhD, is a Scientific Technical Writer at Taconic Biosciences. Her background consists of experience in RNA biology, nanotechnology, and scientific content creation. Email:

Spring 2019 Volume 11 Issue 1

Our Commitment, The Industry Leading Experience

PCI offers flexible and globally compliant development, clinical and commercial scale manufacturing of multiple dosage forms including; tablets, capsules, liquid and semi-solid preparations. Our strength lies in the integrated nature of our services, combining formulation and analytical development with clinical trial supplies through to large-scale commercial manufacturing. Our award-winning center of excellence for the development and manufacturing of highly potent molecules utilizes state-of-the-art contained engineering solutions advancing products from the earliest stages of development through to commercial launch delivering speed to market for our customers.

We invite you to learn more about what our commitment can do for the success of your product.

Š Copyright 2018 Packaging Coordinators, Inc. All Rights Reserved. AndersonBrecon (UK) Limited trading as Packaging Coordinators, Inc. is a company registered in England and Wales with company number 02543975 and VAT registration number GB 549 7026 19 whose registered office is at The Broadgate Tower, Third Floor, 20 Primrose Street, London, EC2A 2RS. Penn Pharma, a PCI company, is a Trading Name of Penn Pharmaceuticals Services Limited, Registered in England and Wales No.1331447 Registered Office: Tredegar, Gwent NP22 3AA UK. VAT Reg. No.762 3299 16. Biotec Services International is part of Biotec Worldwide Supplies Group of companies, Registered in Wales No. 3483803. VAT Registration No. GB 108216149.

Clinical and Medical Research

Highly Potent Molecules: Safe, Effective Processing

The pharmaceutical landscape continues to evolve, with much R&D focusing on more specialised medicines. As the biological activity and specificity of the API increases, dosage strengths decrease – resulting in increased potency of the APIs in terms of occupational handling for drug product manufacture. The marketplace is seeing continued investment in R&D with a visible shift towards speciality/ potent medicines, and oncology a particularly intense area of focus for the global pharmaceutical sector.

Leaders in the development and manufacturing of potent molecules with specialist containment technology provide expertise in the safe and successful management of highly potent active pharmaceutical ingredients (HPAPIs). Here PCI shares its contract development and manufacturing (CDMO) experience.

toxicity profile (Figure 3). Even though a commercial product would be deemed as non-potent (OEL >10 µg/m3), the molecule may have to be treated as potent during early development phases due to limited data at the time of the clinical phase. Data quality and availability are critical to ensure the most accurate API assessment. Figure 1. The Therapeutic Window and Dose Response

Use of occupational exposure limits (OELs) or hazard bands may provide a scientific means of identifying hazards and risks to ensure implementation of exposure mitigation. However even with these, it is evident that no real harmonisation of the bands themselves exists (Figure 2) as systems often differ between companies.

Regulatory demand for effective, lower-dose treatments – combined with growing incidents of cancer, diabetes, and cardiovascular diseases – has seen many pharmaceutical companies focus R&D investments on HPAPI-based products. This focus, alongside ever-present needs to reduce costs, has increased the demand for specialist HPAPI processing services.

What is a Potent Molecule? Although there is no standard classification for HPAPIs, potent molecules can be defined as powerfully active materials requiring very small concentrations to have a biological effect. All substances are potential poisons, since no chemical is completely safe; it is the dosage that distinguishes a poison from a remedy, and even ‘toxic’ chemicals are deemed ‘safe’ if concentration is low enough. General potency definitions: • A pharmacologically active ingredient or intermediate with biological activity at approximately 15 micrograms (µg) per kilogram of body weight or below in humans, or a therapeutic daily dose of one milligram (mg) or below per day • An active pharmaceutical ingredient or intermediate with high selectivity and/or the potential to cause cancer, mutations, developmental effects or reproductive toxicity at low doses • A novel compound of unknown potency and toxicity. 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2. Lack of Harmonisation of Occupational Hazard Banding

A common definition is to classify a molecule as potent if it demonstrates an OEL <10 µg/m3. Such APIs therefore require special considerations during processing activities. As APIs move through the drug development programme from discovery to commercialisation, further toxicology information becomes available and builds a comprehensive

The number of CDMOs claiming to offer HPAPI processing capabilities has increased in recent years, but not all will have invested in state-of-theart contained technology or have the highly specialist experience needed to complete such projects efficiently. Even fewer have the ability to support initial development through to long-term commercial supply. Spring 2019 Volume 11 Issue 1

Clinical and Medical Research peer-reviewed and version-controlled as the API moves through the clinical development phase, which forms part of a project’s continuous review.

Figure 3. Toxicology Knowledge and Understanding Throughout Product Development Lifecycle

HPAPI safe-handling presents a major challenge to the pharmaceutical industry, with high capital costs associated with the specialised containment technology required to protect both employees and the environment. Exposure protection can be categorised in three main ways: engineering controls (including facility design, engineering controls and utilities); administrative controls (including risk assessments, health surveillance, training and policies and procedures); and personal protective equipment (PPE – including items such as overalls, gloves, safety shoes, glasses and air respirators). Assessment and Management of HPAPIs Many pharmaceutical companies and CDMOs claim to offer potentprocessing capabilities; however, many are reliant on PPE and may not have invested in containment technology, which is now considered industry best practice. In addition to lack of containment equipment, some organisations may not possess the highly specialised experience or expertise to manage such projects. Even fewer may have the ability to support the entire development-tocommercial-launch cycle. Any CDMO working within drug product development should be aware of the level of toxicology of an API, the data available, and the ways to perform the required risk assessment to ensure suitable protection for its workforce. The company should place an emphasis on a strong on-boarding process to ensure the suitable handling of the API for its determined classification.

CDMO Project On-boarding An example of one on-boarding process would be to use the philosophy of lean manufacturing which examines safety, quality, delivery and cost. The use of such a gating system prior to entering into any formal agreement with a CDMO ensures a review of the molecule and of the information that senior representatives from each discipline supply, to determine the best approach for the project As part of any on-boarding process, a technical discussion should take place between the client and the CDMO based on an initial questionnaire. It should examine key information, such as the safety data sheet (SDS/MSDS) and toxicology package, dosage form and strength, manufacturing scale, and the method of manufacture if known. In the absence of the OEL being supplied, qualified personnel at the CDMO or a third-party industrial hygiene supplier should perform an assessment of the molecule. Only after this assessment should the client and CDMO enter into an agreement to continue with a potential project. The toxicological and pharmacological assessment of all molecules is required to protect both scientist/ operators and to provide a suitable cleaning assessment to eliminate the risk of cross-contamination to the next product. When a project is awarded, a detailed evaluation of the API should be undertaken by the project team. Within this, the on-boarding data gathered should be catalogued,

When handling potent materials, the key consideration is new product introduction. PCI has developed its concept of the ‘Potent Passport’ and a similar clear and concise summary document is recommended, detailing all new molecules for their occupational exposure limit (OEL) and their permitted daily exposure (PDE). The Potent Passport strongly defines the molecule, its mode of action and the appropriate handling requirements, maintaining operator and environmental safety at all times. A Good Manufacturing Practice (GMP) assessment should be generated using supporting data from the safety, regulatory licensing, equipment train and facilities to ensure the product can be safely processed. Only after all reviews and assessments are complete will a molecule be issued for movement around the facility. Staff Evaluation and Training Of critical importance is the training and medical surveillance of the different project disciplines working with the products. Training should focus on aspects such as potent compound definition, toxicology awareness, industrial hygiene, OEL/ banding systems and engineering solutions. The set training modules should be assessed through examination, and only personnel who pass the examination should have access to the high potent laboratories/ manufacturing facilities. Any personnel working with HPAPIs should also be subject to annual health assessments. Initial health assessment provides a baseline of specific health assessments from lung capacity to eyesight and the annual check will assess for any significant and detrimental changes. Depending on the pharmaceutical therapeutic area of the API class, adverse effects may not be immediate, but health might deteriorate over a number of years. INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Clinical and Medical Research Containment Strategy For CDMOs to satisfactorily work with APIs with OELs <10 Âľg/m 3, best practice dictates that facilities should not rely on PPE alone, given that the main risks of API exposure would be respiratory. Guidance advises that manufacturing activities be performed within a specifically designed facility utilising contained/ enclosed processing equipment. One example of a best practice user requirement specification (URS) for manufacturing within a multi-API facility is shown in Figure 4.

considerations for laboratory-scale, pilot-scale and commercial-scale use. An example containment strategy is illustrated in Figure 5. The recommended primary level of containment is the engineering controls of equipment which are in contact with the HPAPI. Engineering controls can include negative pressure isolators/ equipment, split-butterfly valves, flexible containment bags, pneumatic and vacuum transfer for material movement from one process to another, and local exhaust ventilation.

Figure 4. Best Practice Contained Facility URS

The URS includes primary protection of fully contained processing equipment, combined with a facility design operating a negative pressure cascade into processing rooms, clear personnel and material segregation, and respiratory PPE in the event of a powder breach. The design aspects for a suitably safe and compliant containment facility and the associated equipment are extensive and demanding. The solution is dependent on the potency and batch size being handled; there might also be a need for different

Figure 5. Example of Containment Level Strategy 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

A pressure decay test prior processing is recommended for equipment operating under negative pressure, ensuring that the equipment is in a safe state of containment operation. In the event of a glove ripping, the systems should allow time for changing in a calm and methodical manner as the outlet fan should ramp up to maintain the pressures required. If the fans fail, the seals within the system will allow time for the operator/scientist to calmly remove themselves from the area and raise the alarm. The second level of the containment strategy (Figure 5) is the HVAC system within the facility. Although it is not a regulatory requirement, it is recommended that the HVAC system(s) are single pass air. This is where 100 per cent fresh air is coarsely filtered through F6 and F9 filters, conditioning air to set facility conditions (temperature and humidity) through the process rooms and then exiting the building via terminal H14 filters. The rooms within a solid oral facility should be ISO Class 8 cleanrooms which

provide negative pressure rooms from the corridor ambient pressure, with usually 5â&#x20AC;&#x201C;20 air changes per hour. In addition to the room pressure differentials, airlocks should be implemented at the highest risk areas. This air flow provides the second level of containment but is also a principal mitigation for cross-contamination within a multi-API facility. The third level of containment is facility segregation, which can be broken down to movement of people and materials, restricted access of personnel within the facility, segregation of mechanical/electrical from the equipment and dedicated/ segregated utilities. People and material segregation dictates a clear passage of movement via material/personnel airlocks in and out of the facility. Restricted access is required to ensure that only suitably trained personnel are allowed to enter the HPAPI processing areas and the plant space. Within the specialised designed containment equipment, the majority of the mechanics should be sealed or isolated from the processing area, electrical cabinets and other non-processing elements to be located into technical space or plant room. It is best practice for utilities such as boilers, purified water systems, and effluent treatment plants to be segregated from the facilities as risk mitigation. There is also the need to possess the technical expertise, the management and costs associated with waste water treatment and waste handling. The fourth and final level of containment is the PPE utilised when working with HPAPI within a specifically designed facility. Under the previous three levels of containment strategy, employees should be provided with general GMP PPE such as laboratory coats/suits and footwear, hairnets, eyewear, face masks and gloves â&#x20AC;&#x201C; while breathing apparatus should be considered as part of a breach control and system failure programme. But PPE should never be considered as part of the primary protection barrier during potency assessment or normal operations. Spring 2019 Volume 11 Issue 1

Clinical and Medical Research

The containment strategy must be suitable for the OEL or OEL banding range, with consideration not just of the equipment but of the utilities within the facility and procedures in place in the event of a breach situation. In order for operators and scientists to fully engage with working within specialist equipment, the controls should be consistent with the OELs that the CDMO is working on, or there is potential that the measures will be bypassed. Operating with Contained Equipment Operator and scientist safety is of critical importance, and to successfully perform the solid oral manufacturing process requires a new way of thinking to develop drug products in a controlled facility. Gone are the days of the formulator ‘dark-art’ of touching and feeling of material, with heavy reliance on the data within contained equipment. The recommendation is to utilise PLC-controlled equipment to control processing and gather output data to assess if a formulation or process is providing success against a pre-determined specification. Quality by Design (QbD) and Containment A quality by design (QbD) based strategy is required to ensure process reliability and reproducible product quality. It is necessary to have scientifically designed products and processes and the control of critical process parameters (CPP) with respect to the critical quality attributes (CQA) and quality target product profile (QTPP). To remove manual intervention, automatic controlled adjustment of manufacturing processing parameters is necessary using PLC-controlled equipment with data trending. Statistical experimental design assessment tools can

reduce development time and costs associated with drug losses and unnecessary manufacturing. A quality by design (QbD) based strategy therefore represents the future. Cleaning Philosophy With each new molecule entering a facility, a robust cleaning approach must be developed. The approach must focus on toxicology-based cleaning limits, where a PDE/ADE should be calculated to provide a maximum carry-over of the product into the next batch. A procedure should document methods of testing (swab limits) for detection of detergents and drug substances. The consideration of swab and/or rinse samples and any additional cleaning that is required should be assessed. Equipment capabilities should be constantly reviewed, with oversight of all cleaning verification and validation, resulting in a scientific- and risk-based approach to cross-contamination prevention. Summary As the market continues to evolve with increasing numbers of highly potent molecules in development, it is important to understand the requirements for the safe processing of such molecules, the differing regulatory requirements across the world, and – above all – the safety of employees and the environment. Many pharmaceutical developers with products containing HPAPIs recognise that they have limited in-house capacity or experience and choose to outsource production to a contract development and manufacturing organisation (CDMO), with established capabilities in the handling of such materials in compliance with all the applicable regulations. Cost constraints preventing the implementation of in-house solutions may be another reason for outsourcing, as is the mitigation of risk.

