IPI Winter 2021

Volume 13 Issue 4

Peer Reviewed

Evaluation of an Alternative Solid Dosage Form to Enteric Coated Pellets Containing Ibuprofen Cyber Risk How Can Pharma Avoid Black Swan Events?

Understanding the Challenges of Highly Potent Actives Behavioural Science: An Untapped Opportunity for Medical Affairs Sponsor Company:

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Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

DIRECTOR: Mark A. Barker INTERNATIONAL MEDIA DIRECTOR: Ty Eastman ty@senglobalcoms.com BUSINESS DEVELOPMENT: Michael Hossain michael@senglobalcoms.com EDITORIAL: Virginia Toteva virginia@senglobalcoms.com DESIGN DIRECTOR: Jana Sukenikova www.fanahshapeless.com FINANCE DEPARTMENT: Akash Shama accounts@senglobal.com RESEARCH & CIRCULATION: Jessica Dean-Hill jessica@senglobalcoms.com COVER IMAGE: iStockphoto © PUBLISHED BY: Senglobal Ltd. Unit 5.02, E1 Studios, 7 Whitechapel Road, E1 1DU, United Kingdom Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.international-pharma.com 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 Spring 2022.

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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.

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08 How to Coordinate Your Site Selection with State Economic Development Where are your labs located? Development/pilot/clinical material facilities? Commercial plants? If these do not exist, where should you build them? If outsourcing, where are your CDMO’s facilities located? Louis Garguilo interview with Kimball Hall at Abzena and Bill Bullock at North Carolina Biotechnology Center (NCBiotech) reveals the path to narrowing the decision-making process, pointing to the locations to focus on and the importance of choosing the right area for the companies to end up with the position that works best.

10 Preparing for FDA Remote Inspections: What to Expect for 2022 If there’s one thing 2020 taught the world, it’s that the road ahead is ever-changing. Given the Delta variant on the rise and the significant backlog of FDA inspections, it is unclear when and how the agency will resume a regular inspection protocol. Devon Copley at Avatour discusses this, however, is certain, the government wants to move the needle along and make tangible progress in addressing the backlog. With the government boosting unannounced inspections and considering bringing remote technology into the regular inspection protocol, it is clear times are changing. Companies’ best chance at adapting to the new reality is to be prepared and open to alternative technologies.

12 The New Regulatory World for Medical Devices.

Establishing an Effective Compliance Strategy Now Ahead of the 2022 IVDR legislation – Because There’s More to Come No sooner than medical device manufacturers have completed their MDR compliance project, they must prepare to adapt products, labelling and artwork to comply with upcoming IVDR counterpart legislation. Set for implementation in May 2022 and to be followed by more waves in 2023, 2025 and 2027, IVDR will require many businesses to begin the compliance cycle from the start again, to ensure they can continue to sell in vitro diagnostic products into the lucrative EU market. Many of these challenges will mirror MDR efforts – with lessons to be learned and technological innovations ready to ease the process. Bob Tilling at Kallik describes the top compliance challenges manufacturers must address – and how digital platforms can support ongoing compliance efforts.

14 Hyper-collaboration in Healthcare and Life Sciences The COVID-19 pandemic demonstrated the ability of the healthcare and life science industry to respond to unexpected needs with unprecedented speed. However, independent of the pandemic, the industry was already facing transformation considering multiple, highly disruptive innovations, not only in the traditional field of drug modalities but also in related fields such as digital, AI, data and medical devices. This new “Future of Health” is driven by a multitude of new players and innovations with disruptive potential and new ways of thinking about health, both at a large scale for population health and at an ultra-targeted level through the potentially curative treatment of individual diseases, such as for CAR-T or gene therapies and precision medicine. Dr. Franziska Thomas, Ben van der Schaaf and Dr. Ulrica Sehlstedt at Arthur D. Little’s discuss how the industry’s response to the pandemic and its transformation towards the Future of Health may at first seem unconnected, but they share the same foundation.

18 It’s Now Time for Your OPDP Submissions to be FDA Compliant | Are you Ready?

The Prescribing Information, Labeling, and any other materials used

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Contents for the promotion of Drug Products for their approved indication, or intended purpose of use, are referred to by the US Food and Drug Administration (FDA) as “Promotional Labeling and Advertising Materials for Human Prescription Drugs.” It is imperative that each Marketing Authorisation Holder (MAH) submits these Promotional Labeling and Advertising Materials to the FDA for review and approval for each of their drug products. In the next lines, Prabu Selvaraj at Navitas Life Sciences discusses the two types of labelling recognised by the FDA. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 22 The Brave New World of Rapid Drug Development The COVID-19 pandemic has brought the topic of rapid drug development to the forefront of the life sciences sector. Ray Chohan at PatSnap, believes that we have entered the next generation of pharmaceutical development driven by new technology.

26 Evaluation of an Alternative Solid Dosage Form to Enteric Coated Pellets Containing Ibuprofen: A Case Study Recent works have evaluated the potential of minitablets contained in hard gelatine capsules. To get the benefits and advantages of multi particulate dosage forms, it is necessary for tablets of between 2 mm and 4 mm diameter to be used. Tablets larger than 4 mm could not be contained in a hard gelatine capsule in any great number, similarly, tablets smaller than 2 mm would be extremely difficult to manufacture. Studies have shown that tablets of this size have a similar emptying pattern to standard pellet formulation. Caterina Funaro at IMA Active summarises that the results of this work have shown that minitablets are a good alternative solid dosage form to pellets. Both enteric coating processes were performed on the same equipment, GS coating pan HP025 standard configuration.

CLINICAL & MEDICAL RESEARCH 30 Quality Overtakes Cost as the Priority as Life Sciences Companies Move to Automate Pharmacovigilance Case Intake For the first time, quality has overtaken cost as a priority in plans for automating adverse event (AE) reporting. These are the findings of brand-new research among 200 professionals in senior roles spanning PV, Drug Safety and Product Safety departments. Here, John Price, a long-standing life sciences industry consultant and partner of Arriello, which commissioned this latest research, unpacks the findings.

32 The New Normal: How COVID-19 Became the Catalyst for Change When COVID-19 disrupted life sciences, solutions were needed in real-time. As the pandemic grew, so did the need to innovate.

Workers met the challenges. They completed tasks, fulfilled inspections, and remained vigilant in fulfilling regulatory requirements. This paper by Jürgen Hönig at PharmaLex GmbH, Germany, presents findings from a roundtable hosted by PharmaLex. It examines how life science professionals leveraged disruptive technologies during the pandemic.

TECHNOLOGY 38 Defining and Regulating the Complex World of Software as a Medical Device The medical devices landscape has changed dramatically in recent years with the shift from hardware-based medical devices to the advent of smart, standalone software technology medical devices.

However, the definition of what constitutes software as a medical device (SaMD) is not that simple, and that poses some unique 2 INTERNATIONAL PHARMACEUTICAL INDUSTRY

challenges when it comes to regulations. Yervant Chijian at PharmaLex states that since regulations were written well before the emergence of SaMDs, health authorities have had to consider how to adapt these regulations to the fast-moving nature of the technologies.

40 Cyber Risk: How Can Pharma Avoid Black Swan Events?

Rod Schregardus, pharma manufacturing lead at The Access Group, looks at the IT security threats facing pharma companies today, and the steps that can be taken to prevent the fallout from data loss. He also speaks to Jim Wheeler, a director at UK-based risk consultancy Control Risks who played a leading role in the crisis management team for an organisation severely impacted by NotPetya, the same ransomware which struck Merck in 2017.

44 How Technology Can Make Pharmaceutical Packaging Design an Easier Pill to Swallow Packaging is one of the most vital components of modern commerce. It must define and promote a product and brand whilst being functional and providing relevant information. Steve Morris at Visual Components discusses that the packaging should attract customers, augmenting their interest and confidence. It is an essential part of any product that should never be overlooked.

MANUFACTURING 48 Operational Readiness – The Precursor to Operational Excellence Following any tech transfer project, the subsequent startup of the manufacturing line is almost always full of challenges. The goal is to startup as soon as possible once the project is completed but also to achieve steady-state throughput as quickly as possible after the startup begins. This type of startup is what is called a “Vertical Startup.”

In practice, vertical startups are rare because management teams typically focus their attention on having the facility and the equipment qualified in time to meet the process qualification milestone. Richard Tree reveals that the consequences of this thinking are that a broad range of workstreams are often neglected or receive inadequate attention although they are critical to startup. Workstreams like staffing, training, procedure development, supply chain, analytical methods, etc. must all be ‘ready to go’ by this important milestone.

52 The Case for Smart, Real-time Quality Monitoring in Life Sciences Manufacturing The more fragmented that processes become, the more critical it is that they can be assessed and managed for consistent quality. During the peak of the pandemic, as drug and medical device production continued at pace, manufacturers experienced a deepening challenge of how to monitor, analyse, report and act on quality performance and any emerging deviations. Siniša Belina, a senior life sciences consultant at Amplexor, delves deeper into the potential of modern tools and holds up examples of emerging best practices.

54 Understanding the Challenges of Highly Potent Actives A rising number of active pharmaceutical ingredients (APIs) are classed as “highly potent”. They are being increasingly harnessed by pharma companies developing oral solid dose (OSD) treatments to treat a variety of chronic conditions. For instance, they are being explored as potential new cancer therapies and as treatments designed to block the immunological response to prevent organ rejection following transplants. They even have the potential to provide enhanced contraception capabilities, as well as to manage a range of other disease states and chronic conditions, such as heart disease. Mario Di Carmine, Pfizer CentreOne Lead at the Pfizer manufacturing site at Ascoli, Italy, explores the challenges facing pharmaceutical companies when using highly potent active ingredients (HPAPIs) for the first time.

Winter 2021 Volume 13 Issue 4

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Contents PACKAGING 58 Product Protection via Primary Packaging – Screwcaps to the Rescue The use of screw caps to seal bottles for consumer use vary greatly from region to region. However, in North America, as in Europe, many medicines are sold in containers with screw caps. An important component and part of the packaging of many dosage forms, screw caps are employed to securely close containers holding powders, pastes, liquids, and other products. The tightness they offer, i.e. the low permeability of gases, vapours and aromas, which is guaranteed even after re-closing, is unrivalled, compliance with regulatory requirements and functional reliability aside. Innovative manufacturers of medicinal products are increasingly using screw caps as an additional feature to offer added value to customers, patients, or the pharmaceutical filler. This article by Clemens Boerner at Kisico presents various possibilities of product protection with the help of innovative screw caps.

64 Ensuring Complete Product Packaging Quality Liquid pharmaceutical manufacturers operate under great scrutiny and must set high standards of product quality. In three steps, Jürgen Kress, General Manager for Checkweighing and Vision Inspection, Mettler-Toledo Product Inspection, outlines how sophisticated weighing technology helps ensure that liquid pharma products are safe for consumers and compliant with regulations. He also examines the importance of serialisation and aggregation and how product inspection helps drive transparency in the digital supply chain. Finally, he explains the importance of software connectivity as a critical part of making product packaging quality happen.

70 Delivering Efficiency on The Packing Line The pharmaceutical industry has to deal with many of the same commercial pressures as other industries, and in many cases, the nature of the products means companies are subjected to much greater control and regulation. For the filling and packing process, the need to maximise efficiencies and productivity, to be agile and flexible and able to respond quickly to customer demands are more essential.

Selection of the most appropriate equipment is key to achieving the Right First-Time approach that will help companies meet customer requirements and make the most of all opportunities. According to Richard Aitchison of ATS Packaging Machinery, equipment suppliers can play a key role in ensuring pharmaceutical manufacturers can take the Right First-Time approach to their packing requirements.

require strategic planning and should avail of appropriate assistance, particularly in one area of clinical trial expertise – clinical packaging.

80 Balancing the Complexity-efficiency Equation in a Fast-changing Prefilled Syringe Packaging Market Marcelo Cruz, Director of Business Development and Marketing at Tjoapack, discusses the fast-changing pharmaceutical market landscape and explores the latest trends in prefilled syringes. He explains how companies can balance the complexity-efficiency equation to deliver patient-centric drug products while optimising productivity.

LOGISTICS & SUPPLY CHAIN MANAGEMENT 84 Digital Transformation: The Modern Pharmaceutical Control Tower The next generation of analytical tools provides transparency and visibility into the complex nature of the modern pharma supply chain and services that facilitate proactive responsiveness. Pharma manufacturers and logistics providers today live in an on-demand world. As a result, they need to be able to understand and use tools easily. Ada Palmadottir, a Business Development Director at Controlant, says that the insights available today allow business professionals to detect problems before they occur and to respond appropriately. By identifying all variables in the chain through a control tower, understanding their impact, and turning knowledge into action, supply chain leads can build responsive, collaborative supply chains that are safer and more efficient for everyone.

HEALTH OUTCOMES 86 Behavioural Science: An Untapped Opportunity for Medical Affairs Just proving that an intervention has benefits is not always enough for it to be adopted into clinical practice. Yet in the past, pharma Medical Affairs teams have leaned heavily on empirical evidence to influence the uptake of new drugs and therapies. Here, Ben Routley of Bioscript/Mark Pringle of NeoHealthHub examines how the use of behavioural science techniques (BST) can improve the impact of client communications. BST has been a pivotal part of the guidance issued by the Scientific Advisory Group for Emergencies (SAGE) and of the strategy of the UK Government during the Covid-19 pandemic, and because of this, the practice has come into sharper focus. The more forward-thinking pharma organisations are now starting to embrace this form of customer engagement.

74 Prefillable Syringes in Deep Cold Storage: Is This the Way Forward for Mass Vaccinations?

The world has just witnessed the fastest vaccine rollout in modern medical history. This undoubtedly saved lives – but it placed intense pressure on our healthcare systems, workers, and supply chain. This begs the question: is there potential to make future vaccination programs even more efficient? Guillaume Lehée, R&D Innovation Leader, BD Medical – Pharmaceutical Systems reckons that the solution may lie in prefillable syringes (PFS) which have the potential to minimise the many challenges involved in vaccine production and administration.

The Importance of Clinical Trial Packaging and The Benefits in Outsourcing your Small Molecule Packaging to a CDMO Operating a clinical trial in what is a tightly regulated industry requires comprehensive, big picture thinking. Risks remain at all stages of the clinical supply chain, and they can make the difference between a successful study, or no study at all. Adrian Collins, Production Manager at Almac Clinical Services explains, whilst businesses are continuing to navigate the COVID-19 pandemic, sponsors face challenges that 78

4 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2021 Volume 13 Issue 4

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Editor's Letter Solid dosage forms have been one of the foremost choices of drug administration for generations. However, with an ever-growing global population, evolving customer demands, and continual updates to regulations, comes greater need for advanced medicines and progress in this sector. Pharmaceutical manufacturing companies that work with solid dosage forms are facing a myriad of challenges. Solid dosage forms must keep pace with other advancements in the pharma industry and evolve and embrace technology and new materials to retain their position in the market.

The history of solid dosage forms dates to Roman times, yet medicines in general have developed considerably over the last couple of centuries.

Beginning with the use of tinctures, extracts, syrups, handmade pills, and tablet triturates. In the last century, solid dosage forms have become by far the most popular and convenient option of drug delivery and administration. Despite initial unreliability, tremendous progress has been made and nowadays, stable and accurate dosage means minimal error on the patient’s part, making solid dosage forms an accessible, practical, and safe option. They are cost effective to all stakeholders, manufacturers, the distribution network and, most importantly, the user.

The selection of a lead solid form of an API is a critical step in early pharmaceutical development.

Determining the most suitable chemical and physical form impacts a range of critical parameters including manufacturability, stability, and bioavailability. The selection of a lead solid involves the screening and characterisation of chemical forms (free form, salts, hydrates, solvates and cocrystals) and polymorphs and/or amorphous forms. Every molecule is different with varying propensity for polymorphism and the formation of hydrates and solvates. Additionally, the physicochemical properties of the molecule and the target product profile will determine the need for screening salts, cocrystals or bioavailability-enhanced formulations. These properties will also determine solubility, dissolution rate and/or manufacturability of any solid form. Selection of a solid drug form is a key decision, since an estimated 90% of organic molecules have multiple forms.

In this issue, Caterina Funaro at IMA Active within her article “Evaluation of an Alternative Solid Dosage

Form to Enteric Coated Pellets Containing Ibuprofen” summarises the results of work which has shown that minitablets are a good alternative solid dosage form to pellets.

In the Regulatory and Market section, Bob Tilling at Kallik within his article titled, “The New Regulatory World for Medical Devices. Establishing an Effective Compliance Strategy Now Ahead of the 2022 IVDR Legislation” describes the top compliance challenges manufacturers must address and how digital platforms can support ongoing compliance efforts.

Within the Clinical & Medical Research section, Jürgen Hönig at PharmaLex GmbH, within his article “The New Normal: How COVID-19 Became the Catalyst for Change”, presents findings from a roundtable Welcome to the final edition of IPI of the year 2021. We have had a challenging year, where we had to navigate a lot of unknowns, and get used to the new normal.

But due to the diligence of our industry, we all hope that we can overcome this challenge and come out to a better future.

From this issue of IPI, we have added a new section from this issue of IPI called HEALTH OUTCOMES. Defining health outcomes can be a major hurdle in progressing to collecting and using outcomes data. There is yet no standard definition of health outcomes internationally. It is important to distinguish outcomes from outputs. Health outputs have been the traditional way to quantify healthcare delivery and are an important source of data but do not provide the information required to measure value and improve healthcare. Outcomes include patient-reported measures about patients’ care and specific data about the efficacy of the treatment patients receive in addressing their condition.

Health outcomes, although not defined precisely by clinicians, are understood in a similar way. According to Australia’s New South Wales Health Department, a health outcome is the: “change in the health of an individual, group of people or population which is attributable to an intervention or series of interventions”. This definition is helpful because it makes clear that determining health outcomes,

hosted by PharmaLex. It examines how life science professionals leveraged disruptive technologies during the pandemic.

A very interesting article in the Packaging section

by Adrian Collins, Production Manager at Almac Clinical Services, titled “The Importance of Clinical Trial Packaging and the Benefits in Outsourcing your Small Molecule packaging to a CDMO” discusses how operating a clinical trial in what is a tightly regulated industry requires comprehensive, big picture thinking.

Risks remain at all stages of the clinical supply chain, and they can make the difference between a successful study, or no study at all.

I wish you all a very Merry Christmas and A Happy New Year.

Lucy Robertshaw, CEO LucyJRobertshaw first and foremost, involves measuring a change.

Secondly, they can relate to individual patients or entire populations and finally, the outcomes are related to specific interventions.

Following the lead from the International Consortium for Health Outcomes Measurement (ICHOM) this section will discuss measures to transform health care systems worldwide by measuring and reporting patient outcomes in a standardised way, define Standard Sets of outcomes per medical condition, and then drive adoption to enable health care providers globally to compare, learn, and improve.

In this issue we feature an article by, Ben Routley of Bioscript/Mark Pringle of NeoHealthHub titled, “Behavioural Science: An Untapped Opportunity for Medical Affairs” where they examine how the use of behavioural science techniques (BST) can improve the impact of client communications. BST has been a pivotal part of the guidance issued by the Scientific Advisory Group for Emergencies (SAGE) and of the strategy of the UK Government during the Covid-19 pandemic, and because of this, the practice has come into sharper focus. The more forward-thinking pharma organisations are now starting to embrace this form of customer engagement.

I hope you all enjoy this issue of IPI. I wish you all a wonderful festive season and look forward to meeting you all in 2022.

Virginia Toteva, Editorial Manager – IPI

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research, Center of MCH, Astana, Kazakhstan

Georg Mathis Founder and Managing Director, Appletree AG

(Singapore, Shanghai) Steve Heath, Head of EMEA – Medidata Solutions, Inc

Catherine Lund, Vice Chairman, OnQ Consulting

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

Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories

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

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

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

Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research

Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group

Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Maha Al-Farhan, Chair of the GCC Chapter of the ACRP Stanley Tam, General Manager, Eurofins MEDINET

Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stefan Astrom, Founder and CEO of Astrom Research International HB T S Jaishankar, Managing Director, QUEST Life Sciences Winter 2021 Volume 13 Issue 4

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Regulatory & Marketplace

How to Coordinate Your Site Selection With State Economic Development Where are your labs located? Development/pilot/clinical material facilities?

Commercial plants? If these do not exist, where should you build them?

If outsourcing, where are your CDMO’s facilities located?

Some answers depend on even more elemental questions: Where would you like to live and work? Where might your future employees be concentrated, most easily recruited, and retained?

As they say: Location. Location. Economic Development.

Well, that’s what we should say.

Happy about it or otherwise, many readers will face a level of “site selection” – some of you coming face-to-face with economic development agencies at state, regional or local levels.

•

What should you expect? Fundamentally, economic development officials should have the capability to:

•

•

guide from beginning to closure your decision-making for the selection of a greenfield or existing structure, or to expand a facility (maybe even at your CDMO)

•

•

inform you on details such as whether utilities stop at the street or run up to a site, there’s redundant energy sources, and a sufficient water supply provide data on items regarding airports, traffic, and weather navigate state/local taxes, financial and other incentive packages, and other agreements clarify workforce strengths/weaknesses, and provide entrée to training resources

The above and more should be provided via organised and efficient key point(s) of contact.

First Things First Kimball Hall was an executive at Amgen and Genentech before becoming COO of CDMO Abzena. At all these positions she’s been directly involved in strategic, and ultimately successful, site locations.

Hall starts by telling me of a key decision her global (U.K.-based) company took prior to reaching out to U.S. states for assistance: they would locate their new production facility in the U.S., but not at their current location in San Diego.

This type of internal clarification – even if it is only “somewhere in Europe” – is helpful before getting started in earnest.

Then, subsequent to a conversation with Bullock about the site selection process in North Carolina, Hall says the state dedicated a two-person economic-development team to extend the conversation and help initiate a search.

As is the case for most life science companies considering expanding in

Most recently, she was instrumental in site selection project for Abzena, in North Carolina.

Kimball Hall 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

An initial connection on that project was Bill Bullock, Senior Vice President, Economic Development and Statewide Operations, North Carolina Biotechnology Center (NCBiotech). Bullock has been assisting biopharma-industry companies for over 20 years.

Bill Bullock Winter 2021 Volume 13 Issue 4

Regulatory & Marketplace NC, professionals from the Economic Development Partnership of North Carolina (EDPNC) and NCBiotech formed a team to support Abzena’s site search.

"I presented our overall search parameters to the NC team," explains Hall. "Together we ended up covering a good portion of the state, which afforded me an understanding of a wide availability of property." A specific need-to-know for Hall: Could each candidate location meet all her timelines from a permitting perspective?

tightly connected to the entire life science industry.”

“We keep asking them: ‘What else do you need? How are things going?’ And they are almost always willing to talk to a new company considering locations in the state.”

Lower Pressure, Higher Returns Bullock says it’s a “massive advantage” for biopharma companies to have organised and coordinated economic entities when working with states for facility locations.

She appreciated that the NC team "remained agnostic to where you end up in the state."

What you do not want, he says, “is a myriad of local or regional contacts to start with.”

“Their job,” she says, “is to present you to the facilities – and to the townships and localities – to get you answers.”

“It gets unwieldly. Some don’t know where other appropriate sites might be.

You end up with county commissioners and different incentives and narratives.”

That’s the path to narrowing your decision-making process and pointing you to locations to focus on.

Only subsequent to the above – a point Bullock also made in our conversations – does a focus also fall on financial and incentive programs.

Money talks, but it does so later in the process than perhaps one might expect.

“This creates a fair environment for all the counties and sites in the state, and most importantly, for the biopharma company to end up with the location that works best,” explains Hall.

“I've done this a few times in my career,” she continues. “You go to the states you are interested in and have these conversations.

They lead to introductions to different properties, nearby universities, worker training programs, and other aspects.”

“I also like to talk to the engineering companies in the areas. And others in our industry located there. I ask them: ‘What was good, what was not, and what were your hiccups?’”

Bullock, for his part, continually emphasised this ability and willingness to broker introductions to the established biopharma community as a key component of economic development.

“We’ve worked with most of the companies here, some for many years,” he explains. “Part of our mandate is to stay wwww.international-pharma.com

Instead, as in the case of Abzena and Hall, who Bullock new from prior site-selection activities (there’s those connections), the company could initiate the process on a “much lower key level.”

“A general conversation, really,” Bullock explains. “She says, ‘We’re looking.’ I say ‘perfect.’”

Bullock informs me NCBiotech is actually an independent 501C3 non-profit – not a government agency but funded primarily from a state appropriation.

“Our team knows the entire economic development community here. We know the life science community. We know her language. We meet our clients right where they are within their site selection stage.”

He mentions another example of a relationship leading to success.

The initial call he received from Fuji DIOSYNTH about their recent NC expansion also began as a general conversation.

“Our first exposure to the project was really around an idea and a discussion with their point of contact about possible location options, fit, and process should anything move forward.

“The goal is to bring value to companies by providing a partner to build sustainable relationships. We act as an ongoing connection that offers knowledge of life

sciences with rich partnerships within the economic development community.

“Companies should be comfortable with the economic development process given the importance of the decisions at hand.”

Louis Garguilo Louis Garguilo is chief editor and conference chair for Outsourced Pharma, and a contributing editor to Life Science Leader magazine. He studied public relations and journalism at Syracuse University. Among other positions, Garguilo spent a decade at a global pharmaceutical contract research, development, and manufacturing organisation, and served under the governor of New York in the state's economic development agency, as liaison to the pharmaceutical and biotechnology industries.

Email: louis.garguilo@lifescienceconnect.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 9

Regulatory & Marketplace

Preparing for FDA Remote Inspections: What to Expect for 2022 In March 2020, the U.S. Food and Drug Administration (FDA) made a groundbreaking announcement in response to the COVID pandemic; they would indefinitely pause most foreign and domestic inspections. That stopped many life sciences companies in their tracks, including those creating products in response to the pandemic (such as PPE, test kits, etc..). As routine audits and inspections are critical to bringing products to the market, the FDA announcement left companies scrambling, with millions of dollars and even lives on the line.

With no clear protocol for resuming inspections amid ever-changing pandemic guidelines, the FDA slowly began to roll out limited high-priority domestic inspections in Summer 2020. Over a year later, the FDA is still prioritising mission-critical work, with no transparent plan on what the future will hold. Clearly, the organisation faces a staggering backlog. FDA inspections decreased by 56% in fiscal 2020 compared to previous years. While the FDA did not halt altogether, only three international and fiftytwo domestic examinations were considered “mission critical” between March 2020 to October 2020.

As the world begins cautiously opening up, the FDA has a big problem to solve.

Approximately 23,297 total inspections remain through 2021, 857 of which are for drugs and pharmaceutical companies.

Understandably, the FDA faces significant pressure from the government on how and when the agency will address the backlog. Although a bipartisan group of lawmakers from the House Energy and Commerce Committee released a statement acknowledging that COVID-19 will likely impede in-person inspections throughout 2021, the government is still trying to get ahead of the issue in the form of legislation.

Last month, the House Appropriations Committee released its budget for the fiscal year 2022, which provides a $257 million increase in funding for the FDA. The funds will be used over several categories, notably 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

increased inspections (foreign unannounced and high-risk), data modernisation, and drug safety surveillance and oversight.

The government will allocate an extra $5 million specifically to increased inspections, including unannounced foreign inspections.

The bill includes the following statement on the topic: “The Committee continues to believe that physical inspections, especially when unannounced, are one of FDA’s most important tools to ensure drug safety and quality. While COVID–19 has understandably delayed many routine inspections abroad, the Committee is concerned that FDA may not prioritize physical inspections as highly as other regulatory review methods.”

The bill also endeavours to reduce regulatory barriers and slowdowns through data modernisation and enhanced technologies. Specific budget will go to expanding the scope of emerging technologies to spur innovation throughout the regulatory process.

While the exact inspection protocol may still be murky, the expectations are clear: 2022 FDA inspections will take an entirely different face. There is inherent pressure on life sciences companies to ensure preparation. A failed inspection could mean substantially longer delays in manufacturing and bringing products to market with such a backlog. How can companies use the tools at their disposal to best prepare when their time comes?

One way companies can prepare for the future of FDA inspections is through Virtual Inspection Training. Virtual Inspection training combines remote presence technology with an expert FDA or regulatory consultant agency to prepare global teams before an audit. A mock audit, conducted by an industry expert, aligns members of international groups to get everybody on the same page. These protocols boost employee knowledge of what it is like to work with actual FDA auditors long before the day of their inspection. Virtual inspections are also a convenient and cost-effective method for performing internal inspections as well, and

many companies had to switch to a virtual protocol during the pandemic.

Virtual inspection training requires the right kind of technology to give global teams and auditors the feeling of being present.

If experts or mock auditors are tuning in remotely, the quality of their consult lies in their ability to see an entire space. During the worst parts of the pandemic, companies substituted in-person internal audits with standard videoconferencing platforms, such as Teams or Zoom, to conduct an inspection.

However, these platforms were designed to conduct face-to-face meetings and are not optimal for showing attendees a physical location. Since standard videoconferencing POV is relegated to where the host points the camera, it limits the freedom that auditors or guests have to explore an area and inspect finer details.

When considering the right tools for the job, there are several features to consider to optimise quality and results. Most importantly, technology that enables: • •

•

•

•

A 360-degree view of a facility or environment is crucial to seeing the complete picture.

Autonomous viewing. With 360-degree, remote viewers can take advantage of autonomous viewing to select their own viewpoint, thus providing an extra layer of confidence.

Collaboration. Another way to align participants and create a seamless experience is to ensure your technology provides document and checklist collaboration. With this feature, session hosts can quickly and easily pull up a checklist or other important document in real-time without interrupting the tour.

Session recording is key to eliminating any doubt or questions post-meeting.

Auditors can double-check details, spaces, or discussions for quality assurance.

High-Resolution. It is counterproductive to sort through lagging video and pixelated imaging.

When the time comes for a virtual inspection, either for practice or internal Winter 2021 Volume 13 Issue 4

Regulatory & Marketplace

reasons, there are a few unique steps to keep in mind.

1. Prepare in Advance It may go without saying, but the key to a successful remote audit is meticulous preparation. Careful prep holds true even for remote audits. While remote audits provide a high level of assurance and detail, it’s essential to take extra care to ensure the session runs seamlessly.

Before the inspection, be sure to identify the goal of the inspection and any SOPs or documentation needed. Prepare and share necessary documents or briefings two to three weeks before the audit. It is also essential to determine the schedule and length of the inspection well in advance.