Choosing a CDMO to take on an HPAPI project is a complex process, requiring detailed and careful consideration. Assessing a CDMO’s capabilities in the handling of drug substances, track record in terms of knowledge and regulatory expertise, compliance history, and capacity to provide long-term support for clinical and commercial supply, is central to the success of any outsourcing decision.

David O’Connell David O’Connell is the Director of Scientific Affairs at PCI Pharma Services, an integrated full service provider expertly delivering a seamless transition from development to commercialisation. After graduating from Glasgow Caledonian University in Scotland with a Bachelor of Science degree in applied bioscience, David spent seven years as a Supervisory Scientist working for Aptuit in Edinburgh, Scotland, before moving to Penn Pharma as Head of Formulation Development in 2009. Here he played a vital part in the design of the potent Contained Manufacturing Facility (CMF), which won the ISPE Facility of the Year award for Facility Integration (2014). In 2013, David took on the role of Director, Pharmaceutical Development and in 2017 assumed his current position as Director of Scientific Affairs at the PCI site in Tredegar, Wales, United Kingdom. In his current role, David provides oversight and support to clients in the areas of Formulation Development, Technical Transfer and Scale-up of solid oral, oral liquid and semi-solid products for clinical trials and/or commercialisation, specifically those classified as being potent.



Cell Disruption Equipment Selection – Making the Optimal Choice Technically and Financially Introduction BPE was tasked with identifying the best available technology for a client’s new cell disruption system. There are several methods for achieving cell disruption, however high-pressure homogenisation (HPH) / microfluidisation is the standard approach for the scale of this client’s microbiological cell harvest application. This technique is therefore the focus of this report. The performance of HPH/microfluidisation cell disruption equipment is dependent primarily on the system’s operating pressure and therefore machines from four separate suppliers were analysed, each with a different operating pressure.

There was a significant cost difference between the machine purchase price and its associated operating pressure; refer to Table 1.1 below. The cost difference between the lowest and highest priced machines was approximately GBP 500,000 at the scale of operation.

issues such as limited space for locating the equipment. A preliminary equipment configuration scheme has been included in this report. HPH/Microfluidiser Operational Theory Generally, microorganisms are protected by extremely tough cell walls. In order to release their cellular contents, a number of methods for cell disruption have been developed. Any potential method must ensure that liable materials are not denatured by the process (heat liable) nor hydrolysed by enzymes present in the cell. Although many techniques are available which are satisfactory at the laboratory scale, only a limited number have been proven to be suitable for larger industrial-scale applications. Liquid shear HPH/microfluidisation is widely used and this technique is dominant at medium to large scale. High-Pressure Homogenisation The homogeniser consists of a positivedisplacement pump (providing a constant flowrate) and a ‘homogenising

valve’. The ‘homogenising valve, consists of the valve; seat and impact ring; refer to Figure 2.1 below for details. Smaller models have a single valve system while the larger machines have several valve components. The valve is pushed towards the seat by the action of the hydraulic valve actuator which reduces the flow area between the valve and seat. Since the flowrate is constant, the pressure increases as the flow area is reduced. The cell slurry under pressure from the discharge manifold of the pump impinges against the homogenising valve and then passes through the narrow channel between the valve and the impact ring. The velocity increases and the pressure decreases rapidly (Bernoulli Theorem). This intense energy transformation produces the effect called homogenisation that disrupts the cell wall, releasing the cell’s content. The size of the pressure drop is critical in achieving effective disruption. There may be a need to cool the cell slurry to reduce the loss in product activity due to the heat generation during the process. H P H s u p p l i e rs e m p h a s i s e the differences in their specific valve designs, configurations and materials of construction as offering performance advantages.

Table 1.1 Equipment Purchase Price Range

Amongst other issues, the type of cell culture morphology affects the cell disruption efficiency. High pressure operation is normally reserved for specific yeast strains only (Pichia). A simple analysis was made for a planned future Pichia cell line to assess the financial benefits from purchasing a machine that operates at higher operating pressure with increased cell disruption efficiencies, and whether the additional capital investment was justified. For this specific client application, there were additional engineering 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Fig 2.1 Homogeniser Valve Detail Spring 2019 Volume 11 Issue 1

Technology Microfluidisation The microfluidiser consists of two positive displacement pumps and a fixed geometry interaction chamber that performs the same function as the HPH homogenising valve; refer to Figure 2.2 below for details. The geometrical design ensures that the entire product stream will encounter equal energy per unit volume. The design provides for high operating pressures (up to 40,000 psi) and minimal residence time. This gives higher cell disruption efficiencies and vendor claims of a higher level of reproducibility between cell slurry batches.

considerable heat with potential for inactivation of heat-liable biological products, 6. The activity of cell released proteases which react with the product and suppress yield, and, 7. The nature of the product producing cell (E.coli, yeast etc.) morphology, specifically the cell wall characteristics. Items (4), (5) and (6) are all associated with the retention time within the cell disruptor unit, which is a feature that distinguishes high-pressure homogenisation (HPH) and microfluidisation techniques.

cell disruptor and re-pass through the unit (multiple passes). This technique is not infinite as each pass reduces product yield and increases cell debris due to an increase in overall cell retention times within the disruptor. There is normally an optimum homogenate pass number which provides a balance between high cell lysis efficiencies (item 4) and product yield (item 2). This optimum number will vary with different cell and product types; refer to Table 3.1 below for details. Also, HPH/microfluidisation units in this type of application are not usually operated in a continuous mode and daily run times are limited. This may assist in preventing overheating and damage, specifically to machine seals. Due to the variations in the structure of microorganism cell walls (item 7), there are large differences in the lysis efficiencies of different product producing cultures. In general, E.coli and yeast (Cerevisiae) give high single pass cell lysis values at relatively low operating pressures

Figure 2.2 Microfluidiser Detail

Cell Disruption Overview The objectives of cell disruption are to: 1. Maximise the number of cells that are lysed to release their contents, 2. Minimise the loss of activity (yield loss) for the released liable product; and, 3. Minimise the micronisation of other released non-product material and cell debris to reduce the impact on downstream purification operations. In simple terms, the operation of the cell disruptor is a balance between high cell lysis (item 1) on one side and product yield loss/ debris micronisation (items 2 and 3) on the other.

Table 3.1 Comparison Multi-pass Performance for a HPH *

The impact of the elevated temperature (item 5) can be mitigated to a certain extent by providing cooling to the cell disruptor, this was recommended for the clientâ&#x20AC;&#x2122;s specific application. One method to increase the cell lysis efficiency (item 1) is to collect the first pass homogenate from the

(< 20,000 psi). Traditionally, yeast (Pichia) cells require higher pressures (up to 30,000 psi) for comparable single pass lysis values; refer to Table 3.2 below. It is noted in the literature (reference 1) that the ultimate operating pressures required for Pichia cell disruption are influenced by the specific growth

The loss of product activity (yield) is due to the following factors: 4. Excess mechanical shear on the cells, 5. Elevated temperature due to homogenisation/ microfluidisation generating

Table 3.2 Cell Lysis Efficiencies for Different Cell Types * INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Technology the final decision should be informed on the basis of bench/pilot scale testing using the specific cell culture solution. However, for this client’s feasibility assessment a theoretical approach to machine performance (from literature review) was adopted and all output variables from that selection were tested in a simple economic assessment /payback model against current products and future product forecast sales.

Table 3.3 Performance Comparison

media used during the cell culture feeding stage. The cell wall thickness for Pichia is approximately double the thickness for cells fed on glucose/ methanol when compared with a glycerol-only feed solution. Reference 1 also suggests that the effect of the initial cell concentration is a factor in the optimisation of the performance of HPH units. The research concludes that a lower cell concentration and fluid viscosity can increase overall performance. Ultimately, if cells continue to restrict cell disruption at low to medium pressures, there is an option to pre-treat cells using permeabilisation enzymes. This will weaken the cell walls and achieve high lysis efficiencies at lower HPH operating pressures. To summarise: for difficult Pichia cell disruption, the following techniques are available to enhance HPH performance at lower operating pressures: • • •

Multi-pass through the HPH unit (with cooling). Increasing the cell resuspension dilution and lowering viscosities. Pre-treatment of cells using permeabilisation enzymes.


HPH versus Microfluidiser Comparison Microfluidisers operate in a similar manner to HPH but use fixed microchannels to effect cell lysis. In doing this, the suppliers claim a shorter residence time and lower operating temperatures. Both have a positive impact on items 5 and 6, with a consequential increase in cell lysis performance; refer to Table 3.3 below. Industrial microfluidisers generally operate at higher pressures than HPH units with a consequential increase in cell lysis efficiencies. Cell Disruption Summary From the information presented, the selection of a suitable cell disruptor is a complex process and may possibly involve some subjective decision-making. It is essential that

Economic Assessment Preliminary budget pricing is presented in Table 5.1 below with the theoretical performance yield factors applied for Pichia. The budget pricing is shown for both steamable and nonsteamable disruptor systems. The pricing excludes any additional investment in agitated jacketed feed and collection bag mobile holders. Two HPH systems are shown: one with a limit up to 22,000 psig; and a second system with an operating pressure up to 30,000 psi. The standard operating pressure for the microfluidiser is 30,000 psig at reduced flowrate of 360 L/h. Basis for Economic Assessment for Yeast (Pichia) products This has been based on using a medium pressure HPH#2 (not steamable) machine from a leading UK supplier and assuming a single pass with a theoretical yield of 55%. This is the Pichia cell culture base case. The payback period for the higher cost not steamable cell disruptors, with an allowance for their higher theoretical cell disruption efficiencies, is compared against the base case; refer to Table 5.2 below:

Product Forecast Table For current and future forecast products refer to Table 4.1 below:

Table 4.1 Production Forecast & Values Spring 2019 Volume 11 Issue 1


Table 5.1 Machine Budget Price Comparison

To justify the additional capital cost, the simple return on investment (ROI) payback target advised by the client should be less than 18 months.

Table 5.2 Investment Economic Evaluation

Pichia Cell Product Cost of Goods (COGs) Assumptions: Assume 1,000,000 doses at 2ml per dose. Assume a 50/50 cell concentrate dilution with an overall downstream efficiency of 50%. This equates to a fermentation volume = 2,000 litres or 2,000 / 400 = 5 x 400 litres batches per year. £2 per dose sales = £2,000,000 of sales. Assume 50% cost of goods = £1,000,000.


Technology The proposed flow scheme was to discharge the client’s existing disc stack centrifuge into a singleuse mixing (SUM) bag located in a chilled jacket holder and then pass to second SUM collection bag via the homogeniser. This configuration allowed for multi-pass operation and the mobility of the equipment gave flexibility to the operation which needed to take place in a limited space. Summary The conclusion from the simple financial analysis was that the additional investment in high-pressure HPH #3 or high-pressure microfluidisation did not meet the client’s target for return on capital investment and was therefore not justified. The recommendation was to proceed with a medium-pressure HPH #2 machine that would meet the client’s current and forecast product technical and commercial requirements. The savings in capital investment were significant. REFERENCES 1. Overall key performance indicator to optimizing operation of high pressure homogenizers for a reliable quantification of intracellular components in Pichia pastoris – Xavier Garcia Ortega. 2. Cell disruption: Breaking the mould: An overview of Yeast and Bacteria High Pressure Cell Disruption - Bruce Campbell. 3. Cell rupture of recombinant Escherichia coli using high pressure homogenizer – R. Amad-Raus.

Gary McRobbie Gary McRobbie is a consultant for process engineering firm BPE, one of the UK’s leaders in chemical and biochemical engineering. Gary has 30 years’ experience in the process industries, focusing particularly on the front end design of biopharmaceutical processes.


Spring 2019 Volume 11 Issue 1

Consistency. Proven

Increase viable Sf9 cell density and Baculovirus-based VLP production by supplementation with recombinant Insulin Human AF Sf9 insect cells are the most widely used platforms during the manufacturing process of recombinant protein therapeutics when a fast and flexible system is needed. The baculoviral-insect cell system has shown to be a powerful alternative for the production of recombinant proteins in short time frames. As for the CHO cell-based manufacturing process, increased demand for safety and reliability has moved the standard for Insect cell culture media from Serum to Serum free and further on to chemically defined media. UAB in collaboration with Novo Nordisk Pharmatech (worldâ&#x20AC;&#x2122;s largest supplier of recombinant insulin) has shown a significant increase in viable cell density and baculovirus-dependent VLP production with the addition of animal origin free Insulin into commercially available chemically defined media.

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15 40



5 24 h 0


24 48 72 96 120 144 168 192 216 240 Time (h)


Cell density NI

Cell density 1 mgL

Viability NI

Viability 1 mg/L

ExpiSF CD is trademarks of Thermo Fisher Scientific.