Remote reviews are beneficial in that they can bring global teams together without the need to travel. However, it is still vital to adhere to a strict schedule to respect the participants’ time and ensure everything can be covered.

Furthermore, since the quality of a remote inspection rests in part on the quality of the virtual inspection technology, it’s absolutely critical to consider internet access.

Proactively validate the facility’s connection quality by performing a bandwidth test before the session. Be sure to consider LTE wireless connectivity if needed. Finally, align on data and recording protocols. Bearing in mind the confidentiality of a facility, wwww.international-pharma.com

confirm that recording is allowed and remain transparent in how data is recorded and shared.

To guarantee preparation, it’s not a bad idea to reconfirm the above details a few days before a session is to take place.

2. During the Audit Whether for practice or to perform an internal audit, begin the session by aligning on scope and purpose. Cohesion is especially important with global teams and other stakeholders coming together around the world. If utilising a virtual inspection platform that allows for realtime collaboration, pull up any relevant documents or checklists so that all guests feel like they’re on the same page.

3. Close Out Transparency and trust are key to a successful audit, both before and after the session. After completing the mock or internal audit, take an extra moment to discuss relevant observations, follow-up steps, and reporting processes.

Assessment: The Future of Audits and Inspections If there’s one thing 2020 taught the world, it’s that the road ahead is ever-changing.

Given the Delta variant on the rise and the significant backlog of FDA inspections, it is unclear when and how the agency will resume a regular inspection protocol. One

thing, however, is certain; the government wants to move the needle along and make tangible progress in addressing the backlog.

With the government boosting unannounced inspections and considering bringing remote technology into the regular inspection protocol, it is clear times are changing.

Companies’ best chance at adapting to the new reality is to be prepared and open to alternative technologies.

Devon Copley Devon Copley, co-founder and CEO, Avatour. An expert on live immersive technology, Devon has more than 20 years of experience in online media and VR. Previously, he was Head of Product for the Nokia OZO VR platform, where he expanded the OZO ecosystem to include live VR broadcast, next-generation immersive delivery, and multi-platform playback. Earlier, Devon co-founded the online media consulting firm Interocity (acquired by Chyron) and was VP of Customer Success at the leading cloud video platform Kaltura. Devon studied Computer Science and Theater at Yale and was a Sloan Fellow at the Stanford Graduate School of Business.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 11

Regulatory & Marketplace

The New Regulatory World for Medical Devices

Establishing an Effective Compliance Strategy Now Ahead of The 2022 IVDR Legislation – Because There’s More to Come No sooner than medical device manufacturers have completed their MDR compliance project, they must prepare to adapt products, labelling and artwork to comply with upcoming IVDR counterpart legislation. Set for implementation in May 2022 and to be followed by more waves in 2023, 2025 and 2027, IVDR will require many businesses to begin the compliance cycle from the start again, to ensure they can continue to sell in vitro diagnostic products into the lucrative EU market. Many of these challenges will mirror MDR efforts – with lessons to be learned and technological innovations ready to ease the process.

Here are the top compliance challenges manufacturers must address – and how digital platforms can support ongoing compliance efforts.

The EU’s In Vitro Diagnostic Regulation is set to be implemented in May 2022, but for many in vitro medical device manufacturers, the follow-on UDI implementation deadlines – Class D in 2023, Class C and B in 2025, and Class A in 2027 – will have greater repercussions. Over 80% of devices not requiring certification under the previous IVDD (In Vitro Diagnostic Directive) will now require IVDR certification, affecting quality management, traceability, packaging and beyond. Product labelling and artwork for these devices will need to be adjusted accordingly.

IVDR compliance is simply non-negotiable – and as many manufacturers found during the MDR deadline rush, it cannot be left until the last minute. Failure to comply can bring catastrophic damage to a business, ranging from financial pressures and endto-end operational disruption through to irreversible damage to consumer confidence and brand reputation.

Early Action Solves Many Pain-points A key lesson learned by many medical device manufacturers during their recent MDR compliance projects was the need to get started with planning and execution at 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY

the earliest possible stage. Companies that chose to ‘go it alone’ and push ahead with manual processes, legacy in-house systems and no external compliance expertise often struggled as the scale and complexity of the task became apparent.

IVDR is further complicated by various regulatory nuances and major differences between medical and in vitro device artwork, including layout design changes to accommodate increased traceability information such as Unique Device Identifiers. The sheer volume of work this requires means manufacturers that take IVDR compliance as a critical business issue and prepare a best practice compliance project will stand a greater chance of succeeding, without it absorbing capacity or affecting day-to-day operations.

Here are our four essential tips for medical device manufacturers still considering how to plan and deliver on IVDR compliance projects: 1. Unexpected Complexity: The Silent Threat to Compliance Projects No two IVDR compliance projects are identical in scope. It is vital that businesses get to grips with the scale of their compliance task as early as possible, identifying affected in vitro devices and their labels and artworks – across their entire global operations and supply chain. Judging by the scale of recent MDR compliance projects, affected assets may number in the low thousands through to several hundred thousand – so the volume of work must not be underestimated.

The common offenders for unexpected assets? Siloed data in legacy departmental systems, disconnected regional offices and even new product lines introduced by mergers and acquisitions – all of which can drastically increase the scope and timeframe of the project once identified.

Product translations and global supply chain nuances also pose unexpected challenges during the assessment phase.

Global businesses will need to amend each label and packaging asset in various languages, significantly increasing the scale of work. The EU market alone currently has

24 official languages – amending individual phrase translations on each device in a product range for each of these languages significantly scales up the time and capacity required to achieve compliance.

2. Putting Digital Eyes on the Assets: Standardisation and Accessibility are Key Once manufacturers have identified affected assets and standardised their associated data, attention can turn to identifying and actioning specific changes that must be made to each label and artwork to achieve compliance. These can range from label sizing and placement, to warning symbol positioning and UDI inclusion – with the ever-present threat of further changes to accommodate translations and countryspecific regulatory requirements.

This is where digital solutions such as a centralised label and artwork management platform can add significant value to the process over manual work. For example, a comprehensive ‘Where Used’ feature can help users rapidly identify all labels affected by design changes and act accordingly.

Manufacturers that establish approved label templates within their label and artwork management solution can use this feature to easily make changes to all labels in a product range – removing the burden of committing physical resources to painstakingly identify and update each affected asset.

3. The Outliers – Bring Scattered Global Operations under Central Control Identifying every affected asset and introducing standardisation within a manufacturer’s global business footprint is a major step towards compliance, but businesses should also look to consolidate these assets into a single central source before actioning changes. Managing the edit, review and approval stages across various systems and departments is both inefficient and threatens to introduce costly version errors, further delaying the compliance process. Working centrally unlocks significant efficiency, oversight and management benefits.

Business leaders struggling with disconnected legacy systems should consider adopting a central cloud-based label and Winter 2021 Volume 13 Issue 4

Regulatory & Marketplace

artwork management solution to avoid these pitfalls. These solutions typically provide a singular asset library to consolidate artwork, logos, phrases and other critical product data. This ‘single source of truth’ eases the monitoring, editing and management burdens and helps businesses focus solely on dedicated compliance work through label editing without needing to continually identify, gather and share assets between systems and teams for each amendment.

4. Beating the Capacity Crunch with Automation One of the key takeaways from initial MDR compliance projects is the inefficiency of many manual processes for updating assets when compared to digital alternatives. As the scale of these compliance tasks increase and new regulations are announced, the processes become unacceptably slow, expensive and inaccurate – and risk introducing human error.

Deploying a cloud-based, centralised solution that leverages automation can eliminate much of the uncertainty caused by manual processes, and help companies wwww.international-pharma.com

avoid committing the bulk of their workforce to IVDR compliance efforts. The result is an efficient operation, following best-practice procedures, providing a certain outcome.

These solutions can also harness rulesbased automation to eliminate the need to manually search for, update and republish assets to ensure compliance, and deliver significant cost and capacity savings that scale over time.

Regulation is not a One-off Process: Act Today to Ensure Continued Compliance While these actions can significantly ease the IVDR compliance process, this is by no means the end of the regulatory curve for the medical device industry. MDR and IVDR have brought major operational changes, but further national and regional regulation is on the horizon. Further changes such as the shift from CE marks to UKCA markings in Britain – with further nuances for the Northern Irish market – are posing similar challenges.

This is why manufacturers are wellplaced to establish a digitally driven process for regulatory compliance and future

developments, tackling the pain points of today and preparing for the challenges of tomorrow with technology that will deliver continuous operational improvements.

As witnessed in MDR and IVDR projects to date, digitisation of label and artwork management processes on a global scale will be at the very centre of this strategy.

Bob Tilling Bob Tilling is the VP of Global Sales at Kallik, an enterprise labelling and artwork management company. He has a wealth of knowledge when it comes to the life sciences industry, particularly regarding medical devices. Bob helps businesses in highly regulated industries begin their journey of transforming their labelling and artwork management.

Email: bob.tilling@kallik.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 13

Regulatory & Marketplace

Hyper-collaboration in Healthcare and Life Sciences – The New Paradigm The COVID-19 pandemic demonstrated the ability of the healthcare and life science industry to respond to unexpected needs with unprecedented speed. However, independent of the pandemic, the industry was already facing transformation in light of multiple, highly disruptive innovations, not only in the traditional field of drug modalities, but also in related fields such as digital, AI, data and medical devices. This new “Future of Health” is driven by a multitude of new players and innovations with disruptive potential and new ways of thinking about health, at both a large scale for population health and an ultra-targeted level through the potentially curative treatment of individual diseases, such as for CAR-T or gene therapies and precision medicine.

The industry’s response to the pandemic and its transformation towards the Future of Health may at first seem unconnected, but they share the same foundation – innovation is no longer driven by one or two companies, but rather, by a large number of players in an extended partner ecosystem, requiring collaboration at an unprecedented scale.

Driving innovation at speed requires all players to think and act in large “hypercollaboration” networks.

Although hyper-collaboration itself is not new, it is now becoming central to success in a growing number of sectors. Companies that fail to change and adapt risk being sidelined by newer, more agile players.

The remarkable success of small biotech companies in beating established players in the race for a COVID-19 vaccine is just one recent example of this trend. In this article we look at how hyper-collaboration is now becoming a key success factor for the healthcare and life science industry, and draw some lessons on how to make it work effectively. These lessons are also relevant for other highly complex industries with new and potentially disruptive players, such as aerospace, transportation and finance.

A Fast-evolving Landscape Creates a Need for Hyper-collaboration Innovation is happening at a faster pace than ever, with digital and data-driven technologies alongside new molecular treatments disrupting the healthcare and life sciences industry and causing new players to emerge. This is manifested through a greater ability to combine basic research and large data approaches to rapidly improve understanding of the human body and diseases, as well as new tools to develop and deliver medications in terms of both biological tools (such as CRISPR gene editing) and hardware such as robotics and 3D printing. The time from

discovery to clinical concepts has therefore shortened significantly, with a multitude of new concepts rapidly emerging and moving into usage.

Innovation across the sector is also becoming much more complex. The industry has moved from being dominated by seemingly simple chemical molecules that could be applied as tablets or solutions, such as aspirin, to the introduction around 20 years ago of more complex biological compounds such as recombinant proteins and antibodies (e.g., Insulin or Herceptin®).

These have been driving much improved treatments for diseases such as diabetes and cancer, and have been a major growth driver.

Today, the landscape is changing again, with more and more complex drug modalities, including cell and gene therapies and mRNA vaccines (as seen in COVID-19 vaccines), now becoming commercially available.

The hemophilia example below demonstrates both how innovation has accelerated over the last decade and how well-established players can rapidly be made irrelevant by new and innovative approaches that are often driven by newentrant biotech companies. A further insight is that there are a multitude of radically different new treatment options on the horizon, with some uncertainty as to which technology will ultimately win. The same effect has also been demonstrated in the race for a COVID-19 vaccine, in which traditional methodologies competed with novel and largely unproven new approaches such as vector vaccines and mRNA vaccines.

Ultimately, these were more successful, but it would have been impossible to predict mRNA’s resounding success even a year ago.

As technological complexity and innovation speed increase, effective collaboration becomes central to success.

Managing Greater Complexity in Ecosystems Oncology (the treatment of cancers) is a further example of hyper-collaboration and gives us a taste of the future of medicine in general as we move towards the “Future of Health”. Although cancer treatments are traditionally based on a combined approach of surgery and radiotherapy or chemotherapy, newer treatments also see

14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2021 Volume 13 Issue 4

Regulatory & Marketplace combinations with molecular therapies based on the characteristics of individual tumours. Additionally, in recent years, we have increasingly seen approaches using the activation of the immune system, either in immuno-oncology drugs or with the use of ultra-targeted cell therapies such as CAR-T. For the future, there is an expectation that treatments could well entail the use of between five and seven drugs or drug modalities in combination, which will require a network of multiple players and IPs. In addition to these complex drug combinations, future treatments will require the development of the right diagnostics and tools to analyse tumours, as well as the right support to analyse and curate the data gained to predict the right treatment for the right patient (precision medicine). With constantly improving treatments, cancer is expected to become a chronic disease and will increasingly require treatment of patients in their own homes, supported by remote monitoring. This is where innovations such as Alexa and the logistics offered by an Amazon pharmacy can bring in additional players and innovations. Again, this is a trend that was also accelerated by the pandemic, when immune-suppressed cancer patients were rightfully scared of being treated in hospitals with COVID-19 cases. This results in significant complexity challenges when it comes to organising clinical trials, and also raises questions around the management of IP in order to make collaborations more attractive for small biotech or medtech players, as well as large pharma or tech companies.

How Hyper-collaboration Helped Develop The COVID-19 Vaccine in Record Time Innovation success not only depends on picking the right solution from a widening number of potential treatment options, but also on hyper-collaboration between multiple players and biotech companies.

The development of COVID-19 vaccines is a best-practice example of how companies have tapped into new types of partnerships and technology to successfully bring novel pharmaceutical products to market in record time. During the first half of 2020, hundreds of promising COVID-19 vaccine candidates entered preclinical trials. The majority of these candidates were co-developed by pharmaceutical companies, academic research institutes and governmental agencies, such as AstraZeneca and the University of Oxford, Arcturus Therapeutics and Duke-NUS Medical School, and Moderna and the American National Institute of wwww.international-pharma.com

Allergy and Infectious Diseases (NIAID).

Partnering in such constellations secured joint access to quality research, as well as drug development capabilities and funding.

Of the four established global vaccine powerhouses (Pfizer, Merck, GSK and Sanofi), only the first actually delivered an effective solution – but solely by choosing an unproven technology (mRNA) in a new partnership with BioNTech. The other three major vaccine makers stuck with proven methods involving much longer timelines and failed to get the same results. Merck abandoned its trials, while Sanofi increased investment in mRNA technology, but not for COVID-19 vaccines – it has ceded that to the frontrunners. GSK built out its partnership with CureVac, another company focused on mRNA technology, and although that partnership is in place, the development outcomes have been underwhelming so far.

So what did Pfizer do differently to succeed, not only in the vaccine field, but also by becoming a major player in mRNA technology through its partnership with BioNTech? It acted decisively in mobilising its resources toward developing an mRNA vaccine. It bet on an unproven technology and an untested partnership with BioNTech.