VLP concentration (1010 VLP/mL)

VLP concentration in ExpiSF CD media 100

Viability (%)

Viable cell density (106 cell/mL)

ExpiSf9 Cell Growth in ExpiSF CD media 30

6 1.2 fold 4



NI 1 r-insulin concentration (mg/L)



Why Exceptional Devices are Not the (Only) Answer for Inhaled Medicine Delivery to the lungs promises immense benefits to patients and pharmaceutical companies alike. However, until now, the industry has been unable to realise the full potential and here is why:

While historically, inhaled drugs have been used for the treatment of asthma, COPD and other respiratory diseases, inhalation medicines have experienced a recent increase in consideration as an alternative drug administration route for systemic applications such as insulin therapies for diabetes, due to their promise of faster pharmacological onset and reduced adverse effects. However, drug delivery to the lungs poses fundamental challenges towards pharmaceutical companies that require them to rethink and at times reinvent their development processes. Inhalation medicines only unfold their true therapeutic potential when formulation, the inhalation device and individual patient requirements are harmonised. Leaving the question of the extent to which we tailor our devices to their respective patient group, whether the patient knows how to effectively use the device and whether we have chosen the right formulation or technology to support consistent and accurate dosing.

In order to enable drug delivery to the lungs, there are four fundamental development pathways to choose from based on the underlying principles of the used device: (I) (II) (III) (IV)

Pressurised metered-dose inhalers (pMDI) Dry powder inhalers (DPI) Nebulisers Soft mist inhalers

In development, nebulisers are often discarded due to their size. Each of the options has its own advantages, disadvantages and idiosyncratic developmental challenges. All three options have been around for decades – even centuries. Over the past years, we can observe that DPIs assert themselves as the most promising, technological solution for improved or new inhalation therapies. A development also fostered by ecological concerns and restrictions for propellants that have been traditionally used in MDIs. In the specific case of soft mist inhalers, it remains to be seen whether the technology can prevail and provide substantial, long-term therapeutic success. Deciding the fundamental developmental pathway isn’t the only decision

Figure 1: Benefits of Inhalation Delivery1 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

a pharmaceutical company has to take quite early within the process. It must also take a make-or-buy decision, to develop a proprietary device that perfectly fits the intended formulation respectively providing to adapt the formulation to the device based on their superior functional understanding or source technology from third-party suppliers. It is a careful evaluation of available budget, time resources and manufacturing capabilities as well as economic and legal aspects of potentially prolonged protection. While there is not a golden recipe for success, the number of inhalation devices available to patients suggests that companies rather tend to the development of devices, or at least their own platform technologies, than to rely on more standardised options. A tendency that leaves out the most crucial factor for successful therapies: the patient. The Bottleneck: The Patient Up until now, most innovations in inhalation medicine and devices have been driven by technologists, aiming to improve the efficacy and develop the physical, functional attributes of their devices. While this can be a crucial aspect and builds the foundation for a theoretically successful therapy, the practical success lies – quite literally – in the hand of the patient. In stark contrast to ‘traditional’ orally administered drugs where the limiting factor is the intake by the patient (given a working formulation), inhalers are critically error-prone. Chrystyn et al. have found that 92% of patients handling pressurised metered-dose inhalers and 54% of those using dry powder inhalers perform at least one critical handling error2. Ultimately, whether patients forget, intentionally do not dose themselves or incorrectly adhere to their medication schedule, renders the best drug ineffective and can diminish the biggest blockbuster. Unintentional non-adherence, however, can be reduced by decreasing Spring 2019 Volume 11 Issue 1

Technology complexity as well as increasing familiarity and usability; something that can be understandably perceived as a threat in an industry that has successfully profited from the creation of scientific and economic barriers to maintain their individual status quo and binding (sometimes limiting) patients to a specific solution. The success of some of the biggest companies we know are much rather based around those three qualities and not as much on technological leadership, Apple being the most given example. Apple released neither the first mp3 player nor the first smartphone. Instead, where they excel is providing handling that is so intuitive, children can navigate through digital menus before they learn to speak and this has led to the sustainable success of their iPod and iPhone product ranges. As the pharmaceutical industry has heavily relied on linear, sequential innovation processes, it isn’t surprising the latest surge in developments and innovation originates in non-pharmaceutical companies not bound by this mindset. Patient-centricity and Rationalisation Applying human-centred design principles and nurturing patientcentricity within the development process of inhalation device and inhalation medicines would suggest and promote rationalisation and standardisation while acknowledging the invaluable input medical professionals, patient advocacy groups and business units outside R&D could provide to realise better solutions. This also means pharmaceutical companies must work towards a fundamental understanding of manufacturing, formulation and potential adaptions or improvements to those processes to transfer the device-performance paradigm towards a more deviceindependent foundation. Modelling and Simulation A more device-independent foundation could be realised with the help of computational modelling and simulation, which are new tools that have quite recently entered the stage for studying the performance of inhalers. So far, high-fidelity simulations have only now reached a level where tangible information can be gained. The studies of the Research

Center Pharmaceutical Engineering (RCPE) are focused on dry powder inhalers. For this type of inhalers, for example, modelling the powder release from a pierced, rotating capsule can provide novel insight into the influence of hole geometries on transient powder release. Furthermore, the effect of the capsule motion (rotation and translation, wall collisions) and material properties (e.g., cohesion, friction, and particle size distribution) on the transient powder release from a capsule can be studied.

lung. Particles in that size range have a high surface free energy and tend to stick to each other or to other surfaces. This results in poor flowability and a tendency to be retained in the inhaler device5–7. These small particles are often blended with carrier particles in the range of 50–200 µm to improve adequate flowability and dispersion5–7. Another advantage of carrier-based systems is that the handling of the API during manufacturing becomes easier, which is especially relevant for low-dose formulations8. The attractive

Figure 2: Simulations like these are increasingly used to test performance and critical attributes to ensure efficacy and gain new insights into functional parameters3,4.

Coupling these particle simulations with computational fluid dynamics explains in detail how particles interact with the airflow inside and outside of the rotating capsule. Using different patient respirational profiles as transient simulation boundary conditions, the consequence of patient variability on the emitted dose can be investigated. This approach is expected to bridge the gap between computational device studies and patient inhalation techniques.

force between the active pharmaceutical ingredient (API) and the carrier particles has to be large enough to ensure that the powder can be easily handled, but low enough so the API detaches from the carrier during inhalation6. Therefore, interparticle forces play a very important role in these formulations. Researchers must therefore work towards the control of these interparticle interactions by applying different carrier or API particle engineering technologies.

Besides that, we are also exploring modelling approaches on pharmacokinetics in order to bridge the use of these tools and formulation strategies (described below).

In order to generate small inhalable size particles for inhalation, the most common micronisation technologies based on air jet milling are available. These processes, however, do not always result in optimal particle properties, and they often create disordered surfaces that can cause recrystallisation of the material during shelf storage, which subsequently affects product performance. Consequently, post-micronisation treatment, designed to stabilise the

Formulation Strategies However, from the formulation side, we are still facing the challenge that the drug particles for dry powder inhalation have to be very small (aerodynamic diameters of 1–5 µm)4 in order to be able to reach the deep


Technology material surface and reduce this physical instability, is therefore an important step that must often be considered. Alternatively, besides air jet milling, also alternative processes like spray drying are explored for API engineering and to guarantee a stable formulation already during processing. Besides that, spray drying is available and studied for inhalation carrier engineering. More precisely, via spray drying of common carrier particles like lactose and/or mannitol and varying the process parameters9, and/or the addition of small excipients9, the surface topography of the carrier particles can be tailored. In particular, the surface roughness of the carrier has been shown to critically impact the performance of the formulation. Only rough carriers, where the roughness is smaller than the drug particle size, are advantageous for drug detachment and high lung delivery11, 12.

where a pH-dependent crystallisation of fumaryl diketopiperazine (FDKP) is used to generate nanocrystals, which self-assemble into highly porous microsphere templates or the Promaxx® technology which uses protein dissolution in an aqueous PEG solution at an elevated temperature followed by cooling14, are used for particle engineering. As an alternative, PRINT (Particle Replication In Non-wetting Templates) technology, a mould-based particle engineering platform, has been introduced. Overall, successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler and the patient. From a formulation point of view, the understanding of the complex relationships between particle technology, particle properties, their processability and

different dissolution setups (e.g.: basket, paddle, reciprocating cylinder, flow-through cell, Franz Zell and Transwell systems, etc.) are used. The region and concentration of deposited particles are also largely influenced by the type of device, thereby influencing particle dissolution kinetics. Further understanding and developments of in vitro tools for dissolution testing and drug permeation will be needed to initiate the extension of oral BCS to inhaled product as inhalation BCS (iBCS) (http://www.dissolutiontech. com/DTresour/201508Articles/ DT201508_A07.pdf) applicable in inhaled drug product classification15. Therefore, RCPE is presently working, if some relevant parameters, for example for dissolution testing, can be defined and how standardised protocols could be realised. However, overcoming the current lack of standardisation regarding the dissolution testing will most likely need collaborative efforts of academia, pharmaceutical industry and regulatory bodies. REFERENCES 1.


Figure 3: Spray- dried (left) and jet milled (right) salbutamol sulphate 13

Spray drying can also be used to target other diseases besides asthma and chronic obstructive pulmonary disease (COPD); for example, noninhalative diseases like pain medication. Therefore, RCPE is testing polymers and lipids as excipients for carrier-free inhalation systems. The generation of polymer or lipid excipientdrug particles in the appropriate size (1–5 µm) with adequate flowability should help the circumvention of classic inhalation carrier materials. Consequently, via more sophisticated material and particle engineering, controlled drug release formulations can be generated via the use of either large porous neutral or small, dense negative microparticles. Besides that, new alternative methods like Technosphere® technology, 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

inhalability is crucial for the rational development of stable DPI products that have reproducible and efficient performance. Standardised Tests for Inhalation Products Talking about testing inhalation products for inhalation, there is still a lack of standardised tests for some relevant parameters. For example, in contrast to oral formulations, no established protocols are available for in vitro dissolution of inhaled drugs. Since the importance of dissolution for orally inhaled products was recognised, several studies were dedicated to the development of protocols predictive for dissolution and absorption in vivo. However, so far different simulated lung fluids (SLF) with varying composition and





S. Moore. “What is the future of Inhalation Delivery ” 2016, envigo. https://insights.envigo. com/inhalation-white-paper (last accessed February 2019) H. Chrystyn, D. B. Price, M. Molimard et al. Comparison of serious inhaler technique errors made by devicenaive patients using three different dry powder inhalers: a randomised, crossover, open-label study. BMC Pulm Med. 2016;16:12 B. Benedict and J. G. Khinast. “Understanding the motion of rotating hard shell capsules in dry powder inhalers” Conference Proceeding Drug Delivery to the Lung 2018 Y. Cui, S. Schmalfuß, S. Zellnitz, M. Sommerfeld, and N. Urbanetz, “Towards the optimisation and adaptation of dry powder inhalers.,” Int. J. Pharm., vol. 470, no. 1–2, pp. 120–32, Aug. 2014. Z. B. Tong, R. Y. Yang, and A. B. Yu, “CFD-DEM study of the aerosolisation mechanism of carrierbased formulations with high drug loadings,” Powder Technol., 2016. Z. Tong, H. Kamiya, A. Yu, H. K. Chan, and R. Yang, “Multi-scale modelling of powder dispersion in a carrierbased inhalation system,” Pharm. Res., vol. 32, no. 6, pp. 2086–2096, 2015. Spring 2019 Volume 11 Issue 1

Technology 7. Y. Cui, “Application of the Lattice Boltzmann Method for Analysing the Detachment of Micro-Sized Drug Particles from a Carrier Particle,” Martin-Luther-Universität Halle-Wittenberg, 2016. 8. A. M. Healy, M. I. Amaro, K. J. Paluch, and L. Tajber, “Dry powders for oral inhalation free of lactose carrier particles,” Adv. Drug Deliv. Rev., vol. 75, pp. 32–52, 2014. 9. G. Pilcer, N. Wauthoz, and K. Amighi, “Lactose characteristics and the generation of the aerosol.,” Adv. Drug Deliv. Rev., vol. 64, no. 3, pp. 233–56, Mar. 2012. 10. E. M. Littringer et al., “The morphology and various densities of spray dried mannitol,” Powder Technol., vol. 246, pp. 193–200, Sep. 2013. 11. J. T. Pinto, S. Zellnitz, T. Guidi, E. Roblegg, and A. Paudel, “Assessment of Dry Powder Inhaler Carrier Targeted Design: A Comparative Case Study of Diverse Anomeric Compositions and Physical Properties of Lactose,” Mol. Pharm., vol. 15, no. 7, pp. 2827–2839, Jul. 2018. 12. S. Zellnitz, E. Roblegg, J. Pinto, and E. Fröhlich, “Delivery of dry powders to the lungs : Influence of particle





attributes from a biological and technological point of view,” Curr. Drug Deliv., 2018. (13) S. Zellnitz, H. Schroettner, and N. A. Urbanetz, “Influence of surface characteristics of modified glass beads as model carriers in dry powder inhalers (DPIs) on the aerosolization performance,” Drug Dev. Ind. Pharm., vol. 0, no. 0, pp. 1–8, 2015. E. Faulhammer, S. Zellnitz, T. Wutscher, S. Stranzinger, A. Paudel, "Performance indicators for carrier-based DPIs : Carrier surface properties for capsule fi lling and API properties for in vitro aerosolisation," Int. J.Pharm, vol. 536. no. 1, pp A. H. de Boer, P. Hagedoorn, M. Hoppentocht, F. Buttini, F. Grasmeijer, and H. W. Frijlink, “Dry powder inhalation: past, present and future,” Expert Opin. Drug Deliv., vol. 14, no. 4, pp. 499–512, 2017. S. Radivojev, S. Zellnitz, A. Paudel, and E. Fröhlich, “Searching for physiologically relevant in vitro dissolution techniques for orally inhaled drugs,” Int. J. Pharm., vol. 556, no. December 2018, pp. 45–56, 2018.

Dr Sarah Zellnitz Sarah Zellnitz is a pharmacist by training. During her PhD at the Graz Technical University (AT) she explored glass beads as new model carriers in dry powder inhalers (DPIs) and gained expertise in particle engineering via surface modification and detailed material characterisation. She currently holds the position of Senior Scientist at Area II “Advanced Products and Delivery” at the Research Center Pharmaceutical Engineering (RCPE) in Graz, (AT), where she is leading the Inhalation group and coordinating the different activities in this field. Her research focus is on tailoring DPI formulations via mechanistic understanding of the interplay of material properties, formulation properties, adhesivecohesive force balance and drug detachment.



Breakthrough Capsule Technology for Tailor-made Solutions New pharmaceutical gelatine portfolio offers proven fill release options and long-term stability

Rapidly growing consumer demand for products deemed suitable for vegetarians or vegans means product labels are coming under ever-closer scrutiny. And capsules such as those used in food supplements and over-the-counter medicines are no exception. That’s why, at first sight, hard capsules made from plant-derived cellulose HPMC appear to be an obvious choice for those wishing to avoid animal-derived products, and seeking a more ‘natural’ alternative. Hydroxypropyl methylcellulose (HPMC), also known as hypromellose, is manufactured by chemically-made polymer cellulose, a natural polymer and fibre, which means it is vegan. However, it is important to know HPMC is listed as a food additive – E464. It has an ‘unspecified’ acceptable daily intake. Also, during the manufacturing process, the cellulose is altered synthetically. During production, various highly reactive, harmful or toxic substances are used before then being removed, including propylene oxide (which is considered to be carcinogenic) and chloromethane. So, yes, capsules made from HPMC are suitable for vegetarians and vegans – but are they really all that natural? Natural, Safe and Trusted By contrast, gelatine is a safe and trusted ingredient that has been used for more than 100 years. It is not an additive, and therefore has no e-number, and is GMO-free. Gelatine is a truly natural product, sustainably sourced from pig or bovine skin and bone (by-products from the meat industry) using a gentle hot 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

water extraction technique. Yet even though it is of animal origin, it may be surprising to know that specific varieties of gelatine can be used which meet the strict religious requirements of Hindus and Muslims. There are even Kosher and Halal versions available. Gelatine is highly compatible with other ingredients, is non-allergenic, and comprises proteins that are easily digestible in the gastrointestinal tract, allowing for the release and absorption of active ingredients. Hard capsules made of pure gelatine are available in different sizes and a variety of colours, making them easy to identify and differentiate. The pre-produced two-piece empty shells are opened, filled with a powder or granulate and closed during the production process. For liquid, semi-solid or oil-based fillings, however, soft capsules are the preferred choice. So much so, the soft gelatine capsules market, which was valued at US $1620 million in 2017, is expected to reach US$2010 million by 2023*. Compared with hard capsules, soft gelatine capsules are thicker and require additional ingredients such as glycerin to obtain their soft texture. Depending on the formula, the thickness of the capsule, its elasticity and its degree of residual moisture can be adjusted. Perfectly suited for liquid or semi-solid fillings, gelatine capsules are one of the most popular dosage forms for drugs, over-the-counter products and dietary supplements. In fact, many consumers prefer soft gelatine capsules as they provide a high precision, single-dose format that is easy to swallow. Also, by adjusting the production process of soft capsule gelatine, the specific effect can be modified, along with timing and duration of the fill release to meet specific consumer needs.

Faster-acting for Enhanced Bioavailability However, one of the most important benefits of capsules made from soft gelatine is enhanced nutrient bioavailability. The use of liquid- and paste-fill formulations in soft capsules allows for improved absorption of poorly soluble drugs. This means the contents of the capsules will be faster-acting – typically within five to 25 minutes – offering the opportunity for a reduction in the amount of active ingredients required. When it comes to sensitive ingredients, soft capsules are the preferred choice, as they offer protection from oxygen, light, contamination and microbial growth. Unlike other types of capsule, soft gelatine versions are hermetically sealed and airtight, and so mask unpleasant tastes and odours associated with their contents. That said, consumers have long complained about the unpleasant aftertaste commonly associated with fish oil and fish-derived omega-3 fatty acids. Advanced Enteric Technology An advanced approach allows the production of enteric capsules that dissolve in the small intestine instead of the stomach (as is the case with traditional gelatine capsules). When certain active ingredients are released in the stomach, they float to the top and can cause gastric reflux. That’s one of the reasons why many producers have tried to make their capsules resistant to the harsh environment of the stomach, in order that the contents are not released until the capsule has passed into the intestine. There are two aspects as to why it is very important to control the fill release. First of all, it is necessary to define where in the body the active Spring 2019 Volume 11 Issue 1

Technology ingredient or supplement should be released. Secondly, the speed of release is vital. For a painkiller, for example, it is absolutely vital that it gets into the system as quickly as possible in order to relieve the discomfort. So the requirement here is for a capsule that dissolves immediately when entering the stomach. However, when it comes to other food supplement capsules, the exact opposite needs to be achieved. A fish oil capsule, for example, should not release the fill in the stomach in order to avoid undesired fishy burps. The new enteric technology means the capsule is resistant to gastric juice and thus releases its fill only in the intestine.  Most enteric delivery systems are produced by applying an acid-insoluble coating to soft gelatine capsules. However, this increases the time and costs involved in producing the capsules, and the coating can also create an unattractive opaque shell that is visually unappealing to consumers. It is now possible, however, for manufacturers to produce enteric capsules using existing equipment in a one-step process that also means they remain clear. Tests have shown that capsules made with the first commercially available enteric gelatine product of its kind – comply with US Pharmacopeia dissolution parameters, which means that they do not release their fill in simulated gastric fluid during a period of two hours at 37°C, but are fully dissolved within 45 minutes. Further tests involving 20 enteric fish oil capsules produced with the enteric gelatine produced similarly impressive results – none of the capsules released the fill in simulated gastric acid (representing the stomach) nor did they leak. Cross-linking Solution for Added Value Yet despite the numerous and undeniable advantages of gelatine capsules, certain types of reactive fillings and extreme storage conditions – such as high temperatures and

humidity – may cause the gelatine in the capsule to react and cross-link. This means with time, soft capsules can become increasingly less soluble, which results in slower dissolution times and fill release in the GI tract. However, there is a solution in the form of a reduced cross-linking product, which adds extra value to gelatine capsules. This special grade gelatine significantly reduces the number of cross-linking issues, thus enhancing the dissolution properties of the capsules. Previous attempts by the pharmaceutical industry to reduce cross-linking with additives have been only partially successful. However, a new production process that controls molecular weight distribution has been established, thus minimising dissolution problems in soft capsules. This is achieved by molecules reacting with each other to block self-cross-linking reactions and/ or reactions with other substances within the fill formulation. To guarantee long-term capsule stability for critical fills, the gelatine manufacturer has also developed the next generation of its reduced cross-linking technology. This product provides reduced pellicle formation, which minimises cross-linking potential and supports controlled fill release performance during the entire shelf-life of the capsule. It also promises long-term stability for critical fillings.

Rapid Release with Long-term Stability As previously mentioned, when it comes to products such as pain medication or cough and cold formulas, consumers want instant relief. However, hot or humid storage conditions can delay the medicinal effect because they slow down the release performance of soft gelatine capsules. To address this issue, the gelatine manufacturer took the reduced cross-linking (RXL) concept one step further and introduced rapid release (R²) performance to the market. In a bid to facilitate even faster release of active ingredients, the company worked with the University of Heidelberg to

test the new formulation and analyse the benefits of these soft gelatine capsules. Scientific Proof: RXL R2 In a bid to facilitate even faster release of the active ingredient, especially in hot and humid storage conditions, the University of Heidelberg helped trial the new formulation and analyse the benefits of soft gelatine capsules comprising RXL R2. Capsules were stored for up to 12 months under different ICH storage conditions and, for comparison, both the company’s standard limed bovine bone gelatine and RXL limed bovine bone gelatine with reduced cross-linking performance were assessed. Using ICH protocols, stability testing was done on the capsules in closed glass vials at 22°C/50% relative humidity (r. h.) and 30°C/65% r. h. for 12 months and at 40°C/75% r. h. for six months. Shell dissolution and fill release performance were monitored in simulated gastric acid at 37°C. In addition, the molecular weight distribution of the gelatine in the capsule shell was determined by gel permeation chromatography (GPC). Fresh soft shell capsules produced with RXL R2 gelatine showed the fastest initial fill release rates at pH 1.3. After six minutes, more than 70 per cent of the fill had been released. After 12 months at 22°C/50 per cent RH, this fast initial fill release remained constant. The release rates of standard capsules comprising RXL limed bovine bone gelatine were slightly lower (Figure 1).

The real benefits of the new capsules were clearly demonstrated during the accelerated ICH storage test. No change in the overall fill release profile was recorded at 30°C/65 per cent RH and at 40°C/75 per cent RH (Figures 2 and 3). Under these conditions, soft gelatine capsules made with INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Technology standard limed bone gelatine showed a significantly reduced fill release time within 30 minutes. To be more precise, with RXL R2 capsules, 50 per cent of the fill was released three times faster than standard limed bone gelatine versions. This is down to the molecular weight distribution of the gelatine types, with RXL R2 gelatine containing very low amounts of the high molecular weight fractions of gelatine (>300000 Dalton) compared with the standard and RXL gelatines. *Soft Gelatin Capsules market study drafted by Market Study Report, LLC

Figure 1

The results showed that, even under demanding storage conditions, the gelatine had faster fill release rates for both fresh and aged capsules. This means significant benefits for the development of soft gelatine capsules for which rapid fill release combined with long-term stability is required. The patent-protected formulation therefore provides considerable added value, featuring three times faster fill release compared to standard gelatine capsules.

Figure 2

Figure 3


Tailor-made Solutions Standard, EC, RXL, RXL advanced and RXL R 2 products are pure pharmaceutical-grade gelatines that comply with current regulations. Technical service support not only accelerates product development, but

also reduces the risk that a capsule formulation, once developed, will be found to fail dissolution or storage requirements, or not fulfil consumer expectations. Research specialists are also constantly exploring new and innovative application areas in order to help clients enter new markets all over the world.

Holger Becker Dr Becker studied chemistry at the Technical University of Darmstadt in Germany. In 1999 he started as a scientific assistant at the Ernst-Berl Institute for Technical and Macromolecular Chemistry in Darmstadt and worked on acrylic polymers in cooperation with BASF Ludwigshafen. In 2003 he started his industry career in the R&D department of Naturin Viscofan GmbH. His responsibilities included the development and implementation of new edible casings on the basis of the biopolymer collagen. In 2009 he was appointed to the Bioengineering department, where he focused on the development of collagen-based products.  In 2013 he became a member of the GELITA AG.

Spring 2019 Volume 11 Issue 1



• Breath activated patented DPI’s;

• Flexible for different delivery profiles;

• Designed to deliver metered doses of drug from capsule;

• Safety guiding piercing system;

• Reusable systems: Replacement of the capsule with single doses;

• Available for generic and innovative drugs; • FDA DMF and CE.

Pharma & Cosmetics Patented Devices


Logistics & Supply Chain Management

The Role of Smarter Supply Chains in Reducing Drug Shortages within the Healthcare Industry The role of the supply chain in protecting patients from unsafe medical products is crucial, with the transportation and storage of pharmaceuticals having a significant impact on product integrity, and thus end patient welfare. Yet, with the growth of biopharmaceuticals the significance of getting logistics right becomes even more important. The stricter logistic requirements and significant cost is combined with limited supply, meaning that every batch is vital. We consider how supply chains can work smarter to mitigate the risks that cause product failures and better protect end patients.