The partnership was started on a handshake, and the contracts followed later – which is highly unusual in drug development. In contrast, Merck’s CEO declared early on that timelines of less than a year were unrealistic, and it stuck to its existing development methodology. Pfizer also recognised that

the global need and urgency changed the environment, with risk and short-term return becoming less important. It went all-in for the “moon-shot” challenge of a six-month vaccine development timeline, “doing the right thing” while also playing the new circumstances well and taking full advantage of regulatory flexibility. Finally, Pfizer leveraged the partnership with BioNTech optimally, which is clearly the other big winner in this story. Well before the final terms of the partnership were hammered out, investments were made and confidential information shared because of mutual trust from working together previously.

The Importance of Ecosystems However, Pfizer’s success was not due to a single partnership – there was a whole ecosystem behind it. This included the Chinese researchers who shared the genetic sequences of the COVID-19 virus (which made the fast development of all vaccines possible), the designers of the boxes that allowed vaccines to be shipped and stored at ultra-cold temperatures, and the developers of the lipid nanoparticle vesicles, which deliver the mRNA to the cells in the body. Most importantly, as vaccine candidates moved from preclinical into clinical trials, their developers began to establish additional partnerships with vaccine manufacturers to secure large-scale production capabilities. Given the huge demand, this required partnerships with up to 20 different contract manufacturers for each vaccine, which brought significant challenges around complexity and scale.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 15

Regulatory & Marketplace The hyper-collaboration extended beyond traditional contract manufacturers, as their capacity remains insufficient. This has given rise to a new type of innovative partnership, in which pharmaceutical companies offer their spare capacity to their own competitors.

For example, Sanofi conducts fill-and-finish activities for BioNTech, while Novartis, which no longer has a vaccine business, produces vaccines for Pfizer-BioNTech and CureVac. Of course, Pfizer was not the only winner in the vaccine race, and others also achieved great success due to collaboration. For example, Moderna accelerated its strategy by three to four years and was close on the heels of Pfizer with a highly effective vaccine, which is being produced at large scale by Lonza through a 10-year strategic collaboration.

It saw its share price increase twentyfold.

AstraZeneca was not an established name in vaccines before the pandemic, but it (rather than UK rival GSK) moved fast and quickly established a collaboration with the University of Oxford, and delivered an effective vaccine within the year.

Lessons on Managing Extended Networks Effectively Although alliances are not new to the healthcare and life science industry, their current scale and complexity are, and this will only grow rapidly in the near future.

Instead of traditional bilateral networks, partnerships and alliances will often require involvement of multiple players, including biotech, pharma, medical device and health tech companies, as well as academia, payers/providers and even regulators. This makes it critical to be able to successfully manage not only one or two collaborations, but a network of hyper-collaborations. The same is also true for other highly regulated industries, such as telecommunications and utilities. Hyper-collaboration brings

16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Alliances are collective efforts to achieve a common goal, with each party contributing certain capabilities/ innovations/technologies. Accordingly, it is imperative to clearly define the purpose, strategy, and vision of an alliance and the key elements needed to achieve the goal. When building or entering an alliance, each player needs to understand its role and position, as well as the role of the other parties involved and what each should contribute in terms of human resources, cash, knowledge, IP, and equipment.

multiple benefits, including shared risk, reduced cost, greater utilisation of unused IP, better access to funding and talent networks, more innovation capacity, and improved transparency and trust with patients.

However, there are also challenges, including alignment of goals, objectives and incentives; tracking progress across multiple partners; managing IP; standardising processes around data collection, annotation and sharing; and logistics.

Like any stress test, the pandemic has shone a spotlight on how well – and how badly – businesses are set up to respond to disruption. Executives should be wary of writing off the pandemic experience as a “one-off”, and instead make the most of it to bring about essential and valuable change.

Alliance management is different from project management, requiring a strong focus on governance, communication, culture, problem solving, and conflict resolution. All types of partnerships and collaboration need a well-designed steering committee that oversees the research plans, governs the collaboration, and ensures compliance. This is a key success factor to prevent and solve problems early on to build the relationships, agree on and manage intellectual property, and set the overall objectives of the collaboration. As the partnerships, alliances and networks grow in complexity, the role of the steering committee will become increasingly important for success, as it sets the foundation for collaboration on all levels.

We can draw some lessons from those companies in healthcare and life sciences that have been successful in pursuing hyper-collaboration: •

Alliance purpose, strategy and vision – What to look for in an alliance:

•

Adequate alliance management: With a multitude of different players involved, it will be complex to align the overall objective and make sure all players work towards the same goal. Problems that occur need to be quickly and efficiently resolved, and it is essential to ensure compliance from each party involved. The alliance management and governance structure need to be clearly defined and agreed at operational, tactical and strategic levels. Sufficient resources with the right capabilities need to be allocated to manage the partnership. Specific areas of focus should include information and data management, IP management, commercialisation of outputs, and operational models.

•

Fair risk and benefit allocation – A new business model?: All parties involved need to be adequately incentivised to contribute. With collaboration partnerships becoming more diverse, greater attention needs to be paid to relevant risk-/benefit-sharing models. With a large amount of IP and innovation involved, this will require

Winter 2021 Volume 13 Issue 4

Regulatory & Marketplace new and innovative business models to share development, launch and production risks, while also offering fair compensation models outside traditional IP and patent approaches.

•

Cultural change – From competition to collaboration: Collaborating in alliances requires a different mindset and culture. To make network- and alliance-based collaboration models work, companies need to adopt an open mind-set to share knowledge, data and information, while at the same time protecting key assets. Assess whether your corporate culture encourages

Dr. Franziska Thomas

•

enough entrepreneurial risk-taking, and if not, how it can be changed.

Assess and improve your agility: Companies should learn from their pandemic experience to understand their current level of agility and what can be done to improve it, as well as assess organisational set-up and culture from an “ambidextrous” perspective – can scale/productivity capabilities and speed/creativity capabilities be delivered in a balanced way?

Although none of these factors alone may seem completely novel, the need

Ben van der Schaaf

Dr. Franziska Thomas is a Partner at Arthur D. Little’s Frankfurt office and Head of Healthcare and Life Sciences for Central Europe.

to be proficient in all of them has now become central to companies that want to remain relevant leaders in their fields.

Healthcare demonstrates this – in the recent pandemic we have seen examples of big players being sidelined by small biotech companies or competitors that were able to build meaningful alliances, such as Pfizer and AstraZeneca. In the future, corporate success will depend on having the capability to build, maintain and drive complex networks of alliances and collaborations that are attractive to all players – will you be able to shape the future, or will you be relegated to the margins?

Dr. Ulrica Sehlstedt

Ben van der Schaaf is a Partner at Arthur D. Little’s New York office and a member of the Healthcare and Life Sciences Practice.

Dr. Ulrica Sehlstedt is a Managing Partner at Arthur D. Little’s Stockholm office and Global Leader for the Healthcare and Life Sciences Practice.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 17

Regulatory & Marketplace

It’s Now Time for Your OPDP Submissions to be FDA Compliant | Are You Ready?

Post Marketing

The FDA generally recognises two types of labeling for a Product: 1. Labeling required for Product Approval – Prescribing Information, Package Insert/ Patient Information, and Structured Product Labeling, etc.

Office of Prescription Drug Promotion (OPDP)

Submission Type

OPDP Submissions (or) Ad Promo Submissions (or) 2253 Submissions

Submission Requirement

2. Promotional labeling – Advertising materials, television advertisements, brochures, booklets, detailing pieces, websites, print advertisements, sound recordings, and radio advertisements, etc.

Effective from June 24, 2021, the FDA have made it mandatory that the following Office of Prescription Drug Promotion (OPDP) submission types will only be accepted in eCTD format and may only be submitted through the Electronic Submissions Gateway (ESG) as per Section 745A(a) of the Food, Drug, and Cosmetics Act.1

Document Requirement

Best Practises | 2253 Submissions Form 2253 • The current version of the fillable Form 2253 must be used • Include the appropriate NDA, ANDA, or BLA number • For OPDP, ensure that submissions that require correspondences are addressed for the attention of the OPDP Project Manager.

• On Form 2253, Section 13 titled “For CBER Products Only”: • For OPDP Submissions: Do NOT check the “Draft” or “Final” boxes • For Advertising and Promotional Labeling Branch (APLB) Submissions: Check the “Final” box only for Final post-marketing submissions • On Form 2253, Section 2 titled “Application Information”: • For a Single Product: Submission should include product details of only one application number • For Multiple Products: Submission should include lead application 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

•

Accelerated Approval Office of Prescription Drug Promotion (OPDP) and Advertising and Promotional Labelling Branch (APLB)

Submitted to

Specimens of labelling and/or advertising material devised for promotion of the drug product

Fillable FDA form 2253 Copy of the product’s current professional labelling Promotional material(s) Firms are encouraged, but not required, to submit annotated versions of the promotional material(s) cross-referenced to the product labelling and references, if applicable

details and attach separate sheet that identifies the other referenced products (e.g. application type and number, trade name, and established name).

For 2253 submissions to OPDP, if a drug has multiple approved indications that are covered by different reviewers in OPDPi,firms should submit (when possible) promotional materials that only promote one indication separately from promotional materials that promote only another indication.

In such cases, firms may choose to communicate the indication being promoted in the promotional materials in the Comments section of Form FDA 2253

Others • Do not include Form FDA 356h for submissions to OPDP or Advertising and Promotional Labeling Branch (APLB) • Professional and consumer materials should be submitted separately and should not include a cover letter or correspondence.

• • • • •

Accelerated Approval Pre-submission Pre-approval review period: copies of all promotional materials intended for dissemination or publication to be submitted within 120 days following marketing approval (Launch) After 120 days: Submit promotional materials at least 30 days before the intended time of initial dissemination of the labelling or initial publication of the advertisement (non-launch) For draft promotional materials submitted to APLB under 21 CFR 601.45, use Form FDA 2253 with Section 13 titled “For CBER Products Only” checked as “Draft” Cover letter stating that it is a presubmission of promotional material(s) for an accelerated approval product, Applicant should mention clearly in cover letter whether the application is for Launch or Non-launch material and subject line should include “Request for Advisory Comments on materials A clean version of the draft promotional material(s) that does not include annotations to the label or references An annotated copy of the proposed promotional material that clearly identifies the source of support for each claim The most current FDA-approved PI and, if applicable, the FDA-approved patient labelling or Medication Guide with annotations cross-referenced to the proposed promotional material Annotated references to support “product claims not contained in the PI” and “disease or epidemiology information”, crossreferenced to the proposed promotional material, if applicable

Do NOT include any files under Section 1.15.1 Headings when submitting 2253 submissions Promotional Materials should be included under Section 1.15.2 Promotional Material Attributes include promotional material type, material ID, and issue date Do not submit duplicate material IDs under the same 2253 submission Issue Date format should be YYYYMMDD Winter 2021 Volume 13 Issue 4

Regulatory & Marketplace Let’s look at a couple of visual examples of the eCTD structure for 2253 Submissions.

Example | 2253 Submission for a Single Product

Example | 2253 Submission for Multiple Products

Format for Submission of Promotional Materials Electronically The FDA will now only accept eCTD submission format for 2253 submissions and Accelerated Approval Pre-submissions, the submissions should be submitted through the Electronic Submissions Gateway (ESG) as per Section 745A(a) of the Food Drug and Cosmetics Act. • •

Best Practises | Pre-submission of Promotional Materials for Accelerated Approval Products • • • •

Do not use Form FDA 2253 for the submission of draft promotional materials for accelerated approval products to OPDP. For draft promotional materials submitted to APLB under 21 CFR 601.45, use Form FDA 2253 with Section 13 titled “For CBER Products Only” checked as “Draft”.

Include the appropriate NDA, ANDA, or BLA number.

For OPDP, address submissions that require correspondences to the attention of the OPDP Project Manager

Let’s look at a couple of visual examples of the eCTD structure for accelerated approval products.

Example | Accelerated Approval Products Launch

wwww.international-pharma.com

•

Applicant to submit in eCTD format using us-regional-v3-3.dtd.

Promotional Labeling and Advertising Materials for Human Prescription Drugs should comply with the following FDA guidance.

• Submissions using the eCTD Backbone Files Specification for Module 1.

• eCTD specification for file name, leaf titles, operator attributes and envelope information for Module 1.

Submission Process and Coding: • Based on the submission history, applicant should select the Submission-Type as “Promotional Labeling Advertising” and Submission-Sub-Type as “Original/ Resubmission/Amendment”

FDA Metrics on OPDP Submissions • The FDA have handled some 68,000+ 2253 submissions in 2020, with this number expected to increase in 2021. With the implementation of the eCTD submission format, both the submission and review process of 2253 submissions have become easier for the FDA and companies alike.

• The FDA work with a defined timeline of 45 days in which to complete the review of initial “Launch” promotional material submissions. Over the past 6 months, the trend confirms that the FDA can comply with their defined timeline for all launch submissions INTERNATIONAL PHARMACEUTICAL INDUSTRY 19

Regulatory & Marketplace Example | Accelerated Approval Products Non-launch

in terms of moving away from the traditional Paper/NeES format to an eCTD format.

BIBLIOGRAPHY 1.

2.

3.

4.

5.

6.

How eCTD is Proving Helpful with The Current COVID-19 Situation • The eCTD submission format requirement is helping both the FDA and submitting companies. With no requirement for the submission of hard copies of promotional and labelling materials to FDA, both the submission and review process have become easier and less time consuming.

Key Points to Consider while Submitting 2253 Submission and Accelerated Approval Pre-submission • Promotional materials which are used for promotion of product need to include the information as approved by the FDA • The application should clearly mention that the submission is for Consumer or Professional promotional materials • Firms are encouraged to submit promotional materials that promote more than one product (i.e. a multipleproduct submission) as a grouped submission, but grouping of a submission is only applicable when the application type is the same. For example, if a promotional material is

20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

•

• • •

•

applicable for both NDA and BLA, a company should submit a separate Ad Promo submission for each application type.

All references and supporting journals which are provided in the Package Insert as annotation need to be submitted under the respective section for Accelerated Approval Products Use current eCTD dtd version for building regional documents Overstatement of efficacy claims in promotional materials is to be avoided OPDP/ALPB submissions have short turnaround time which need proper planning and execution to meet the submission due date Selection of inaccurate “material type” for the Ad/Promo materials is one of the common mistakes done by company. Same language/material type should be used in all the sections of Ad/Promo submissions

It is imperative that organisations ensure that their OPDP submissions are compliant to the FDA regulations. We appreciate that there is something of a transition required

https://www.fda.gov/media/128163/download? utm_medium=email&utm_source=govdelivery https://www.fda.gov/about-fda/reportsmanuals-forms/forms https://www.fda.gov/media/83809/download? utm_medium=email&utm_source=govdelivery 2253 submissions: required by 21Code of Federal Regulations (CFR) 314.81(b)(3)(i) and 21 CFR 601.12(f)(4)) Accelerated Approval Pre-submissions: required by section 506(c)(2)(B) of the FD&C Act, 21 CFR 314.550, and 21 CFR 601.45) and Other products where such submissions are required for approval under section 505(b), (i), or (j) of the FD&C Act

REFERENCES 1.