Defining drug shortages Drug shortages are recognised as a global issue by the World Health Organisation (WHO) with research indicating that the problem has been increasingly affecting European countries. Although there is yet to be a commonly accepted definition of medicine or drug shortages, most researchers tend to encompass four situations in their description which can be summarised by De Weerdt and Simeons’ outline: • • • •

supply is unable to meet demand supply is interrupted the medicine is not able to be delivered the medicine is unavailable to patients

The intricate and complex nature of the healthcare industry means that, almost by definition, the causes for stock shortages are vast, complex and hard to isolate – with the leading cause often difficult to distinguish. The role of the supply chain in protecting patients from unsafe medical products is critical and, according to WHO, should have no weak link. They further emphasise the importance of transport and storage, which must demonstrate an unbroken series of steps. 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Market Challenges Limited supply The growing complexity of regulatory compliance has made it increasingly challenging for pharmaceutical organisations to bring new drugs to market. This has led to an industry shift to biologics, living organisms that work with the patient and have significantly reduced negative side effects. However, the intricate nature of these and the high associated R&D investments adds further intricacies to an already complex and lengthy process. Limited production capacity and stricter temperature requirements throughout the supply chain means that every batch is vital to patient welfare; with any deviance from these regulations potentially leading to quality release issues. This risks further restricting supply and increasing exposure to additional supply challenges and costs. Limited resource As leading pharmaceutical patents expire, the entry of generics into the marketplace reduces the sales of the original patented unit. This is due to the lower cost base that generics can operate at, with significantly lower R&D investments, and a tried and tested target market. With patents expiring, the need for high R&D is essential to develop the next blockbuster. Thus, with higher costs and reduced revenue, there is growing pressure for organisations to create leaner and smarter operations. This is alongside many government agencies enforcing price ceilings. Rise in risk The rise of e-commerce has transformed the traditional marketplace as we know it. New online businesses can set up with low overheads and, for many industries, have saturated the market with their low-entry pricing. This is together with continuing rises in cargo crime and cyber crime. Online platforms enable the speed at which threats can be escalated and acted upon to be at

its highest in history, with organised criminal groups exploiting technology to aid illicit schemes and further their global reach. This is amongst growing political unrest causing a rise of illegal immigration at country ports. Rise in legislation For the healthcare industry, the risk of new potential online competitors has a far greater implication across the entire supply chain. The development of e-commerce has led to more readily available counterfeit pharmaceuticals in the marketplace, risking patients’ wellbeing and the industry’s integrity. These counterfeits have the potential to damage the reputation of both products and brands – taking years to rebuild, if they could at all. In order to tackle counterfeits, the Falsified Medicines Directive has issued regulations for full end-toend traceability and tamper evident features on packaging, adding yet further complexity to an already highly regulated supply chain. Logistics Challenges Temperature deviations Across the pharmaceutical industry, reports suggest over $15Billion in product losses are due to temperature excursions alone. Furthermore, this figure rockets to a staggering $35B when taking into account the costs associated with replacing those goods and the root cause analysis process. Research shows that 20% of temperature sensitive products are damaged during transport due to a broken cold chain. What’s more, the importance of adhering to strict temperature controls is likely to increase in the coming years with the growth of biologics – which are predicted to reach 50% of the top 100 pharmaceutical product sales by 2022. The high cost and low volume nature of biologics emphasises the importance of reducing unnecessary Spring 2019 Volume 11 Issue 1

Logistics & Supply Chain Management product losses through compliance failure, and the control of storage and transportation temperature is a major factor in maintaining the quality and integrity of these intricate products. Quality failures Safeguarding patients from compromised pharmaceuticals is, first and foremost, the most important role of a healthcare supply chain. To protect patients from unsafe medical products, WHO state that it is critical that no weak links in the supply chain exist. Yet research shows that approximately 30% of scrapped pharmaceutical can be attributed to logistics issues alone. This figure is set to increase as regulatory compliance for healthcare companies continues to advance, both in terms of complexity and intracity, and these regulations vary across countries and regions. This is coupled with pharmaceutical companies adopting just-in-time inventory strategies that are better suited for biologics and products containing active pharmaceutical ingredients. By delivering goods only as they are needed in the supply chain, waste is reduced and efficiency increased. However, further pressure is placed on the supply chain, with any delay in the collection or delivery potentially compromising the quality, and thus integrity, of the product. Cargo theft Drugs account for 15% of the estimated $8 billion to $12 billion in annual cargo theft across the US, according to the global logistics security services company FreightWatch International. The high value of pharmaceuticals means these are one of the most lucrative targets for organised crime, with one report showing an average value of $3.7 million per pharma theft incident. Within Europe, the EU has estimated cargo theft at an estimated €8.2 billion annually. Further research suggests that €33.5 million of these figure is attributed to pharmaceutical thefts. However, the true extent of this figure is difficult to determine, with many cargo thefts unreported and only the product value being reflected.

What’s more, with reports showing that stolen pharmaceuticals often re-enter the legal market, the true extent of the effects of theft in the industry remains largely unknown. Without the strict environmental controls that safeguard the pharmaceutical structures and compositions, the integrity can no longer be guaranteed and this risk is passed on, unknowingly, to the end-patient. Defining smart supply chains Smart supply chains are a response to the changing market demands, following disruption from key new players. In today’s dynamic environment, the processes to fulfil the fundamental requirements for logistics (“having the right product at the right time at the right place and in the right condition”) are getting more and more complex (Uckelmann D., 2008). Instead, research suggests that logistic networks require new methods, products and services, with a focus on flexibility, adaptability and proactivity – the smart supply chain. Transparency in Logistics As the healthcare supply chain continues to grow in complexity, so does the difficulty in controlling and managing a growing number of stakeholders across different regions. Complete transparency across routes, regions and modes is required to maintain efficient stock flows. Transparency creates a leaner operation in terms of realising potential efficiencies and optimisation opportunities, as well as providing an overall picture of the operation. This highlights the importance of one central viewpoint, enabling all stakeholders to access the same information at the same time. Without such, the capability of an operation to flex to demands and address supply issues is limited; instead, transparency allows the operation to work as one entity. Compliance in Logistics The role that logistics plays within the healthcare supply chain is vital to safeguard product integrity, protect patients and prevent unnecessary product losses. It is a role that is likely to become further emphasised as drug shortages increasingly affect European countries, and as

the growth of biologics adds tighter time, temperature and environmental restrictions and compliancy regulations on the supply chain. That’s why being able to adapt to new legislation across the entire supply chain is crucial to prevent pharmaceuticals failing to comply. However, ensuring international compliancy within the supply chain is just one step towards smarter logistics. Across the pharmaceutical industry, it is estimated that 25% of vaccines reach their destination degraded because of incorrect shipping. Minimising compliance failures is essential to prevent unnecessary stock shortages. Visibility in Logistics Key performance indicators (KPI) are vital for smart logistic supply chains, and should be constantly monitored, reviewed and improved. These will highlight any areas of vulnerability and help implement strategies to strengthen and mitigate risks to product integrity. KPI surrounding exceptional quality control, superior security measures and accurate delivery times to mitigate product losses are critical within the healthcare vertical. Yet, all of this is only possible if the data provided is accurate and up to date. Up to date visibility allows proactive management of potential delays and temperature deviations, helping to minimise the risk of product losses. Visibility plays a significant part in maintaining the integrity of a healthcare supply chain. At any stage, a pharmaceutical product could be compromised. That’s why it’s essential for logistics to work smarter, with visibility and a customer focus at the heart. REFERENCES 1.


https://www.researchgate. net/publication/266242636_ Drug_shortages_in_European_ countries_A_trade-off_between_ market_attractiveness_and_cost_ containment?enrichId=rgreqd9f9cc5f1bab25a9e7d301351460942dXXX&enrichSource=Y292ZXJQY WdlOzI2NjI0MjYzNjtBUzoyMDkw NDg5OTg4MTM3MDBAMTQyNjg1M jU3MzM4NQ%3D%3D&el=1_x_3&_ esc=publicationCoverPdf


Logistics & Supply Chain Management

publications/druginformation/WHO_ DI_30-2_Medicines.pdf 3. index.jsp?curl=pages/regulation/ general/general_content_000588. jsp&mid=WC0b01ac05807477a5 4. docs/Commentary%20on%20EIU%20 report%20vEIU-FINAL2.pdf 5. uploads/2013/07/seminar-arminpresentation-eipg-madrid.pdf 6. access-medicines/getting-medicinespatients-role-quality-logistics 7. 8. docs/Commentary%20on%20EIU%20 report%20vEIU-FINAL2.pdf 9. access-medicines/getting-medicinespatients-role-quality-logistics 10. 8/2/3/4/82343370/supply-chain58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

intelligence-iot-whitepaper-2015.pdf 11. 12. Article/2016/02/04/Mafia-behind-mostEU-pharma-cargo-theft-30m-worth-ofdrugs-stolen-each-year-says-expert 13. user_upload/wydawnictwo/JEM_ Artyku%C5%82y_1_30/JEM_27/07.pdf 14. (AD896EFE-ECA0-57AB-43AF22740BB589B0).pdf 15. cgi?article=1030&context=nitlart 16. Improving_supply_chain_performance_ through_improved_visibility.pdf 17. Uckelmann D. (2008) A Definition Approach to Smart Logistics. In: Balandin S., Moltchanov D., Koucheryavy Y. (eds) Next Generation Teletraffic and Wired/ Wireless Advanced Networking. NEW2AN 2008. Lecture Notes in Computer Science, vol 5174. Springer, Berlin, Heidelberg

Ellena Austin Ellena Austin has carved a career in Marketing with a vast range of experience from fashion PR to corporate events and copywriting for a number of verticals including Healthcare, Consumer Electronics and White Goods.  Currently working as Marketing Executive for Yusen Logistics UK, Ellena executes the UK marketing strategy in line with regional and global directives.  Within her company she holds Regional Brand Ambassador and Regional Connected Ambassador roles, representing the EU region.

Spring 2019 Volume 11 Issue 1

Corporate Profile

Temperature Control Equipment from Klinge Corporation, the World’s Leading Manufacturer of Specialized Refrigerated Transport Containers

As a world class innovator in the transport refrigeration industry, Klinge Temperature Control provides superior transport container solutions for a variety of industries, including for chemical, oil and gas, pharmaceutical, food processing, and military customers. Our container refrigeration units are built to the highest standards and made to hold up under tough conditions, making them ideal for military and government use as well as for commercial industries. As cold chain losses continue to plague pharmaceutical companies, reliable transport has become paramount. Approximately 4% of pharmaceuticals do not arrive at their destination in usable condition due to temperature deviations. This costs companies hundreds of thousands of dollars in wasted supplies and quality analyses. For this reason, it is critical for pharmaceutical shipping companies to invest in transport containers that can maintain the exact temperatures required for their contents. The use of high-quality cold transport containers in the pharmaceutical transportation process is essential for ensuring that pharmaceutical companies can overcome the numerous shipping obstacles they face:

Today, pharmaceutical reefer units are available that will control the temperature of pharmaceutical products and allow the shipper to monitor it throughout the journey. These containers are equipped with sensors that can detect small temperature variations. Klinge offers several pharmaceutical transport container options to meet the temperature requirements of pharma products from -65°C up to 20°C, including dual-redundant options with optional integral power packs and remote monitoring. This enables the shipper to maintain a consistent temperature throughout the journey regardless of the atmospheric conditions. We offer a variety of transport refrigeration and freezer containers, including Dual Reefer Systems, ExplosionProof Reefers, Tank Container Reefers, Offshore Reefers, Blast Freezers, Deep Storage Freezers, Quick Thaw Containers, Expandable Containers, DNV Refrigerated Containers, and more. We provide customers customized options for transport refrigeration when standard products fail to get the job done. Please email us at: or call us at + 1 717 840 4500 to learn more.

The most important and obvious benefit of refrigerated pharmaceutical shipping containers is their ability to maintain appropriate temperatures throughout the transportation cycle (or even for static storage steady temperature control at a production facility). A temperature variation of as little as two degrees can be enough to spoil the product, which could result in losses totalling hundreds or thousands of dollars for smaller orders and millions for larger shipments.


Logistics & Supply Chain Management

Blockchain in Life Sciences: Moving From Hype to Adoption Over the last number of years, along with IOT, AI and Big Data, blockchain has emerged as one of the most significant disrupters in the technical industry. The evolution of blockchain began in 2008 around the emergence of the bitcoin cryptocurrency, blockchain being the underlying platform that permits bitcoin transactions to occur. However, given the initial hype and fluctuating value of cryptocurrency and the fact that blockchain was intrinsically linked to cryptocurrencies, it had not been recognised initially as something to be adopted autonomously. Therefore, through lack of adoption, blockchain was still maturing.

In recent years, the rules of the game have changed – notably the desire for a more decentralised way of doing business. Public and consumer confidence in large, centralised organisations has been dwindling due to the centralised nature of how they transact and collect data. Often there is a feeling that data is not secure and is becoming a commodity that big business can buy or sell without permission. Industry experts now proclaim the end of web 2.0 and the emergence of web 3.0. Whilst web 2.0 was and still is the age of social media, mobile applications, blogging and data streaming, all stewarded by the large social media firms, web 3.0 imagines a world of disintermediation where we all manage and own our own data via decentralised applications. Blockchain's association with radical technological and business disruption is related to its decentralised nature. Most individuals and modern organisations conduct business via a central authority or middlemen, meaning that transactions have to pass through various central clearing houses, brokers, contract arbitrators and social media players to complete. All of these central institutions retain control through ownership of third-party data through which they can apply any level of 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

security and levy an undefined level of charges to store and move that data. Blockchain imagines a peer-to-peer landscape where all individuals store a complete copy of the transactions so that if one actor on that peer-topeer network conducts a transaction, all of the actors retain a copy of that transaction. The model that would be most analogous to this would be a peer-to-peer file-sharing network, such as bit torrent.

Underpinning all of this is the idea of consensus and security – a transaction cannot be added to the blockchain without all the actors on the chain concurring to create that transaction. This means that all the actors on the chain own and manage the data. In addition to that, each block on the chain is privately encrypted and immutable, meaning that no bad actors from outside the group can add a transaction to the chain, nor can they tamper with the chain. This translates to a highly secure distributed ledger of data between agreed parties acting as a permanent system of record between them.

Public and private organisations continue to divert investment towards this area, with current estimates being in the projected realm of $300m by the year 2024 in the US alone. Given the significant inflation of hype and hyperbole surrounding the blockchain, due primarily to its initial association with the bitcoin cryptocurrency, there is a temptation to assume blockchain is a solution for all problems. It is important for individuals and organisations to understand the fundamentals of the blockchain, so that solid and logical use cases can be formed that blockchain can actually solve. The blockchain platform has proven to lend itself to other use cases that relate not only to the financial sector, but also within sectors such as law, life sciences, identity management and media. Within life sciences there are myriad opportunities to leverage this technology, from a pre-clinical perspective IP (intellectual property); for example, how to track research ownership and provenance – an immutable shared ledger to track copyright between owners, users and authors would accommodate fair distribution of recognition, both financial and intellectual. Regulatory transparency across the supply chain could be represented by an immutable set of blockchain transactions. There is also the evolving concept of personalised medicine aligned with an individual’s medical record stored

Spring 2019 Volume 11 Issue 1

Logistics & Supply Chain Management on the blockchain. The individual’s medical record could contain genome information, mappings of the human brain, even health insurance data for medical insurance payments. This immutable information all could reduce the need for patient input via IRT on a clinical trial. One of the areas of interest for contract manufacturing and development organisations (CDMOs) is the digital track and trace potential the blockchain introduces. Considering their role, they have to be cognisant of the various regulations that will impact how we do business. In 2013, the Drug Supply Chain Security Act was introduced by the FDA and enacted by Congress. It outlined a proposal to build an interoperable platform that would enable the efficient track and trace of all drugs throughout the United States. The ultimate aim going forward is to prevent customers and patients having exposure to drugs that may be contaminated, stolen or counterfeited. This law demands that all prescription drugs should be tracked and traced through the supply chain by the year 2023. The key statement for technologists within companies is interoperability and how we can be part of building this system that will ultimately become the industry standard for track and trace. Some believe that blockchain is the standing solution for this i nt e ro p e ra b l e p l atfo r m . Th e blockchain itself consists of an immutable list of transactions that are represented using a cryptographic code. This cryptographic code contains not only an encrypted version of the agreed transaction, but also an excerpt of data from the previous block/transaction – this inherently means that every transaction on the blockchain is not only unique but intrinsically linked to the predecessor block. Consider applying this to the prevention of counterfeit drug proliferation. Normally how this is accomplished is by the regeneration and subsequent forgery of existing serial numbers, but if we have an immutable and unique chain of serials per drug, no serial is the same and every serial is traceable. Further to that, those in the industry have requirements for their internal

and external clinical customers to report and track through the clinical supply chain. Such tracking provides customers, partners and regulators study visibility, provenance and reassurance throughout the lifetime of those clinical studies. Often this tracking involves any number of stakeholders from suppliers/ customers who release manufactured inventory, distribution depots and facilities, couriers and drug dispensing locations such as doctor’s surgeries or hospitals. The type of data captured varies in nature and could extend to certificate of origin reports, order number, pick date, packaging specification and invoice number. The key challenge has always been the disparate nature of the data and the ease of accessibility to regulators. Through engagement in blockchain technologies, the industry is exploring this accessibility and transparency surrounding this data on clinical supply chain. In the past, companies have had autonomous and standalone integration points between many of the stakeholders in the clinical supply chain. What if through a private consortium of stakeholders, we could have a shared blockchain that could represent all the data points through that supply chain. A private permissioned blockchain offers this possibility by presenting an invite to participate on the chain and further permission is required to post transactions to the chain. This allows CDMOs and their partners the opportunity to work in partnership with regulators and define the scope of regulatory information required on the chain and, in tandem, reduce the considerable cost overhead on cross-company data correlation and amalgamation. All of this introduces some interesting questions: How much data should we store on the blockchain? What does the agreed dataset look like in different scenarios? Do we have a separate blockchain per clinical study? How do we archive this data and how much do we store ‘off-chain’? Only through a shared intra-organisation vision can these questions be accurately answered. Amidst any early adoption of a technology, market players and their

partners need to always retain data integrity. Throughout these operations we have a historic record of applying strong regulatory processes and tools. We believe that through the immutable nature of the blockchain and the secure nature of transactions that are placed on the blockchain, this could complement our internal and external regulatory processes. Through conversations with our partners in the life sciences industry and indeed continuing to maintain regulatory compliance, the pharmaceutical industry has a vested interest in the future direction of any interoperable platforms that internal/ external stakeholders might adopt. Our IT systems are advanced and positioned well to integrate with any future blockchain proposals that may arise from the use cases described. However, in the world of blockchain, adopting a solid collaboration strategy through your chosen industry can prove to be just as strong a differentiator.

Mark McColgan Mark McColgan is a Software Development Manager currently employed in Almac Group. Both he and his team work primarily with clinical supply chain and clinical manufacturing applications and have a passion for leveraging technology in the life sciences industry. Mark is an eminent advocate of blockchain technology, has spoken on the subject before and believes that given the evolving regulatory landscape in the industry, large scale appropriation of the technology is imminent”



Overcoming the Challenges of Developing Inhaled Medicine Drugs formulated for inhalation or nasal delivery have numerous potential advantages over other dosage forms. For example, medicines delivered to the lungs usually have a more rapid onset of action than those that pass through the digestive tract. Similarly, drugs delivered via the nasal mucosa have more direct access to the central nervous system. This means they have considerable potential for the treatment of neurological disorders. Inhalation and nasal delivery can also help drugs achieve higher bioavailability than those administered via other routes. This allows developers that are reformulating oral solid dosage forms for inhalation to significantly reduce dosage strength. In this article with International Pharmaceutical Industry, Aditya R. Das, Ph.D., MBA, Director of Business Development at Recipharm, explores the growing popularity of inhaled and nasally deliverable dosage forms. He also outlines the primary considerations that pharmaceutical companies should make during product development, manufacture and the regulatory review process. Increasing Popularity Inhaled and nasally administered formulations are well established. Research indicates that inhalation, in particular, has been used as a delivery route for thousands of years1. In modern medicine, inhalable formulations have primarily been used for the treatment of diseases of the respiratory tract, like asthma, bronchitis and emphysema, where localised accumulation of the drug in the lungs is required. In recent years, this focus on respiratory diseases has begun to change in line with growing industry recognition of the benefits delivering drugs via the lungs and/or nasal 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

mucosa can achieve2. One of the main advantages is that drugs formulated for inhalation or nasal delivery can reach the systemic vasculature without having to pass through the digestive tract. This means they are not broken down by the liver – known as the ‘first pass effect’ – and can more easily achieve therapeutic serum concentrations than medicines formulated for oral delivery. As a result, pharmaceutical companies working on inhalable and/ or nasally deliverable formulations can reduce the dosage strengths required in each administration, which significantly lowers the potential for adverse effects. Diabetes has been an area of particular interest for companies seeking to develop inhalable formulations, with the primary driver being patient demand for alternatives to insulin injections usually used to treat the disease. While it is true that inhalable insulins launched to date have had limited success, this underperformance is related to commercial factors rather than the efficacy of the products3. Beyond metabolic disorders, inhalable treatments are also being developed for hereditary conditions. Cystic fibrosis is perhaps the best example, with several companies working on inhalable formulations of gene therapies4. In the field of nasal delivery, it is neurological disorders that are the focus. A number of developers are working on nasally deliverable treatments for diseases like Alzheimer’s and Parkinson’s5. The rationale is that nasal delivery offers easier access to the brain than other routes of administration. Formula for Development Success Developing any pharmaceutical is a major undertaking, but formulating drugs for oral inhalation or nasal delivery is particularly challenging. Considerable expertise is required to create a stable formulation that

can be delivered appropriately using the selected device. For example, producing a successful formulation requires specialised inhalation and characterisation expertise as well as a detailed understanding of the variables that can affect both performance and product quality. Similarly, proper delivery depends on producing a formulation in which the active pharmaceutical ingredient (API) and excipient are dispersed easily on inhalation. This requires detailed analysis of the active substance particle and variables like the mass median aerodynamic diameter. Likewise, achieving regulatory approval for such formulations can be a daunting prospect for teams more used to working on oral dosage forms. Manufacturing Production of inhalable and nasally deliverable formulations is also a highly complex process. To be effective, the API particles need to be a precise shape and optimised to interact with excipients in formulation and to behave correctly when administered using the specified delivery device. Combining these engineered APIs with excipients to produce a formulation requires the application of a range of advanced manufacturing technologies and techniques. Fortunately, in recent years various new manufacturing techniques that are ideal for the production of inhalable and nasally deliverable drug formulations have emerged. Spray drying, for example, has become highly popular among producers of inhalable formulations. The approach is a one-step process that can be used to manufacture drugs comprised of particles of precise morphology. These are then combined with excipients to create formulations that are suitable for pulmonary delivery. One of the main advantages of preparing drug particles using spray Spring 2019 Volume 11 Issue 1


drying is that the process decreases cohesive forces between particles, which improves the efficacy with which an inhaled formulation can be delivered to the lungs. This in turn allows higher doses to be delivered in fewer inhalations.

The 505(b) (2) pathway allows developers to both reformulate products for different routes of administration and to modify dosage strength, which fits very well with the features of inhaled formulations discussed previously.

development challenges and ensure project success.

Spray drying can be applied to a wide range of drug substances, from small molecule ingredients through to proteins and monoclonal antibodies, all of which can therefore be formulated for inhalation or nasal delivery.

The overall aim of the new pathway is to allow developers to avoid having to trial drugs that have already been assessed. Full safety and efficacy reports are still required; however, under 505(b)(2) the reports can contain data from studies not conducted by the applicant. Ultimately, the idea is to encourage innovation for drugs that have already gained approval, which makes it ideal for developers of inhalable and nasallydeliverable formulations.


Commercial Opportunities Another positive for pharmaceutical companies interested in developing inhaled formulations is that regulators have begun to support the application of novel delivery approaches that make drugs safer and more effective. In the US, for example, the Food and Drug Administration (FDA) has introduced the 505(b)(2) new drug application (NDA) pathway, which is designed for companies developing novel formulations of drug ingredients that are well understood.

Final Thought In short, there are a huge amount of benefits to be gained by opting for inhaled medicines, as well as the potential to increase the efficacy of certain treatments. However, before deciding on this dosage form, pharmaceutical companies need to ensure they have access to the right expertise to help them overcome


4. 5. articles/PMC5278812/ jdd/2016/8290963/ articles/PMC5001220/ early/2017/05/30/respcare.05624.full.pdf pubmed/29772289

Aditya R. Das Aditya Das, Ph.D., MBA, is a Director of Business Development at Recipharm AB. Dr. Das coordinates the interface between client needs and services/capabilities to facilitate optimal product development and global registration. He is based at the Recipharm facility at Research Triangle Park which focuses on transmucosal drug delivery and development.



Top Challenges the Medical Device Industry is Facing in the EU The date of implementation of Regulation (EU) 2017/745 of 5 April 2017 on medical devices (MDR) is rapidly approaching, and medical device manufacturers are striving to ensure that they will meet the requirements and obligations imposed by the new rules by 26 May 2020, when the revised legal framework becomes fully applicable. Should the latter not be the case, they would seriously risk being placed out of the market since no grace period is foreseen.

Although the MDR should be considered an evolution rather than a revolution of the current legal framework governing medical devices in Europe, it introduces significant changes that would require medical device manufacturers to reconsider their business model and to streamline their operations. The driving factor which led the European Union to revise the rules applicable to medical devices was not only the need to update the legal provisions in order to better address the features of a market characterised by the constantly evolving technology and the significant scientific progress occurred over the last 20 years, but also the need to recover trust in the accountability of the system after a few scandals (such as the PIP silicone breast implants), that showed the weakness of the legal framework and undermined the confidence of patients, consumers and healthcare professionals in the safety of medical devices. What remains unchanged is the classification of medical devices on a risk-based approach (class I, IIa, IIb and III, with class III covering the highest risk products), and the conformity assessment rather than the originally envisaged pre-authorisation procedure. The MDR repeals the existing Medical Devices Directive (93/42/EEC) (MDD) and the Active Implantable Medical Devices Directive (90/385/EEC) (AIMDD). It is not a mere replacement, 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

as the regulation will introduce harmonised rules that will be uniformly and consistently applicable in all the EU Member States, which was not the case with the former directives as each Member State enjoyed some flexibility when implementing them in their respective jurisdictions. Looking at the main novelties introduced by the MDR, one should mention the new category related to reusable surgical instruments; the broadening of the scope of the regulation with the inclusion of cosmetic and other devices not intended for medical purposes, such as liposuction equipment and epilation lasers; the traceability of the device through a unique device identifier (UDI) to be added to the label, and the introduction of an â&#x20AC;&#x153;implant cardâ&#x20AC;? providing the patient with all the relevant information concerning the implanted device. The UDI, widely known in the United States but representing an innovative tool in Europe to increase the reliability of safety requirements for devices provided to patients, healthcare professionals and institutions, will also imply regulatory liabilities on all economic operators involved in the supply chain. To comply with the new rules, medical device manufacturers will have to modify packaging and labelling of their products to incorporate UDI information which will have to appear on the revised packaging and labelling together with information concerning the manufacturerâ&#x20AC;&#x2122;s authorised representative in the EU and the indication for use (IFU). The MDR also foresees that UDI-related information is captured by the extended scope of EUDAMED, the European Database on Medical Devices, aiming to help European authorities conduct market surveillance on medical devices through information exchange. Pursuant to Article 33 of the MDR, EUDAMED will also aim on one hand at enabling the public to be adequately informed about devices placed on the

market, the corresponding certificates issued by notified bodies, the relevant economic operators and clinical investigations. On the other hand, it will represent a valuable source of information for both manufacturers and competent authorities to enable them to comply with their respective obligations. The EUDAMED IT team of the European Commission DG GROW has compiled the EUDAMED implementation plan and the draft Functional Specifications for all electronic systems/modules (on registration of UDI and devices, on registration of economic operators, on certificates, on clinical investigations/ performance studies, on vigilance and post-market surveillance and on market surveillance). The finalisation of all modules is expected for external audit later this year, as going through a positive audit is required in order to meet the 2020 target date for the first release of EUDAMED. The new regulation further pursues the target of tightening the ex-ante control for high-risk medical devices, establishing a new procedure which foresees pre-market scrutiny performed by an expert committee at European level. The Medical Device Coordination Group (MDCG), composed of persons designated by the Member States based on their role and expertise in the field of medical devices, supports and advises the European Commission and, in the framework of the mechanism for scrutiny of the conformity assessment of certain class III and IIb devices (i.e. the higher risk ones), may, based on reasonable concerns, request scientific advice from expert panels in relation to the safety and performance of any device. In addition to that, the MDR contains a series of provisions reinforcing the rules on clinical evidence and including an EU-wide coordinated procedure for authorisation of multi-centre clinical investigations, it strengthens post-market surveillance requirements for manufacturers, and Spring 2019 Volume 11 Issue 1