2.

https://www.fda.gov/about-fda/center-drugevaluation-and-research-cder/opdp-ectd https://www.fda.gov/AboutFDA/Centers Offices/OfficeofMedicalProductsandTobacco/ CDER/ucm154886.htm

Prabu Selvaraj Prabu Selvaraj has over 14 years of experience in Regulatory Affairs and Operations. In his current role as Senior Manager, Prabu manages the end to end Regulatory support for a leading Top 5 Pharmaceutical Company and several small and mid-sized Pharmaceutical / Life Sciences companies. He manages a team of 100+ colleagues spread across global locations. As part of his ongoing customer engagements, he supports projects in Labeling & Artwork management, CMC Management, Submissions Publishing, Regulatory Strategy for dossier filling across various regulatory applications as per Health Authority requirements. Prior to Navitas, Prabu worked in Fresenius Kabi and Indian Pharmacopeia Commission, where he was responsible to deliver Initial Registration and Post Approval Submissions for various countries across the globe and also handled regulatory queries. Prabu has an excellent working knowledge and command in Global Drug Regulatory Registration, Approval Processes, and Regulatory Operation Tools and Systems.

Winter 2021 Volume 13 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 21

Document SPL1001 22 June 2021

Drug Discovery, Development & Delivery

The Brave New World of Rapid Drug Development

The COVID-19 pandemic has brought the topic of rapid drug development to the forefront of the life sciences sector. Ray Chohan, co-founder and VP of new ventures at connected innovation intelligence expert PatSnap, believes that we have entered the next generation of pharmaceutical development driven by new technology.

Before the outbreak of COVID-19, the time taken to develop a new drug or vaccine could take upwards of ten years. Granted, peer reviews, the roll-out of field testing and international approvals were key barriers to speeding up the process, but what is not widely appreciated is the transformation that has taken place in the area of earlystage drug research – specifically where patents and IP are concerned.

In her new book Vaxxers, which discusses the remarkable development of the AstraZeneca vaccine, Professor Sarah Gilbert explains that her team managed to develop the first working vaccine within sixty-five days, simply by trialling novel approaches that had not previously been adopted.

Gilbert stresses that during the development and testing phases of the vaccine, the same precautions that would have been followed during previous new drug trials were taken, but the research phase was effectively streamlined thanks to pioneering new technology. While the concepts of rapid drug development and personalised medicine are far from new, the pharma industry’s sequencing of COVID19’s DNA in just three days was clearly astounding, marking a defining moment for the life sciences sector and illustrating that the development process can be fast-tracked without compromising on safety.

A key differentiator in the development of the AstraZeneca vaccine was the adoption of new ways of working – namely through the adoption of technology, to reduce research time and increase collaboration between scientists.

22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

While we are not out of the woods yet when it comes to COVID-19, with the race on to stay ahead of new variants and produce a vaccine capable of providing immunity against all betacoronaviruses, we have demonstrated what is possible – and achievable – in terms of rapid drug development.

Indeed, alongside delivering one of the most significant discoveries of our time, the COVID-19 vaccine development process has taught us many future lessons that can be used to pioneer the next generation of drugs. Previously, it was anticipated that the development process of any new vaccine would cost more than $3bn and require more than a decade to reach a commercialisation point. This was all calculated in-line with the accepted parameters and established timeframes of peer reviews, the roll-out of field testing and international approvals.

Successful commercialisation has therefore proven historically very expensive and been fraught with risk. Indeed, 14 drug candidates typically fail clinical trials for every one that makes it to market.

Pharmaceutical companies have previously been unable to bring down the costs of research and development, and the pressure to adopt value-based and outcome-based pricing models has rapidly intensified.

Equally, the faster a vaccine can be brought to market, the more lives can be saved. Indeed, infectious diseases still account for c.40% of all recorded deaths worldwide.1 As such, organisations need to fail fast and fail cheap, harnessing the power of big data analysis to overhaul the current speed of research.

So how have processes changed over the past 18 months? Well, while the speed of development is well publicised, what is not universally known is the quiet revolution that has taken place in early-stage drug research, especially regarding patents and IP. Historically, vaccine development began with a very manual set of processes that took highly trained researchers months to undertake. This front-end development phase of drug development is hugely time consuming, requiring many hours of sifting

through patent applications to see if a particular molecular structure has already been registered.

Manually searching for relevant research and peer reviewed papers to see whether previous studies provide credence to current investigations is an exercise that could soak up weeks of valuable time. And, of course, the added possibility of human error – such as the misfiling of new-found data – can have a very significant impact on the early stages of progress.

This administrative burden was crying out to be automated. We simply needed the vision and technology to fix it. This data can be easily refined, filtered and sorted by clinical trial and agency, such as REACH, US FDA, Chinese FDA and more. Condensing this huge amount of data enables meaningful analysis of a particular chemical area via AI, helping manufacturers to quickly map the innovation process from investment to commercialisation.

We’ve now proven that what once took years to deliver, in terms of drug efficacy and trials, can now be delivered in a fraction of that time. Granted, the political will to find effective vaccines to combat the global pandemic was unprecedented, but the adoption of novel technologies and practices to significantly reduce time to market represents a watershed moment.

Indeed, now organisations expect data providers to be able to generate immediate answers to a wide array of business-critical questions.

From our own experience working with global pharmaceutical companies involved in the successful development of COVID-19 vaccines, the contribution of AI and machine learning cannot be overestimated. What used to take almost a year can now be delivered in just 20 minutes, using proprietary software that collates data form thousands of sources and presents it as usable management information.

The scale of automation is thus the prime driving force behind the new revolution in drug development. Technology’s ability to grind down millions of pages of data into Winter 2021 Volume 13 Issue 4

WHERE PASSION BECOMES ACTION. Whatever we do, wherever we are, we have a common purpose – utilise our strength and innovation to maximise partner value and improve patient outcomes.

WE CARE. WE CREATE. WE DELIVER. wwww.international-pharma.com ltslohmann.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 23

Drug Discovery, Development & Delivery useful information in a matter of hours, not months, is helping to enable a new age of effective vaccines and wholly bespoke and tailored drug therapies – a significant industry breakthrough. Researchers cite the variability in patients and the unique way in which individual patients respond to a particular drug as the Achilles’ heel in any drug discovery programme. After all, drugs that work identically in closely related laboratory mice don’t necessarily translate to clinical patients with their own unique and diverse needs.

Perhaps because of wider change and increasing industry awareness, biopharmaceutical research and development stakeholders are more readily focused on boosting clinical development times with data-driven approaches to reduce the amount of time taken to guide drugs through the development cycle. Indeed, combined, both small and large pharmaceutical companies brought a record 66 new drugs to market in 2020, with particular success noted in oncology and treatments for rare diseases, in addition to the tremendous achievements of the COVID-19 vaccine, and in spite of substantial industry disruption and adaptations to new working methods.2 Of course, we cannot ignore the fact that COVID-19 has been one of the world’s most serious pandemics, and definitely the most notable in our lifetime. However, it has also brought about much needed change and

24 INTERNATIONAL PHARMACEUTICAL INDUSTRY

provided hitherto unimagined opportunities for innovation, heralding the dawn of a new era which will finally see the emergence of tailored drugs, personalised medicine and reduced side effects to people across the world.

It’s hugely encouraging to see that postCOVID, medium cap and large corporations have put technology investment to the top of their budget lists. A recent survey by Pistoia Alliance (which represents most big pharma companies in the USA) confirms that AI, machine learning and blockchain will be the prime areas for investment over the next 12 months. Meanwhile, Pfizer has also noted an increase in AI investment from pharmaceutical brands.3 The average funding size in AI drug development increased from $10.7 million in 2015 to $51.7 million in 2020. In total, the pharmaceutical has already invested $2.1 billion in AI technology this year.4 In the next ten years, life science businesses will look much more like software companies, as organisations start to collaborate more in regard to research and development. In fact, we’re already seeing that shift, which is incredibly exciting. Big pharma businesses are already considering the benefits of a more open business model, where platform, data and knowledge is shared. This enlightened strategy has enabled countless phenomenal

business to become global success stories.

A similar model is developing within life sciences. We are entering a new era of rapid drug development, which is heralding a new open culture of collaboration. Big pharma corporations are assessing the advantages of a more collaborative, open style, which will see the opening up of IP access rights and allow smaller enterprises to use their platforms and knowledge to develop and deliver new drug therapies, much in the same way that the various COVID-19 vaccines were developed across the world.

Indeed, the increasing convergence of technology and healthcare will provide fresh opportunities for the industry. The areas that we believe will shape investment in the life sciences industry this year are oncology, cell and gene therapies and rare diseases.

Recombinant DNA technologies and monoclonal antibodies (mAb) are central to these sectors, providing the most potential for preventive and curative solutions. These technologies are highly expensive and require a substantial amount of investment, which is where the availability of patent protection, including the effects of recent case law, really comes into its own for firms considering this level of outlay. Subsequently, intellectual property will continue to be a high priority for the life sciences industry, as emerging

Winter 2021 Volume 13 Issue 4

Drug Discovery, Development & Delivery

technologies, personalised medicine and targeted therapies promise optimistic cures to health conditions.

Patent cliffs can also present a significant challenge to business growth, but a risk that can be mitigated through machine learning. The term refers to a situation in which a number of patents representing a large portion of sales revenue are due to expire simultaneously, allowing the market to open up and eroding share. For example, despite Pfizer’s huge success in developing the COVID-19 vaccine, its market share has risen by a mere 12% in the past year, as the brand is due to face multiple IP expirations.

Patent cliffs are therefore a highly important issue. Research predicted that more than $198 billion in global prescription drug sales were at risk between 2019 and 2024 from patent expirations.5 Indeed, a patent cliff can lead to over $100 billion in lost sales – a critical pain point for larger biotechnology and pharmaceutical companies, which have already endured huge expense and substantial start-up costs in a highly regulated industry, and that in turn may prohibit future research and development.

The pharmaceutical industry experienced its first patent cliff between 2011 and 2016, during which time hundreds of billions of brand name drugs, some of which comprised large percentages of company sales, lost wwww.international-pharma.com

patent protection. While companies can pursue options such as patent extensions and supplementary protection certificates, the risks presented by patent cliffs indicate a need for increased data coverage in patent intelligence platforms providing an insight into the life sciences.

Now more than ever, the ease of sequence searching and patent synthesis has the potential to deliver significant financial and strategic gains. For smaller companies, the ‘first-to-file’ race could be vital to company health and longevity, making efficient patent searching a priority.

Effectiveness and efficiency are vital to companies in the early stage of research and development and the strategic filing of patents, in addition to intelligent patent cliff prediction, and could mean the difference between success and closure to smaller businesses. In identifying patent timelines and potential regulatory hurdles, organisations will be able to reduce costs and focus solely on innovation.

Machine learning techniques have the capability to not only accelerate drug discovery, but also drug development. Datadriven approaches to development can substantially impact the significant issues of both research and development costs and industry failure rates. Indeed, industry predictions forecast that the pharmaceutical industry could boost revenue by more than 45% by making investments in AI, heralding

in a new golden era of innovation and sector-wide collaboration.6 REFERENCES 1.

2.

3.

4.

5.

6.

Andre, F. et al. Vaccination greatly reduces disease, disability, death and inequity worldwide. WHO (2011) https://www.pharmatimes.com/magazine/ 2021/julyaugust_2021/global_trends_in_ clinical_research https://www.genengnews.com/insights/ai-indrug-discovery-starts-to-live-up-to-the-hype/ https://aibusiness.com/document.asp?doc_ id=770984 EvaluatePharma, World Preview 2019, Outlook to 2024 Henstock P. Artificial Intelligence in Pharma: Positive Trends but More Investment Needed to Drive a Transformation. Arch. Pharmacol.

Ther. 2020

Ray Chohan Ray Chohan is the co-founder & VP of new ventures at connected innovation intelligence expert PatSnap. PatSnap specialises in the development of AIdriven R&D and IP analytics. The global business has significant experience in the life sciences sector and counts GW Pharmaceutical, Arbor Biotechnologies and Erytech Pharma among its clients.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 25

Drug Discovery, Development & Delivery

Evaluation of an Alternative Solid Dosage Form to Enteric Coated Pellets Containing Ibuprofen: A Case Study Introduction Recent works have evaluated the potential of minitablets contained into hard gelatine capsules.3,4,5 In order to get the benefits and advantages of multiparticulate dosage forms, it is necessary for tablets of between 2 mm and 4 mm diameter to be used.

Tablets larger than 4 mm could not be contained in a hard gelatine capsule in any great number, similarly, tablets smaller than 2 mm would be extremely difficult to manufacture. Studies have shown that tablets of this size have a similar emptying pattern to standard pellet formulation.6 The demonstration of the feasibility to obtain Ibuprofen minitablets alternative to pellets was the performance of a comparative study of the two enteric coated solid forms.

Shape, size, surface, porosity, density, hardness and friability of pellets obtained by powder layering are different from those of minitablets obtained by granulate compaction. Even if the nature of the substrate used may be basically equivalent, the variations of such physico-mechanical properties may influence the film adhesion as well as the uniformity of distribution of the coating on the surface of every unit in the batch. Consequently, the enteric coating of these different dosage forms needs specialised coating equipment very efficient in the operations of mixing, spraying and drying.

The GS Coating System is an innovative automated pan equipment (Figure 1) drying air system that drives the air across the core bed by means of two immersed perforated swords (Figure 2).

It is considered the most efficient airhandling system which mimics the fluid bed technology.2

Aim of the Study The aim of this work was to evaluate the feasibility to obtain a multiparticulate solid oral dosage form alternative to enteric coated Ibuprofen pellets.

Experimental Methods Materials Ibuprofen (average size, about 20 microns) was selected as a drug model because it represents an interesting and serious challenge for the aqueous film coating process (low melting point and post compaction relaxation). Solium lautylsulfate, colloidal silica dioxide, talc and magnesium stearate, hydroxypropylcellulose, mathacrylic acid copolymer and triethylcitrate, microcrystalline cellulose, sodium carboxymethylstarch and sugar spheres were used as received.

Preparation of Pellets Pellets were prepared by drug powder layering onto sugar spheres using pilot equipment.

Generally, the reasons for using an enteric coating are to protect the stomach wall from the effect of the drug contents in a dosage form or to protect the drug contents in a dosage form from the degradation effect of gastric contents. It can also be used to deliver the active ingredient to the particular region of the intestine (e.g., the upper part of the small intestine), so as to enhance the bioavailability of the drug. In any case, the multiparticulate dosage forms, consisting of a single dose of drug subdivided into many small dosage units, are the more suitable system to protect and delay the drug release.

In fact, multiparticulate disperse freely in the gastro-intestinal tract to maximise the absorption, minimise the side effects, and reduces inter and intra-patient variability.1 Enteric coated pellets contained within a hard gelatine capsule are widely used as a protection or delay release device; an alternative to the coated pellets may be the coated minitablets contained within capsules too.

Pellets and minitablets are two different drug delivery systems showing different difficulties to apply the enteric liquid, particularly when the film coating is obtained from aqueous polymer dispersions.

26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 1 – GS Coating Equipment Winter 2021 Volume 13 Issue 4

Drug Discovery, Development & Delivery

Table 1: Physical properties of the multiparticulate products before the enteric coating process.

Figure 2 – GS Coating Equiment perforated swords

After blending drug and auxiliary substances in a suitable mixer they were applied alternatively (Figure 3) onto rotating sugar cores.2 Preparation of Minitablets Granulate containing drug and active surface agent (the same ratio used for pellets) was compressed on an instrumental rotary tablet press, equipped with small concave punches of a 2.5 mm diameter. Tableting speed was maintained at 24 rpm: tablet thickness was set near the diameter size and the compaction force of 8 kN was applied.