Manufacturing fosters coordination between national competent authorities in the fields of vigilance and market surveillance. Another major innovation, also dictated by the intention to reinforce reliability of the system, relates to the reinforcement of roles and responsibilities of notified bodies and, at the same time, of the criteria for designation and processes for oversight of their activities. Namely, the MDR empowers notified bodies to perform quality system conformity audits, to carry out unannounced factory inspections, and to conduct physical or laboratory tests on devices. On the other hand, notified bodies will be subject themselves to more demanding quality and standard requirements, and monitoring of their activities by national competent authorities will be tightened and enforced. Because of the new rules, intended notified bodies will have to apply to be (re-)designated and for extension of scope (if any), and they will be eligible to obtain a positive assessment and hereto be included in the list of notified bodies according to the new rules, and providing that they meet the new requirements set by the MDR. Conversely, any existing product will have to be recertified to abide by the new regulations. Transitional provisions (and namely article 120 of the MDR) are quite critical and burdensome for medical device manufacturers. In particular, article 120(2) of the MDR says that certificates issued by notified bodies in accordance with AIMDD and MDD prior to 25 May 2017 shall remain valid until the end of the period indicated on the certificate, whilst certificates issued by notified bodies in accordance with AIMDD and MDD from 25 May 2017 shall remain valid until the end of the period indicated on the certificate, which shall not exceed five years from its issuance. They shall however become void at the latest on 27 May 2024. And all that implies that, in the near future, all existing products will have to be recertified in order to ensure that they comply with the stricter quality and safety requirements imposed by the MDR. This is far from being a straightforward or painless exercise for medical device manufacturers, as companies will

be required to update clinical data, technical documentation, and labelling to expect a positive outcome of the new conformity assessment. Manufacturers will need to provide more in-depth clinical data which proves safety and performance claims, and have tighter equivalency standards. Namely they will have to plan, conduct, and document a clinical evaluation to demonstrate conformity with the relevant general safety and performance requirements set by Annex 1 of the MDR. This evaluation, and the related documentation, will have to be then kept constantly updated with post-market clinical data throughout the life cycle of the device. Actually, the MDR introduces specific requirements related to the inclusion of a post-market surveillance system for each device as an integral part of a comprehensive quality management quality (QMS) that not only manufacturers but also importers and distributors will have to implement. Finally, the MDR places a great emphasis on market surveillance and safety reporting. All manufacturers will be required to implement a post-market surveillance (PMS) system based on a post-market surveillance plan. According to Article 83 of the MDR, a PMS will have to be planned, established, documented, implemented, maintained and updated by manufacturers for each device in a manner that is proportionate to the risk class and appropriate for the type of the concerned device. That system shall be an integral part of the manufacturer's quality management system and shall be suited to actively and systematically gathering, recording and analysing relevant data on the quality, performance and safety of a device throughout its entire lifetime, and to drawing the necessary conclusions and to determining, implementing and monitoring any preventive and corrective actions. As a part of post-marketing surveillance, the regulation introduces reporting requirements that must be actively monitored and reviewed. In particular, manufacturers of class IIa, class IIb and class III devices shall prepare a periodic safety update report (â&#x20AC;&#x2DC;PSURâ&#x20AC;&#x2122;) for each device and where relevant for each category or group of devices, summarising the results

and conclusions of the analyses of the post-market surveillance data gathered as a result of the post-market surveillance plan. The relevant information will have to be submitted to the concerned notified body for review, as well as to EUDAMED for a broader exchange of information. A separate regulation for in vitro diagnostics (the IVDR)Â complements the MDR and will become mandatory two years later, as of 26 May 2022. Unlike the MDR, the new IVDR has substantially changed the classification as in vitro diagnostics medical devices will be now re-classified into four new risk classes (A, B, C and D, according to a progressive grade of risk). As a main consequence it has been estimated that each class will require a notified body to review about 90% of the devices. The prospective new scenario is putting a lot of pressure on medical device manufacturers, most of which are currently struggling to adjust their organisation in order to make it compliant with the new requirements by the set deadline. May 2020 is rapidly approaching and medical device manufacturers that will not be able to fulfil the new requirements are ineluctably destined to be put out of business, as no further period of grace is likely to be granted.

Vincenzo Salvatore Vincenzo Salvatore is counsel and leader of the Healthcare and Life Sciences Focus Team at BonelliErede. Full Professor of European Union Law, he joined BonelliErede in 2015, bringing his specific regulatory and compliance skills in terms of clinical trials, marketing authorisation procedures, pharmacovigilance, personal data protection, promotion and marketing of medical devices, inspections and enforcement. Vincenzo has gained significant experience in complex litigation representing public and private entities before the European Court of Justice based in Luxembourg, in EU law disputes. In addition, he was Head of the Legal Service at the European Medicines Agency from 2004 to 2012.



Understanding how Serialised Data Can Impact Warehouse Operations originally created for the EU market b) Returned to a wholesaler from an authorised party and cannot be added to saleable stock c) Scheduled to be destroyed d) Requested as a free sample by a competent authority e) Distributed to an institution that is declared to be outside of the pharmaceutical supply chain.

The EU Falsified Medicines Directive (FMD) deadline is now days away and all segments of the pharmaceutical supply chain are focused on finalising their solutions to comply with the regulation. Many companies responsible for distribution in the European market have prioritised connecting to the European Hub so they can exchange product master data across the supply chain to verify product before it is released or dispensed. It is vital that companies are also prepared for three important exception-based use cases that, if unaccounted for, will mean non-compliance with the FMD. Larry Hall, General Manager of Smart Supply and Logistics at TraceLink, describes each use case and the solution required for all three.

1. Product leaving the supply chain prior to point of dispense Articles 16, 22 and 23 of the Delegated Regulation affect companies responsible for pharmaceutical distribution in the EU when it comes to decommissioning and reporting on products that leave the supply chain without being dispensed. The articles provide for several instances where responsible parties will be required to decommission and report this event to either the European Medicines Verification System (EMVS) or the appropriate National Medicines Verification System (NMVS). Specific occurrences are: •

Article 16 – when products have had safety features removed or covered and been put into a different container or re-labelled. This can occur often when supplying clinical trials where returns from trial sites are more prevalent and supply requirements can change regularly as a result of attrition rates. Article 22 – when a product is: a) Being exported outside the EU to another country and was


Article 23 also addresses product that is shipped to certain entities within the EU other than a hospital or pharmacy such as universities, veterinary surgeons and government bodies. Its implementation is open to interpretation by each Member State’s healthcare authority.

Warehouse operations are directly impacted by each Article and there are a number of inherent complexities to be managed. Most prominently, warehouse operations must figure out which system, the NMVS or the EMVS must be notified for each product and then spend time on the actual decommission reporting. These additional processes could distract operations teams from their core activities where resources are more efficiently spent managing inventory or receiving, packing and shipping within the warehouse. 2. Risk-based verification for saleable returns Currently, warehouses do not have to verify saleable returns, defined as a returned product intended to be put back in stock for redistribution, but this will be a requirement under the FMD. Warehouse teams currently rely on manual, paper-based processes and phone calls for verification when asked to confirm and decommission a product that came from their site. Bringing risk-based verification into your processes to ensure compliance is going to create the need for operational warehouse changes.

When a product follows its normal distribution path – moving from the manufacturer to the wholesaler/3PL and on to the point of dispense – and decommissioning only occurs at the point of dispense, risk-based verification is not required by FMD. However, products can deviate from this ‘normal’ path and when they deviate it adds complexity to tracking down the origin of a product, verifying it and validating its authenticity. This can cost a warehouse a tremendous amount of time. A typical example of deviation is when a wholesale distributor sells a product to another wholesale distributor or 3PL, or when a 3PL sells a product to another 3PL or distributor. With risk-based verification, product must be verified against a national system by rescanning product to verify identity and isolate any potential risks as much as possible. Without an automated solution in place to verify product, the process could be quite lengthy and the costs could be significant. 3. Serial number status change or updates As stated above, a normal path of distribution is defined as product moving from the manufacturer to wholesaler/3PL and then pharmacy or point of dispense where the product is decommissioned from the supply chain. There are a number of events that can occur along this path that will require reporting. For instance, if a product has been damaged or locked for investigation, its serial number status must be changed in the respective NMVS. This can also occur if a product was incorrectly reported to the NMVS, in which case an organisation will have ten business days to make the correction to the appropriate government system. Spring 2019 Volume 11 Issue 1

Packaging Preparing for and Managing these Use Cases For some organisations, only a small percentage of shipments may be impacted by these use cases, a number small enough to weaken the business case for changing the scanning operations of an entire warehouse, but large enough that it canâ&#x20AC;&#x2122;t be ignored. So what is the answer? Since compliance is a main priority for companies, particularly with the regulation being enforced on 9 February 2019, you will need a solution to deal with these exceptions, and selecting a solution provider with proven expertise in serialisation will be essential to making sure you are prepared and compliant. Warehouse management systems are highly complex and customised and most canâ&#x20AC;&#x2122;t handle serialisation requirements, including the storage of the massive amount of data generated, connecting with the EU Hub and delivering the necessary reporting capabilities and updates necessary to accommodate future

them to focus on core operational tasks.

Larry Hall FMD mandates. Further customisation to include these use cases could be a time-intensive, costly and high-risk undertaking. Therefore, a seamless solution that minimises disruption in workflow is essential. An application that can layer serialisation requirements alongside a warehouse management system, rather than embed them into one, would allow for real-time information scanning and ensure compliance while increasing business efficiencies. Additionally, with a cloud-based network approach, automated verification can be done in real time, freeing warehouse staff from the complex and error-prone manual verification processes and allowing

Larry has over 30 yearsâ&#x20AC;&#x2122; experience in management, business process design and enterprise software solution sales, design and implementation for global corporations in pharmaceutical, logistics, aviation, defence, high-technology and other industries. As an individual contributor, he has defined implementation methodologies and implemented major solutions for a number of Fortune 100 companies. Larry was the co-founder and Vice President of Sales and Operations of ROC IT Solutions, the leader in intelligent edge data capture for serialised product inventory in the pharmaceutical supply chain, before it was acquired by TraceLink in 2017.



Sensitive Medical Packaging: Meeting the Needs of the Pharmaceutical Market Today, biologics and biosimilars are in the focus of the pharmaceutical industry. Whether for inflammatory autoimmune diseases such as rheumatism, chronical metabolic diseases like diabetes or cancer suffering – biologics and biosimilars are one of the medical revolutions of the 21st century and have become indispensable. But this significance unfolds not only new potentials, but also many challenges that pharmaceutical companies and their suppliers have to overcome to guarantee a certain demand for quality and, from the patient's point of view, provide administration of the active ingredient as simple and suitable for everyday use.

The sensitivity of biologics and biosimilars regarding storage and packaging requirements, as well as their complexity during administration, led to the demand to meet the highest quality standards, including strict controls at all stages in the manufacturing process. For gentle storage, the right packaging plays a crucial role, especially when it comes to an appropriate protection of the drug. The efficacy and safety of the active ingredient can be negatively affected by even the smallest deviations and inconsistencies in production and material performance. That’s why, in the field of sensitive biologics and biosimilars, the protection of the active ingredient is of key importance, and companies are constantly seeking for new packaging solutions in order to provide the best environment for packing and producing the drugs. Requirements for Highly Sensitive Medical Packaging Solutions The increasing demand for highly sensitive drugs such as biologics and biosimilars, which are often dispensed in liquid form, leads to constantly growing challenges for manufacturers of drug packaging and elastomer components. Elastomer components are frequently used, not only as closure solutions, but even in the area of prefilled syringes. Also in 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

cartridges for pens, for example for self-administration of insulin, they are a central element. The rubber components are in long-term contact with the liquid pharmaceuticals. It must be ensured that visible and subvisible particulates are reduced and that the compatibility of the rubber components with the drug formulation is guaranteed, which leads to a growing complexity of formulations and an increase in new types of components. It also means that the interaction of extractables and leachables from the rubber in the solution have to be limited to the absolute minimum. Therefore, innovative barrier technologies and manufacturing under cleanroom conditions are the key to fulfill these special requirements.

Figure 1: Biologics and biosimilars are often dispensed in liquid form. These liquid drugs require high quality closures.

Siliconisation: A Must for Good Processing and Functioning of Uncoated Closures To achieve good processability and functionality, the sealing components usually have to be siliconised – which takes place at the end of the washing process and thus shortly before the products are packaged. The degree of siliconisation depends on the intended purpose of the product and is tailored to the type of seal. In general, a vial stopper gets a lower siliconisation degree than a plunger due to the specific use. The silicone oil prevents clumping in bags and makes sure the products are running perfectly on the filling lines of the pharma companies. The process also avoids the plunger

sticking to the barrel during long storage and as such, contributes to achieving an acceptable break-loose force so that the syringe contents can be administered to the patient in a proper manner. It will also contribute to a good gliding of the plunger in the barrel, although gliding is more determined by the surface treatment of the barrel than by the plunger. However, siliconisation entails challenges regarding biologics and biosimilars. Whenever the active ingredients get in contact with silicones, changes may occur: The proteins can aggregate, which potentially could result in ineffectiveness or immunogenicity of the protein. In the worst case, even the efficacy of the drug is no longer guaranteed. In order to counter the sensitivity of biologics and biosimilars to impurities, the production of all components must meet the highest quality standards. As a result, the siliconisation method for surface treatment is not recommended for all pharmaceutical components – especially not for the two mentioned above. The specific properties and characteristics of biologics and biosimilars require a barrier technology that ensures highest safety and effective drug supply. Other barrier properties are the prevention of absorption and/or adsorption of the active ingredient or excipient to the packaging, which can lead to potency loss and stability issues. Due to the high number of challenges involved, the production of packaging specifically designed for these sensitive drugs and their properties can be seen as an extension of the manufacturing process of the drugs itself. As a result, packaging suppliers work closely with drug manufacturers to develop a solution that ensures drug effectiveness. An important step on the way to the best handling of biologics and biosimilars is fluoropolymer-coated closure solutions. The coating makes the use of silicone oils obsolete, which Spring 2019 Volume 11 Issue 1

Packaging is an advantage needed for siliconesensitive proteins. Fluoropolymer Coating: An Inert and Silicone-free Barrier Taking the specific requirements into consideration, a fluoropolymer coating has many advantages in comparison to the siliconisation technique. Taking a look at its material composition, it is chemically inert and has a low permeability to organic molecules and aqueous ions. It can be applied by film laminate coating or spray coating. In the spray coating process, the fluoropolymer coating is applied in a two-step process. In the first step, the proprietary fluoropolymer film is applied by a tumble spray coating. The second step consists of a post-treatment process which provides sufficient thermal energy to bond the coating covalently to the butyl substrate and to form a smooth, continuous fluoropolymer film. Due to the line-of-sight nature of the spray coating, the entire closure surface is covered with a thin and flexible coating. Thanks to spray coating technology, a big range of designs can be coated: from small components like 0.5 ml plungers to large closures like infusion stoppers. The total coverage by the coating stands in contrast with the partial coverage of most film coatings and therefore offers the benefit of providing a complete barrier. Due to the low coefficient of friction of the coating, there is no need for siliconisation of the closure in order to obtain a good processability and functionality. Fluoropolymer coated closures not only have barrier properties which enable superior chemical compatibility, but also the added benefit of eliminating the largest source of subvisible particles: silicone oil-based coating containing subvisible particles.

Figure 2: The plunger is a critical component of any prefilled syringe. Even after several years of storage, it must ensure that the medication is administered safely to the patient. 69 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3: In state-of-the-art plants, products are manufactured under cleanroom conditions.

Cleanroom Manufacturing Environment and Strict Quality Standards for Maximised Safety To ensure that the components for pharmaceutical packaging, especially for biologics and biosimilars, meet the highest demands, the production environment is a quality critical attribute. For this purpose, a cleanroom manufacturing environment is essential, including innovative automated processes and appropriate gowning, to conform to the highest industry standards. Each zone is designed and constructed to prevent biocontamination and is equipped with easy to clean machines mainly made of stainless steel. Each zone is in overpressure versus the next zone. An example in this regard is the pass-through washing machines: automatic loading is done in one zone and its automatic unloading side is in a zone of even higher cleanliness. In addition, state-of-the-art camera inspection techniques are used to eliminate any remaining defect or contamination to ensure zero defects. The process flow, gowning protocols, personnel and material flow, and automation all result in the lowest endotoxin, bioburden, particulate, and defect levels available in the industry. Due to this high-level clean processing, absolute purity of pharmaceutical packaging components for drug administration can be guaranteed. Next to this, Good Manufacturing Practice principles are used in the production and control, which are of great importance for the safety of the patient. With regard to biologics and biosimilars, this is highly important because the purity of the sensitive drugs can be guaranteed not only by the coating, but also by the manufacturing itself.

Individual, Ideal Coating Solutions for Specific Drug Needs Taken together, the proprietary, inert fluoropolymer spray coating is the most advanced coating technology on the market, providing unique barrier properties for biologics and biosimilars. Components treated with this material offer minimal interaction potential between packaging material and the filled drug, while the production environment and processes guarantee an uncompromising, consistent quality. Thus, the fluoropolymer coating can be considered as a response to the ever-increasing demands for better packaging solutions for sensitive drugs. The high-performance fluoropolymer coating technology meets all the compatibility and functional requirements of the biologics industry, and simultaneously improves the lives of patients who depend on treatments with these drugs.

Carina Van Eester Carina Van Eester has a masters degree in chemical engineering and has been working in the pharma industry for 15 years as a packaging engineer. She has now worked at Datwyler for 11 years. After many years of experience in technical key account management and validation, she is now Global Platform Leader for Prefilled Syringes and Cartridges, taking strategic initiatives related to Datwylerâ&#x20AC;&#x2122;s components for these applications. Email:

Spring 2019 Volume 11 Issue 1


BioAgilytix Europe Appoints New Scientific Officer BioAgilytix, a leading global bioanalytical testing laboratory specialising in the bioanalysis of biopharmaceuticals, is pleased to announce the appointment of its new Scientific Officer for BioAgilytix Europe, Dr Lydia Michaut. Lydia brings a wealth of experience in immunology, genetics, gene therapy and regulated bioanalysis to the company, and is perfectly placed to liaise with clients to ensure that BioAgilytix delivers high quality laboratory services tailored to their specific needs.

Passionate about life sciences, Lydia obtained a PhD in molecular biology and innate immunity from Louis Pasteur University, Strasbourg – where she studied with Nobel Laureate Professor Jules Hoffmann – before taking up a postdoctoral position with the world-renowned developmental biologist Professor Walter Gehring at Biozentrum, University of Basel. After 15 years in academia, Lydia moved to Swiss pharma company Novartis,

where she became one of the first members of staff dedicated to the scientific interface between the company and bioanalytical contract research organisations. She also acquired expert knowledge in regulated bioanalysis supporting the clinical development and approval of biological drugs, as well as in bioanalytical strategies specific to gene therapy compounds, such as qPCR and immunogenicity assessments. A key part of Lydia’s role in the pharma industry has been communication with regulatory authorities, including the European Medicines Agency, the US Food and Drug Administration, the Japanese Pharmaceuticals and Medical Devices Agency, Health Canada and the China Food and Drug Administration. ­This involved ensuring compliance with the latest guidelines for the duration of a study, and correct completion of all the necessary documentation

prior to submission to the relevant authority. A decade of experience in this role has given Lydia an in-depth understanding of what clients look for in a bioanalytical testing laboratory, which will be invaluable in her position at BioAgilytix. “I have been fortunate to work with some very high-calibre scientists, learning a great deal from them. I am thrilled to be joining a forwardthinking company and look forward to putting this knowledge and my experience in the pharma industry to good use in my challenging new role. It’s a very exciting time,” said Lydia.   Global Chief Scientific Officer for BioAgilytix, PD Dr Arno Kromminga, commented: “We are delighted to welcome Lydia to the company as we grow the business. Her expertise and experience in working with regulatory authorities worldwide will be crucial to helping support our clients’ bioanalytical needs.”

Mr. Turhan Ozen, Chief Cargo Officer at Turkish Airlines, elected to the International Air Cargo Association (TIACA) Committee. Turhan Ozen, serving as Chief Cargo Officer at the global brand Turkish Airlines, was elected to the International Air Cargo Association (TIACA) Committee, the joint voice of the industry that aims to enhance the air cargo profile with intensive efforts towards the global standards.

Having a vast amount of knowledge about Balkan countries, the Middle East and Africa region, as well as the surrounding regions of Turkey, Mr. Ozen has been leading Turkish Cargo, the fastest growing global air cargo brand, flawlessly since 2016. Leading the upswing trend of Turkish Cargo, which will have the capacity to handle 4 million tons of cargo on an annual basis at its new mega cargo facility equipped with the state-of-the-art technology at 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Istanbul Airport, Mr. Turhan Ozen said: "Effective leadership is required to handle the customers' constantly diversifying demands accurately across the air cargo industry. I truly believe that my new membership duty of the TIACA committee will reinforce this leadership, and provide a positive contribution to development of the international air cargo industry."

to be an important impulse and driver for Turkish Cargo, which aims to be one of the top 5 global air cargo brands by 2023 and keeping its upswing trend, to achieve its targets.

Sebastiaan Scholte, Chairman of TIACA and CEO of Jan de Rijk Logistics, said: “Following the stunning Istanbul Airport, Turkey has become a mega hub for air transportation between Europe and Asia. All steps taken and experiences gone through by Mr. Ozen for completion of this giant project will be invaluable for TIACA committee and its members." Equipped with an experience of nearly 20 years, Mr. Ozen continues Spring 2019 Volume 11 Issue 1


Exyte remains on strong growth path in Q1 2019 Exyte AG (“Exyte”), a global leader in the design, engineering and construction of high-tech facilities, plants and factories, achieved sales of € 852 million in the first three months of 2019. This corresponded to year-on-year growth of 13%. The company thus succeeded in outperforming what was already a strong first quarter in 2018.

At € 42 million, the adjusted EBIT figure for Q1/2019 rose at an even faster rate than sales, up 17% on the

prior-year value. The EBIT margin increased to 4.9% (Q1/2018: 4.8%). Following a 24% average increase per annum in the order intake since 2015, this figure declined as expected in the first three months of 2019 compared with the previous year (Q1/2019: € 1.2 billion), as a major project with an exceptionally big volume was booked in Q1/2018. Exyte’s order books remain wellfilled, however, with an order backlog of € 3.3 billion. “We are very satisfied with business performance over the first three months of the current financial year,” commented Exyte CEO Dr. Wolfgang Büchele. “This growth path underlines once again the huge potential of our company and confirms that our strategic business segment realignment to focus on Advanced Technology Facilities (ATF), Life Sciences & Chemicals (LSC) and Data Center (DTC), as well as the various strategic initiatives we have kicked off, are yielding the desired results.”

ATF remains the strongest business segment ATF, which serves Exyte’s customers in the semiconductor industry, remains the company’s strongest business segment with sales of € 722 million (+26% on Q1 2018). As in the LSC and DTC segments, Exyte continues to capitalize here on global megatrends like digitalization, Industry 4.0 and the ever-expanding global population. These trends will accelerate demand for Exyte’s unique solutions. Significant growth in the Asia-Pacific and Europe regions The Asia-Pacific (APAC) and Europe (EMEA) regions in particular performed excellently in the first three months of the current financial year. In the APAC region, where Exyte spearheads the semiconductor market, sales increased by just under 10% (Q1/2019: € 499 million). Exceptional growth in EMEA meanwhile saw the sales figure increase by 77% (Q1/2019: € 262 million).

Nephron Pharmaceuticals Implements Kit Check for Serialization of Prefilled Syringes Radio-Frequency Identification (RFID) tags are embedded on all prefilled syringe products at the Nephron 503B Outsourcing Facility.

Nephron Pharmaceuticals has announced a new serialization initiative in which Kit Check RadioFrequency Identification (RFID) tags are embedded on all prefilled syringe products at its Nephron 503B Outsourcing Facility. The goal is to ensure all products are identifiable throughout the supply chain, using tracking and automation tools. Each pre-tagged syringe will work automatically in a Kit Check scanning station; no additional labeling or activation necessary.

The serialization effort will provide enhanced data on drug usage, allowing Nephron to tailor products to specifically suit the needs of a hospital. Products including Phenylephrine, Succinylcholine, Glycopyrrolate and more are available. “Nephron is proud to be the first company implementing Kit Check across all syringe products,” says Lou Kennedy, Chief Executive Officer, Nephron. “We believe this will set a standard of care within our industry.” “Kit Check is happy to support this effort with an automated solution for adding serialized RFID tags to prefilled syringes,” says

Nick Petersen, Vice President at Kit Check. “We have tracked more than 50 million medications in the U.S. and learned the best approach for syringes is embedding the item-level tags at the time of production. More than 400 hospitals using Kit Check can now automatically recognize Nephron 503B prefilled syringes out-of-the-box.” Nephron is one of nine partners certified for the Works with Kit Check program. Customers will no longer be required to add RFID tags to prefilled syringes to use them with Kit Check. Scanners will automatically identify the syringes in terms of NDC, lot number, and expiration date, saving time for hospital staff and reducing the risk of medical error. INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

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Emphasys Industrial Kahle Automation

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Sartorius AG Source BioScience Schott AG Taconic Biosciences Inc. Turkish Cargo VALSTEAM ADCA ENG

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Spring 2019 Volume 11 Issue 1

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