Table 2: Processing and technological features of the final coated products (8% theoretical weight gain).

Results and Discussion The physical characteristics of pellets and minitablets are collected in Table 1.

As mentioned above, two different kinds of particulate substrate have been selected. Pellets are much smaller, denser,

Coating Process Pellets and minitablets were coated in the same GS pilot 7.1%, Syloid 244 3.1%, Eudraflex 2.1%, purified water 53.3%. Pan loading was defined on basis of apparent volume of the products, so the core bed remains at the same distance from the spray nozzle.

The coating conditions applied to both the multiparticulate dosage forms were as follows: load volume, 15 litres; pan speed, 12–15 rpm; inlet temperature, 65° C; core temperature, 35°–36° C; spray rate, 30–40 g/min; nozzle port size; 1.2 mm; atomising air pressure, 1.0 bar.

During the coating process 100g of products was withdrawn after the application of 4 and 6% coats and dried in a lab pan at 50°C for 1 hour. The coating was then completed up to 8% coat and the drying was performed as described above.

Physical Testing Tests such as sieve analysis, apparent density, friability, were performed as previously reported.2 The dissolution rate from enteric coated pellets was assessed according to USP 23 method A, page 1795 (apparatus 2, 100 rpm, 37°C, acid stage: 750 ml of 0.1 N hydrochloric acid for 2 hours and buffer stage: add 250 ml of 0.20 M tribasic sodium phosphate and adjust to a pH of 6.8). wwww.international-pharma.com

Figure 3 – GS Coating Equipment powder dosing device INTERNATIONAL PHARMACEUTICAL INDUSTRY 27

Drug Discovery, Development & Delivery Conclusion The results of this work have shown that minitablets are a good alternative solid dosage form to pellets. Both enteric coating processes were performed on the same equipment, GS coating pan HP025 standard configuration.

REFERENCES 1.

2.

3.

Figure 4 – Drug release profiles from uncoated and coated pellets

4.

5.

6.

Bianchini R., Vecchio C., Bol. Chim. Farm., 126 (II), 441-448, 1987.

Vecchio C., Spadoni A., Zema L., Gazzaniga A., 2nd World Meeting on Pharm. Biopharm.

Pharm. Tech., pag. 451-452, Paris.

Colombo P., Conte U., Caramella C., Gazzaniga A., LaManna A., J. Contr. Rel., 1:283-289, 1985.

Davis S.S., Feely L.C., UK Patent, 2:176999.

Munday D. L., Fassihi R., De Villiers C., Int. J. Pharm, 69:123, 1991.

Feely L.C., Davis S.S., Parr G.D., Proceed Int. Symp. Contr. Rel. Bioac. Mater., 12:94-95, 1985.

Figure 5 – Drug release profiles from uncoated and coated minitablets

more friable, more porous, less resistant and have a more extensive surface area than minitablets.

When the pellets were submitted to the coating process, they were observed to move rolling faster and more uniform than minitablets, so the pan speed was adequately adjusted. Despite the difference of porosity between the compacted and layered materials, a good adhesion of the polymeric film to both the substrates was pointed out in the initial phase of coating process. Sticking was prevented by slowly spraying the coating dispersion for the first fifteen minutes.

Even if the pellets are individually smaller, they showed no tendency to aggregate throughout the coating process.

Data relevant to processing and technological features of the coated products are reported in Table 2.

28 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Obviously, the duration of the coating process of minitablets was shorter than that of pellets because they have lowest surface area to volume ratio and require a lower level of polymer coating than pellets or granules with irregular shape and rough surface. The coating application yield more than 98% for both dosage forms as well as the weight uniformity showing a good distribution of film on the substrates, demonstrate clearly a good performance of the GS coating system.

The release profiles relevant to both uncoated and coated multiparticulate products are shown in Figure 4 (pellets) and Figure 5 (minitablets).

Both the enteric coated multiparticulate dosage forms complies largely with the gastro-resistance specifications of acceptance limits. The coating efficiency is resulted higher for the pellets, even if their surface area (mathematically calculated) is about three times more extensive than that of minitablets.

Caterina Funaro Process R&D Laboratory Manager at IMA Active. Caterina Funaro got her degree in Chemistry and Pharmaceutical Technology at the University of Bologna in 1998. She is currently employed at IMA Active as Process Laboratory Manager and her main responsibilities are technical assistance to sales for all solid dose equipment, after sales process assistance, R&D, training and cleaning support for solid dose manufacturing equipment.

Winter 2021 Volume 13 Issue 4

From design to manufacturing, we partner in your device strategy

NEMERA: YOUR COMBINATION PRODUCT PARTNER wwww.international-pharma.com

Patients first.

Always.

Partnering in drug Going the extra-mile. delivery devices.

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 29 Holistically.

Clinical and Medical Research

Quality Overtakes Cost as the Priority as Life Sciences Companies Move to Automate Pharmacovigilance Case Intake For the first time, quality has overtaken cost as a priority in plans for automating adverse event (AE) reporting. These are the findings of brand new research among 200 professionals in senior roles spanning PV, Drug Safety and Product Safety departments. Here, John Price, a long-standing life sciences industry consultant and partner of Arriello, which commissioned this latest research, unpacks the findings.

Although the COVID-19 pandemic has stalled progress with digital process transformation, many life sciences companies’ ambitions to apply smart solutions to rising pharmacovigilance workloads remain central to the investment agenda. These are the findings of Arriello’s second annual transatlantic survey into the industry’s PV automation intentions.

This year, quality overtook cost to become the primary criterion for automating PV workloads. Yet fear for human jobs, along with validation issues, persist as barriers to automation.

The context for the research is the shift in companies’ treatment of PV. A decade or so ago, as AE reporting workloads began to soar, companies across the pharmaceutical industry sought to reduce the cost of their operations – first by outsourcing and then by offshoring their activities. In more recent years, Pharma has begun to realise that any associated cost savings have come at the expense of quality. Now some are seeking to rebuild internal PV capabilities, despite higher costs and a talent shortage, by harnessing smart technology. But how far have companies come?

Unsurprisingly the pandemic has dominated decision-making over the last year which has been reflected in setbacks to automation initiatives. The proportion of respondents claiming to have PV automation solutions in place in 2021 was much the same as in 2020, despite around 40 per cent of last year’s respondents expecting to introduce automation within the coming year. Intentions remain strong, however.

30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Only two per cent saw automation projects curtailed completely.

Targeting Improvements Whether categorised as robotic process automation (RPA), standalone PV automation, or PV automation as part of something bigger, up to two-thirds of companies claimed to have solutions “already in place” or were “likely” to do so in the next 12 months.

Yet it soon became clear that respondents were not typically referring to the application of smart solutions to endto-end case processing (case collection, database work, triage, reporting). Rather, many seem to be leveraging IT to support isolated elements of case processing, such as auto-scheduling reports for submission and auto-narratives.

This is a shame, given the broader process automation opportunities now – for instance to simplify the work of reporters (healthcare professionals, patients), enabling them to make their reports directly into the PV database, circumventing the effort of data entry. This is similar conceptually to electronic data capture (EDC) in common use in clinical trials.

Our own observations suggest that many organisations employ EDC in clinical development, in electronically reporting safety cases to agencies, in generating autonarratives, in programme tabulations and listings for aggregate reports, and so on.

This functionality is often included in the platforms provided by safety vendors and tends to add little in the way of new value to PV teams.

When the 2021 survey asked where companies planned to invest in smart (AIenabled) or robotic process automation (RPA), clinical documentation management was the area most likely to have been automated already, followed by product quality compliance information handling and medical information management, then standard document compilation (forms, PSMF, aggregate reports, etc.).

For investment over the next 12 months, literature screening and auto-narrative

generation dominated plans: beyond that, smarter regulatory intelligence management and automated document compilation.

Yet, still, the figures are perplexing.

What Do Companies Mean by AE-Related Automation?

AE reporting remains a high-pressure activity for pharma organisations and, in this year’s findings, 42 per cent of all respondents (rising to 48 per cent in the UK alone), claimed to have automated AE reporting solutions already in operation.

Yet our experience suggests that automation of end-to-end case processing is relatively rare in the industry. The high AE automation rates reported in the current survey are more likely to refer to very limited application, then – linked to specific elements of the overall AE processing system – rather than implementation of a novel, comprehensive platform to alleviate manual data management.

Anticipated Benefits of PV Automation To find out more, the research pushed for the drivers for investing in PV automation – finding that quality (cited by 71 per cent) outranked cost (cited by 63 per cent) by some margin, and was even ahead of speed of delivery speed (mentioned by 67 per cent).

Quality-wise, improved data quality is the chief objective, cited by 35 per cent of respondents – rising to 40 per cent among those in Drug Safety roles. For speed-related improvements, accelerated processing was the main benefit sought, cited by 34 per cent – rising to 38 per cent for Drug Safety teams, who also prioritised prompter reporting.

In terms of cost reduction benefits linked to automation, Product Safety teams were most likely to be seeking reduced infrastructure costs, and least likely to be targeting labour replacement.

Further probing, linked to existing capabilities, revealed that automation solutions clearly hold perceived value in a PV context, but that companies need the scope to increase and for the benefits Winter 2021 Volume 13 Issue 4

Clinical and Medical Research to be more visible and easier to access.

As one respondent noted in an openended response: “PV automation makes quality assurance easy. It’s just a matter of overcoming validation requirements and providing ease of access. Usability issues and fear of the unknown are what hold people back, which is a shame given that integrating functional events through PV gives awesome results.”

Barriers to Automation In last year’s PV automation survey, the three top perceived barriers to PV automation were IT related. This year, although the familiar challenge of system validation remained a key concern, cited by more than four in 10 respondents (as in 2020), familiarity, ease of use and cost were the next most significant barriers to embracing new automation opportunities.

Fear of human replacement was a particular issue for PV teams (cited by 42 per cent of this cohort, in contrast to 22 per cent of those working in Product Safety). This

suggests a misconception that job losses are inevitable when an automated solution is implemented, when in reality automation paves the way to retain talent which is currently considerably over-stretched.

A perceived lack of suitable solutions was cited as a barrier to adoption by 43 per cent of UK survey participants, compared to 27 per cent in the US. This further supports the conclusion reached last year, that there are differing perceptions of what constitutes ‘automation’ – i.e., that the technology and service provider industry must work harder to educate the market on emerging options.

That system validation still presents as such a high barrier to process innovation/ improvement is disappointing. PV professionals know how to validate a system and have the resources needed to monitor systems and confirm they are doing what they are supposed to do, with the quality and consistency required. This apparent barrier warrants further exploration, certainly, with a view to ensuring that it

doesn’t go on to prevent take-up of more innovative IT solutions that could benefit PV teams enormously.

Conclusion Overall, there remain encouraging signs that PV and Safety functions want to do more to advance the automation of their operations, and to improve the quality of data and the speed of processing/report delivery in particular.

One of the next priorities for the industry must be to find ways round issues of system validation which continues to prevent companies from more readily capitalising on the rapid evolution of next-generation automation capabilities.

Encouragingly, companies are clearly prioritising quality and processing speed above cost now when exploring new automation options. As PV functions strive to harness capabilities closer to home, the option to take up accessible and userfriendly AE automation solutions – whose productivity benefits are immediate right from case intake – offers significant promise. *About the Research The 2021 Arriello survey was conducted by Censuswide in July/August. As in 2020, it polled 200 senior professionals in PV, Drug Safety and Product Safety functions across life sciences companies of all sizes, split evenly between the UK and US.

Dr John Price Dr John Price is an executive physician with 25+ years deep experience working across regulatory affairs and pharmacovigilance worldwide. He has held senior roles at the UK MHRA, as well as Pfizer, J&J, Alexion Pharmaceuticals, and worked in academia. John is an advisor to Arriello, a provider of risk management and compliance services to the life sciences sector – including market consultancy, global regulatory affairs strategy and implementation, complete PV solutions, clinical drug safety, and quality and compliance auditing systems.

Email: drjsprice@pharmacovigilantes.com

wwww.international-pharma.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 31

Clinical and Medical Research

The New Normal: How COVID-19 Became the Catalyst for Change Abstract When COVID-19 disrupted life sciences, solutions were needed in real-time.

As the pandemic grew, so did the need to innovate. Workers met the challenges. They completed tasks, fulfilled inspections, and remained vigilant in fulfilling regulatory requirements. This paper presents findings from a roundtable hosted by PharmaLex. It examines how life science professionals leveraged disruptive technologies during the pandemic. In the talks, industry leaders focused on what worked well, what needs to be improved, and what comes next. The program included six topics: • • • • • •

Decentralised clinical trials Modern data management Cybersecurity Rolling submissions Virtual inspections COVID-19 regulatory impact: What technology and business investments will be accelerated?

For life sciences, embracing disruptive technologies played a crucial role in ensuring continuity of service. Quickly adopted, disruptive technology elements became a part of day-to-day operations.

Professionals adapted to work smarter, increase efficiency, and sustain quality levels. Here is a wide-ranging look at lessons learned throughout the coronavirus pandemic. Including the tools and solutions that are likely to remain in the new normal.

Keywords Decentralised clinical trials, modern data management, cybersecurity, rolling submissions, virtual inspections, business continuity, disruptive technologies, life science industry, artificial intelligence, machine learning.

The global pandemic caused by coronavirus disease 2019 (COVID-19) forced the life sciences industry to rethink processes and procedures to continue operations. Lockdowns, travel restrictions, 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

and the race for a vaccine all impacted operations for pharmaceutical companies and regulators, while a heavier reliance on technology to conduct business was needed to keep patient safety at the forefront.

PharmaLex hosted a round-table of experts to discuss how disruptive technologies in life sciences (DTLS) helped during the pandemic, and how they can be used in the future. The Disruptive Technologies in Life Sciences consortium was formed in early 2018 by a group of industry leaders with the aim of discussing advanced technologies in the life science industry. The consortium consists of representatives from pharma and biotech companies, Health Authorities (HAs) and leading technology providers. The talks of this year’s roundtable focused on six topics: decentralised clinical trials, modern data management, cybersecurity, rolling submissions, virtual inspections, and COVID-19 regulatory impact. The results of this year’s roundtable are to focus on the following question: What technology and business investments will be accelerated? This paper looks at how the aforementioned topics have been influenced by COVID and what trends we are likely to see further in the future.

Decentralised Clinical Trials Decentralised trials (DCTs), a novel approach to clinical trials in which the trial is conducted partially or fully at the location of the patient rather than at a clinical site, have been of interest to and piloted by pharmaceutical companies for the past few years for several reasons. By making trial participation less burdensome to patients, DCTs present an opportunity to recruit patients faster and increase diversity in the patient population, and because of the increased convenience of trial participants, discontinuation rates are expected to be reduced. Prior to the COVID pandemic, health authorities (HAs) showed interest in this approach but, with few exceptions, were moving slowly towards its acceptance, and many of the supporting technologies that enable DCTs were under discussion concerning their regulatory status.

These technologies include: • • • • • •

Telemedicine Home nursing Use of local Health Care Providers (HCPs) and local laboratories Electronic Informed Consent tools (eConsent) Direct-to-patient Investigational Medicinal Product (IMP) shipments Use of wearables and sensor technologies

The COVID pandemic significantly disrupted clinical trials worldwide. Patients couldn’t or weren’t willing to travel to clinical sites due to lockdowns and fear of infection. Pharmaceutical companies and investigators scrambled to figure out how best to mitigate these challenges, including how to retain trial patients in a safe and secure manor. Health Authorities also put into place guidelines to allow for flexibility in trial conduct and many of these approaches are the same as those utilised in the DCT model. Telemedicine and/or telephone-based visits, home delivery of study medications and remote monitoring were some of the most widely authorised and utilised emergency procedures employed during this time.

The emergency measures enacted due to the pandemic have provided a boost to the acceptance of DCTs by Health Authorities (HAs) and we note, substantially increased their interest and involvement in the running of pilots as well as the development of guidance. Hurdles, however, do remain.

HAs are progressing at different speeds regarding the acceptance of DCTs and the lack of harmonisation across regions makes global trials a challenge to run. In addition, some DCT enabling approaches are regulated not by HAs at all but by national laws, for example, those related to nursing licenses, electronic signatures, and drug distribution, and differ from country to country. Further research is required to demonstrate comparability in remote versus in-person assessments. This is especially true for primary endpoints, which require validation before implementation, and for trials in which some visits or some sites are remote, and others are not. There are also Winter 2021 Volume 13 Issue 4

Clinical and Medical Research data and privacy law concerns, including patient consent and confidentiality that must be considered when implementing these novel approaches.

Despite these hurdles the DCT approach is gaining acceptance rapidly, significantly catalysed by the flexibility required by the extraordinary circumstances faced in clinical research as a result of the COVID pandemic.

Modern Data Management Pharmaceutical and medical companies oversee vast amounts of data. Whether it’s raw data or data (pre-)processed by algorithms, data is valuable and becomes an organisational asset with unique properties. Looking forward to trends in data management, standards and governance can help guide organisations, and this topic has been in the news recently as more organisations start planning their data strategy.

Data management is life cycle management. All datasets are different and require varied management and curation.

Managing the quality of the data takes planning, and for organisations, that requires buy-in from leadership. Whether it’s pharmaceutical companies or healthcare organisations, these organisations can’t do everything alone, and partnering with trusted and verified technology vendors is a way to get expert help and immediate data management support.

Implementing a modern data management framework now will help lay the groundwork for organisations to later adopt future disruptive technology. Regardless of proposed roll-out dates, planning should begin much earlier since these new initiatives are time-consuming and costly.

For example, when organisations look to deploy disruptive technology to handle data management tasks, they must realise the technology will not solve existing or legacy data quality problems. Artificial intelligence (AI) and machine learning (ML) are not capable of cleaning data. It’s the other way around: an organisation must input clean data for AI and ML to manage it effectively.

Not only is this important for organisations to know before initiatives begin, because data remediation costs can be a barrier to entry. Also consent compliance with international technical standards and harmonised implementation of technical rules must be ensured from the beginning in a sustainable way. At the start wwww.international-pharma.com

of a study, a group must determine how far back they wish to go, because that will determine how much manual data clean-up will be needed, with costs directly tied to the timeframe.

information, along with safeguarding an organisation’s network.

One option can be to leave legacy data static, with the possibility of revisiting it later. In this case, an organisation should examine if regulatory or compliance issues are at risk. If this is a viable option, the legacy data can be left in place, and then new data can be fed into AI and ML emerging technology activities.

•

It is obvious that, at least internationally, acting companies and sponsors must take care of a broader range of requirements/ aspects to comply with expectations or needs from different regions. Sponsors are implementing data management activities and connecting them with those occurring at the FDA and other HAs world-wide. Both industry and HAs see the value in data, data standardisation and data management moving forward. In the United States, the U.S. Food & Drug Administration (FDA) published its Data Modernization Action Plan (DMAP), on March 3, 2021, which “proposes a framework and actionable recommendations for FDA’s Data Strategy.”

The FDA listed three key components: 1.

2.

3.

Identify and execute high value driver projects for individual centres and for the Agency.

Develop consistent and repeatable data practices across the Agency.

Create and sustain a strong talent network combining internal strengths with key external partnerships.

Similarly, in the EU an interoperable data access infrastructure for the European Health Data Space has been established in order to facilitate secure cross-border analysis of health data; tested in 2021 with a pilot project involving EMA and national authorities, it will support digital transformation, personalised medicine, high-performance computing and artificial intelligence during the next 5 years and beyond.

Cybersecurity Pharmaceutical and medical companies and health systems host and warehouse sensitive data about their patients, manufacturing processes, scientific methods and other intellectual property deserving protection. To protect that data, strong cybersecurity is key to protecting patient

Actions to take for organisations focusing on their cybersecurity include:

• •

Digitising processes to be safe and secure across the organisation. This should be a single plan, not multiple plans that may conflict with one another.

Align ambitions with business strategies.

Account for future plans. Keeping in mind that speeding up processes can improve patient access, which should also count R&D as a critical component.

The goal of cybersecurity is to ensure the network is always accessible, yet guard against bad actors, malware, and hacks. In this environment users can be either an organisation’s strongest point or its weakest point. Network users need to be fully trained and certified. Often, intermediate users and end-users who have their privileges increased can open the system up for a hack. Exploitation of vulnerabilities via ransomware happen when a user account is compromised. In particular, phishing attacks via email have become more sophisticated.

In the past, clicking on a link could lead to an attack, but now, merely hovering over a link can trigger some malicious code to run.

One potential DTLS solution to guard network security is implementing AI monitoring agents. Since AI agents can run autonomously with little to no human intervention, AI is a 24/7 solution that can provide increased network security and monitoring around the clock.

Generally, AI may learn by examples or instances, which can pose challenges if there are sophisticated techniques of delivering data integrity. For example, hidden values may exist in that data, which would alter the way AI behaves. Clean, holistic data gives expected results, while cryptic data, maybe including unknown ciphers, will give unusual results. This is an important consideration, when using AI technology within cybersecurity as well as other use cases.

As effective as AI can be in monitoring network security, organisations need to be aware that AI intrusions are also possible. AI can learn by monitoring over large periods of time. During this time, it can learn to INTERNATIONAL PHARMACEUTICAL INDUSTRY 33

Clinical and Medical Research and adapt to complexity, while ultimately finding solutions that human users have not thought of. For example, a single human is unlikely to sit long enough to manually unleash a brute force attack; however, automating this task and including a selflearning mechanism may lead to unlimited evolving iterations of a process.

Cybersecurity is critical for an organisation, because if you can’t protect the business processes, you risk not having a viable business. It is business-critical that cybersecurity delivers for the patient, and it depends on the provider’s ability to protect the resources in a cost-effective, timely and innovative manner.

Rolling Submissions Because COVID-19 spread so quickly, vaccine development had to be accelerated in the interest of public health. The European Medicines Agency (EMA) accepted a rolling submissions model, where sections were submitted for review, instead of waiting until entire information and datasets were completed for an all-at-once submission.

For example, under the rolling submission model, the nonclinical section of the dossier can be finalised while clinical trials remain ongoing.

The EMA approved accelerating regulatory procedures for R&D, along with fast-tracking marketing authorisation applications (MAAs) for COVID-19 vaccine work. This accelerated model also applied to new medicine development apart from vaccines.

Beyond the success of vaccine development, there was also heightened collaboration among experts. Increased data sharing, exchange of thoughts, and identifying areas for future collaboration –

like working toward a more standardised way to submit documents – have all been attributed to organisations working together during the COVID-19 pandemic.

While these rolling submissions and reviews have led to unprecedented successes in vaccine development, organisational leadership should recognise that this came with costs. Staff worked around the clock due to the urgency of the worsening pandemic. Having staff work increased hours to provide very rapid assessments without compromising on quality is needed in a pandemic. But maintaining that level of work and the burdens it places on staff is unsustainable.

Long-term organisational planning will need to be mindful of this from a workforce standpoint. Otherwise, the pharmaceutical industry will need to increase resources greatly if this pace continues for how new drugs will be evaluated in the future.

Regarding DTLS, the AI is not quite ready to analyse and manage data from a decisionmaking perspective. The level of trust does not yet exist for true artificial intelligence to make decisions that can be relied upon. Currently, artificial intelligence can analyse, summarise, trend, and recommend outcomes that a human can consider when developing strategy or making decisions.

While the decision-making capability is not yet ready, digital technologies can be utilised to handle automating tasks to save time and speed through submissions.

Utilised as more of a natural language processing tool, processes can run to automate submissions and fill in templates used along each point in an assessment.

Organisations looking to implement these time-saving processes can easily test the outputs of automation or natural language

processing by using historical data. By gathering some training datasets and validation datasets, tests can run and be checked for accuracy in a manner that is not difficult. Deploying these automated processes will preserve workforce hours that an organisation can allocate for other strategic tasks.

Technology tools should be reliable, predictable, and yield the same results every time. Organisations should also consider open-source software over proprietary software to gain more flexibility for use over time.

Virtual Inspections The lockdowns forced by COVID resulted in inspections relying on a virtual model. No longer able to conduct site visits, auditors had to overcome obstacles and use virtual tools to meet commitments. Still, the goal of an inspection is not to be on-site, it is to gather and assess enough objective evidence. If this evidence proves that a site is operating in a controlled environment and meeting all regulations and requirements, a virtual inspection will serve its purpose.

As with many trends brought on by the pandemic, virtual inspections will likely remain in some capacity after lockdowns have been lifted. Inspectors will benefit from flexibility and time-savings since they can conduct many more audits remotely without time spent traveling to sites.

Instead, experienced inspectors will gain more availability to conduct audits and run them remotely.

For a virtual inspection to run successfully, the right technology tools must be in place: for both the inspector auditing remotely and the site itself.

Before an audit begins, inspectors and sites should establish a plan to ensure resources are collected and ready for inspection day. Ask what would be done on-site and then figure out how each step can be done remotely. Then pick the correct technology tools to help conduct a thorough audit. Examples include: • • •

Phases of COVID-19 (modified after Siddiqi, J Heart Lung Transpl (2020) 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Introductory meetings can be conducted on a video conferencing platform Documents can be accessed and distributed with cloud-based filesharing sites Facility tours can utilise 360-degree cameras Winter 2021 Volume 13 Issue 4

Clinical and Medical Research

• • • •

In situ facility cameras can be accessed as another layer of visibility during the audit Facility floorplans can leverage virtual reality to give insights on location of processes Augmented reality glasses can provide point-of-view access during walkthroughs Hiring a photographer to fly a drone around the facility and livestream it to inspectors can help prove location and configuration accuracy

Layering these technologies together can provide a clear picture. Emerging disruptive technologies can be used to assist inspectors, but these technologies can also be used in dishonest ways.

Deepfakes can be problematic for inspectors who are not present at the site.

If site operators can manipulate the images being streamed, then they will provide what inspectors want to see, and not the reality on the ground. From making sites appear cleaner than they are to adding wwww.international-pharma.com

false walls to conceal rooms that are not in compliance, manipulated media will challenge auditors. By not standing within the facility, inspectors must remain vigilant during virtual inspections and carefully examine what is presented to them.

Uncovering hidden rooms or secret walled-off areas can be assisted by technology like Building Information Modeling (BIM). Because modern buildings are designed with BIM technology before a steel girder is put in place, BIM gives auditors an accurate sense of space.

Taking this a step further, leveraging augmented reality systems to overlay CAD drawings onto video footage will show consistency between the facility design and the actual construction. Combining BIM modelling with this augmented reality, inspectors will get a true picture of the facility. Discrepancies will be apparent, and inspectors can insist on closer looks of things that don’t look right by scrutinising floorplans and machinery for a more complete, accurate audit.

COVID-19 Regulatory Impact: What technology and business investments will be accelerated?

For the last presentation of the roundtable, findings were shared from the 2020 COVID-19 Pandemic Regulatory Impact Pulse Survey, which was conducted by Gens & Associates.

Surveys were taken from 52 unique global companies, with a total of 183 responses being tallied.

The study revealed these key themes and insights: • • • •

Increasing speeds of implementing changes by breaking free of “time to change beliefs and mindsets” Growing organisational dilemmas in relation to workforce flexibility and effectiveness Accelerating organisational agility and finding innovations from within Maximising global and virtual investments

Breaking free of “time to change beliefs and mindsets” saw companies with COVID-19 INTERNATIONAL PHARMACEUTICAL INDUSTRY 35

Clinical and Medical Research products (vaccines, diagnostics, therapies etc.) move more quickly with a variety of standard regulatory activities. Additionally, most participating companies adopted change (e.g., new initiatives) quicker than they have in the past. The pandemic forced many organisations to look for solutions quickly, and what used to take months to consider and gradually roll out was reduced to several weeks.

This shift in speed has also led to greater transparency as virtual environments have made teams more aware of other segments of the business (e.g., like a small local affiliate) and how work is connected among groups. Quicker decision-making and much faster rollouts have led to streamlined adoptions of new processes and systems.

Trends toward virtual work and processes had been ongoing since 2014, according to the study, but are being greatly accelerated by the pandemic.

“We believe the significant investment in regulatory organisations focused on end-to-end processes, global systems, and data quality since 2014 has resulted in the ability to rapidly shift and adapt to a virtual and remote environment.” – 2020 COVID-19 Pandemic Regulatory Impact Pulse Survey, Gens & Associates The study lists regulatory information management investment priorities in 2020 and beyond: 1.

2.

3.

4.

Global Dossier Strategy and Dossier Management Operations End to end Label Management End to end Variation Management Registration and Health Authority Commitment Management

According to the study, businesses and teams have progressed through three phases: from Crisis Mode (“Action Out of Necessity”) to Recovery (“Reimagining a Better Way”) to Renewal (“New Normal”).

This new normal will see norms stabilise and temporary changes that have been effective become permanent.

Study respondents looked to the future by highlighting moving toward a more global virtual environment, speeding up technology solutions for more access and collaboration, more flexibility in remote working and adopting virtual solutions, and overall issues in preserving COVIDera efficiencies to be used in long-term planning.

36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Conclusion COVID-19 has disrupted all aspects of the life sciences industry, as confirmed above by the thought leaders during the roundtable discussions. Changes within regulatory, technology, and industry affected the pharmaceutical space and healthcare in general. In the future, some of these changes are likely to remain. While no one can predict the lasting changes, hybrid approaches should be expected surrounding decentralised clinical trials, modern data management, cybersecurity, rolling submissions, and virtual inspections.

Increases in virtual approach will provide both benefits and challenges to complete what was formerly only conducted on-site or in-person. COVID-19 acted as a catalyst for change, and life sciences professionals became adaptable and overcame numerous obstacles within unusual, unprecedented conditions. Their race against the virus led to historical successes, all while focusing on speed and agility and not compromising on patient safety.

Key observations that came out of the discussions were that there has been a remarkable shift of mindset in the usage of technology innovations as an integral part of modern life sciences research and development. The pandemic situation due to COVID-19 has triggered and accelerated this shift. While much has happened, many activities are far from being completed.

The authors conclude that further efforts for digital transformation in Life Science, especially in the above-mentioned topics, will focus on important improvements for Industry and Health Authorities: 1.

2.

3.

Fast access to safe medicines Cost- and resource-effective drug development and Market Access Security and privacy of data and intellectual property, esp. in an evolving digital and virtual environment

Disclaimer The opinions expressed in this paper are the personal representations of the authors and do not reflect any endorsement or official status of their hiring organisations.

REFERENCES 1.

2.

3.

4.

DAMA-DMBOK: Data Management Body of Knowledge: 2nd Edition (2017) https://www.fda.gov/about-fda/reports/datamodernization-action-plan (2021) https://www.fda.gov/about-fda/reports/fdastechnology-modernization-action-plan (2019) https://ec.europa.eu/health/ehealth/data

5.

6.

7.

8.

space_en https://www.ema.europa.eu/en/documents/ other/hma-ema-joint-big-data-taskforcephase-ii-report-evolving-data-drivenregulation_en.pdf (2019) Phases of COVID-19 (modified after Siddiqi, J Heart Lung Transpl (2020) https://vac-lshtm.shinyapps.io/ncov_vaccine_ landscape/ 2020 COVID-19 Pandemic Regulatory Impact Pulse Survey – Gens and Associates identifying areas for future collaboration – like working toward a more standardised way to submit documents – have all been attributed to organisations working together during the COVID-19 pandemic.

Dr. Jürgen Hönig Senior Director, Regulatory Business Intelligence. Jürgen Hönig is in a position as Senior Director, Regulatory Business Intelligence of PharmaLex GmbH, Germany. He joined the company in 1999 and his main focus in his current position is identifying new trends on a global or local level within regulatory affairs framework.

Jürgen has using his extensive network across pharma associations and direct liaison with authorities bodies to manage regulatory and business intelligence for external and internal use. Over 15 years, he was responsible for all worldwide submission activities for clinical trial applications, new marketing authorizations and lifecycle management activities. He is a notable speaker and session chair on international conferences and seminars.

Authors Sammy Sambu, Associate Director AI Solutions (UCB)/Carla Jonker, Senior Regulatory Project Leader (Dutch MEB)/ Kate Coleman, Director, Quality Management (PharmaLex)/Steve Gens, Managing Director (Gens & Associates), Klaus Menges, Regulatory Affairs and eSubmission Specialist (formerlyBfArM)/Scott Cleve, Head of Regulatory Operations (Bluebird bio)/Timm Pauli, Senior Director, Head of Global Regulatory Informatics and Operations (PharmaLex)/ Juergen Hoenig, Senior Director, Regulatory Business Intelligence (PharmaLex)/ Andrew Fried

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 37

Technology

Defining and Regulating the Complex World of Software as a Medical Device The medical devices landscape has changed dramatically in recent years with the shift from hardwarebased medical devices to the advent of smart, standalone software technology medical devices. However, the definition of what constitutes software as a medical device (SaMD) is not that simple, and that poses some unique challenges when it comes to regulations. Furthermore, since regulations were written well before the emergence of SaMDs, health authorities have had to consider how to adapt these regulations to the fastmoving nature of the technologies.

The use of software in medical devices has grown exponentially and in different ways. However, SaMDs are a distinct class, separate from what is referred to as software in a medical device (hardware incorporating software as an integral part of its function) and software used to help manufacture or maintain a medical device. The introduction of the SaMD class brings with it a new group of innovators and manufacturers, many of whom have no or very little experience with regulations and are struggling to get up to speed with the different global regulatory requirements and what they mean for their products.

The Regulatory Landscape Let’s explore the key regulatory challenges that are triggered by these evolving technologies and the steps regulators and standards bodies are taking to address these challenges.

A product is defined as an SaMD if the software is standalone and meets the definition of a medical device, which is that it is intended to be used for diagnosis, screening, prevention, monitoring, treatment or alleviation of disease.

While the nature of SaMDs is complex and there are inevitably different interpretations in different jurisdictions, as a result of this, there are efforts to harmonise regulatory approaches. The International Medical Device Regulators Forum (IMDRF), a voluntary group 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of medical device regulators, formed the Software as a Medical Device Working Group aimed at encouraging innovation and access to SaMDs by establishing key definitions, a risk categorisation framework, quality management system principles, and a clinical evaluation pathway.

A SaMD will be regulated in the same way as other medical devices of the same risk category, however, the classification rules that exist for medical devices currently only consider the possible harm caused by physical interaction of the medical device for human. As software does not have this physical interaction, the risk associated with these types of products relate more to the information provided by the SaMD for diagnosis and clinical treatment recommendations, such as analysis and calculation errors, inaccuracies, and poor user interfaces (UI/UX). The risk classification from these potential inaccuracies have been laid out by the IMDRF depending on the type of condition it supports. These include: •

•

•

Non-serious, where interventions are normally non-invasive, giving the user an opportunity to detect flawed recommendations. Users can either be specialised users or lay users Serious, where disease progression is moderate but where major therapeutic intervention isn’t required or time critical. Again, users can either be specialised users or lay users Critical, where the health of the patient is life-critical and where intervention can be time critical, meaning the user may not be in a position to reflect on recommendations. In these circumstances, only specialised, trained users should interpret the SaMD information.

Exploring the Regulatory Frameworks The next question manufacturers might have is: how do these categories affect the way a product is regulated?

At a high level, there are two main regulatory frameworks for SaMDs, as there are with hardware devices. The first is the GHTF framework, which encompasses most jurisdictions beyond the United States –

Europe, Australia, Canada, Japan and others.

The GHTF framework relies on the compliance with a set of essential requirements for safety and effectiveness, as opposed to clinical experience for the demonstration of safety and effectiveness.

The second framework, adopted by the U.S., adopts a premarket submission approach where classification is based on product codes, which are contained in FDA's Product Code catalogue for the various device types. The class classification found within each product code will then determine the submission pathway – either a premarket notification, premarket approval, PMA, or de novo if a product code does not exist for a software device. The means of compliance is typically based on clinical experience, evidence, trials and on demonstrating substantial equivalence to a predicate device.

While these two frameworks form the basis of the SaMD regulatory pathway, each jurisdiction has its own set of requirements.

The US Regulatory Framework The US FDA has been at the forefront in trying to address the challenges of regulating SaMDs, with the introduction of the 21st Century Cures Act back in 2016. In particular, the Act included a section that adds a definition of a SaMDs in line with IMDRF recommendations.

As a result, a number of changes were made to the regulations, including to offthe-shelf software use, cybersecurity, as well as new guidance documents specifically for medical device software, such as guidance for mobile medical applications, general wellness devices, medical device data systems, artificial intelligence and machine learning.

One of the new initiatives that came out of the 21st Century Cures Act was a launch of the software pre-certification pilot program aimed at helping to inform the development of a future regulatory model that will provide more streamlined and efficient regulatory oversight of software-based medical devices developed by manufacturers who have demonstrated a robust culture of quality and organisational excellence, and who are committed to monitoring realworld performance of their products. The Winter 2021 Volume 13 Issue 4

Technology The Health Canada guidance also covers exclusion criteria for certain types of SaMDs.

FDA’s Pilot Digital Health PreCert Total Lifecycle Approach (www.fda.gov/medical-devices/digital-health-center-excellence/digital-health-software-precertification-pre-cert-program)

focus of the program is on a total product lifecycle approach, as opposed to pre-market applications.

The EU Regulatory Framework In May 2021, the new Medical Devices Regulation came into effect, which includes significant changes for SaMDs, with clear definitions of what an SaMD is, as opposed to software intended for lifestyle and wellbeing. The In Vitro Diagnostic Regulation (IVDR) also includes stand-alone software as an IVD device, which is treated like any other IVD device, including classification and regulatory options and requirements.

With the MDR in place, most software previously classed as class one under the Medical Devices Directive is likely to be up-classified to class IIa or higher. Other changes include recognition that software can be regarded as an active device, inclusion of requirements around software development lifecycle, information security and mobile computing platforms, and special labelling requirements.

In addition to this, in 2019 the Medical Device Coordination Group in Europe published guidance on qualification and classification of software for the MDR and

IVDR. The guidance provides definitions and criteria around SaMDs, as well as greater clarity and examples of how to apply the new rules for various types of software.

Australia’s Regulatory Framework As of February 2021, the Therapeutic Goods Administration (TGA) has implemented reforms to the regulation of SaMDs. One of the significant changes was the introduction of new classification rules. Most devices will remain in the same class if they provide direct diagnosis or monitoring. Devices intended to provide therapy by the provision of information, for example, a medical device intended to provide cognitive behavioural therapy, could potentially be classified as a higher class.

There have also been a number of changes to the essential principles, one example with regards to the management of data and information as it applies to cyber security, and requirements relating to development, production and maintenance.

One amendment allows information, where applicable, to be provided electronically, rather than on a leaflet, for SaMDs. The TGA has also released software guidance documents for excluded or exempt devices for certain types of SaMDs. Canada’s Regulatory Framework In December 2019, Health Canada published a guidance document on SaMDs and adopted the IMDRF framework. Under the new guidance, low risk software is classified as class I and higher risk software is classified as class III, based on the significance of the information provided by the SaMD to the healthcare decision, and the state of patient’s healthcare situation or condition.

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Staying Ahead of Regulatory Change The rapidly evolving nature of software technologies inevitably has a knock-on effect on regulations as health authorities scramble to ensure the safety of patients.

But, while staying ahead of change can be difficult for SaMD manufacturers, the majority of new regulations go through a public consultation period, which gives the industry an opportunity to provide feedback and influence the regulation. It’s important, therefore, that companies stay abreast of new regulatory developments, take part in the consultations, and provide their feedback.

Yervant Chijian Yervant, Director, Team Lead Medical Devices/IVD, Australia, provides expert technical consultancy for Medical Device regulatory compliance in major markets, ensuring efficient market access.

Yervant has spent the last 20+ years in the Medical Device field, including both manufacturing and product development, his prior roles include RA/ QA Director, Quality Assurance Manager, Operations Manager, Production Manager, and Product Development and Manufacturing Engineer. Utilising his strong technical background and hands-on expertise to provide practical solutions to the challenges faced by his clients in any phase of their product lifecycle. Yervant’s expertise lies in Regulatory Strategic Planning, particularly in the United States, Europe, Canada, Australia, and New Zealand markets, and in Product Development and Design Controls, specifically in Software and Electrical technologies. Coupled with his experience in Manufacturing Processes, Quality Management Systems (ISO 13485 and MDSAP) and Product Lifecycle Management, he brings a comprehensive skillset to support clients navigate through the variety of regulatory pathways and requirements.

Email: yervant.chijian@pharmalex.com Web: www.pharmalex.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 39

Technology

Cyber Risk: How Can Pharma Avoid Black Swan Events?

Rod Schregardus, pharma manufacturing lead at The Access Group, looks at the IT security threats facing pharma companies today, and the steps that can be taken to prevent the fallout from data loss. He also speaks to Jim Wheeler, a director at UK-based risk consultancy Control Risks who played a leading role in the crisis management team for an organisation severely impacted by NotPetya, the same ransomware which struck Merck in 2017.

The digitisation of the pharmaceuticals industry is transforming everything from R&D, to production, to sales, vastly improving both health outcomes and the commercial performance of vaccines and therapies.

Manufacturers have been steadily ramping up investment in automation, machine learning and AI, data analytics and predictive modelling, and the internet of Things (IoT) for some time now. Of course, these technologies were also instrumental in delivering a safe and effective Covid-19 vaccine at record speed. It was a race like no other and falling behind would have had severe consequences for the health of entire populations, as well as economic and geopolitical repercussions.

Now that data-led technologies have been proven on a large-scale and under the public gaze, the pace of innovation is only going to increase further over the coming years. It’s certainly giving more pharma companies the impetus to move more of their manufacturing operations to the cloud.

The reason for this is clear. With real-time data flowing freely between applications and machines, production teams can improve their decision-making, optimise resources, speed up production and reduce risk (of say, contamination and wasted batches). Data is available remotely and employees no longer have to create and update production plans manually, nor engage in lengthy handovers with colleagues because they can access critical information as and when they need it.

But greater connectivity creates new vulnerabilities in IT systems for hackers 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

to exploit. A ransomware attack, whether the result of a blanket or targeted spear phishing email, could mean substantial data losses. The malware infection spreads across all networked devices, including internetenabled machines on the shop floor, making it difficult to isolate and stop.

As a result, production comes to a standstill as senior managers grapple with the impossible question of whether to pay the ransom for the safe return of their data.

They’re acutely aware of the impact the delays could have on the delivery of lifesaving drugs and stockpiles.

Operational disruption can be extremely damaging, both in terms of patient health and commercial performance, but it’s certainly something no pharma manufacturer can countenance in the current climate.

Demand for Covid-19 vaccines, boosters and therapeutics remains high; drug stocks were depleted during the pandemic and pharma has experienced supply chain issues just like other industries have recently.

When The Sost Is Too High While it’s difficult to assess the true cost of a data breach, taking into account production downtime, reputational damage and potentially lost contracts and investment, figures from IBM make for sobering reading.

According to its annual report, the average cost globally of a cyber-attack in pharma stands at $5.04million in 2021, just down from $5.06million in 2020. It’s the third costliest of any industry, behind financial services ($5.72million) and, unsurprisingly, healthcare ($9.23million).

Delays may lead to entire batches being scrapped, which on its own could cost anything from half-a-million to several thousand pounds. That’s before any fines, litigation, lost contracts and reputational damage are factored in.

The value of its IP (intellectual property), and the speed at which teams have worked over the past 18 months, made pharma and associated public bodies particularly susceptible to cyber-attacks. Remote

working, though not possible for everyone in this industry, is also thought to have increased the risk of a successful cyberattack, due to weaker IT controls at home and more sophisticated ransomware.1 In July last, the UK’s National Cyber Security Centre (NCSC) reported that organisations developing a Covid-19 vaccine had been targeted by ‘Russian cyber actors, known as APT29’.2 Then in December, the European Medicines Agency (EMA) was subject to a cyber-attack resulting in ‘some documents relating to the regulatory submission for Pfizer and BioNTech’s COVID-19 vaccine candidate, BNT162b2, which has been stored on an EMA server, [being] unlawfully accessed.”3 Neither Pfizer nor BioNTech’s systems were compromised, but it does show pharma is a prime target.

As custodians of proprietary data, including sensitive patient details, results from clinical trials and drug recipes, pharma companies have rightly always been a ‘closed book’ to the outside world. But as we’ve seen, connected IT systems open up more opportunities for hackers to get their hands on commercially sensitive information compared to previously.

Jim Wheeler says that while security has always been a priority, some in the industry believed that the complex nature of pharma – highly-regulated and researchled – afforded it a degree of protection from IP theft. He told me: “You can’t just come up with a new drug and make money from it because you’d have to demonstrate its safety and efficacy with registered research, studies and testing.

“That way of thinking has changed over the past 18 months due to demand for Covid-related vaccines and treatments.

Unscrupulous governments don’t care where they get their IP from, they just want to be able to manufacture drugs quickly and get them out to their population.

“On top of that, there’s the wider question of counterfeit drugs. Are drug designs being Winter 2021 Volume 13 Issue 4

Technology shared with huge industrial producers in other parts of the world so they can create saline replicas to be sold?”

It’s not only IP that cyber-criminals and hostile nation states will target either, according to Jim. Financials, employee details and other confidential documents are also at stake. Moreover, senior managers don’t always appreciate the potential fallout that could follow if hackers gained control of the company website.

“A public-facing website might not contain any obviously sensitive material but every hour, you might have tens-ofthousands or even millions of attempted administrator log-ins,” he said.

“It would only take one successful attempt and the result could be defamatory material published on the website, or a link to ransomware. The reputational damage from that would be huge.”

Systemic Failings Any attempted or successful data breach will prompt pharma companies to question whether they could have been better

prepared. It usually feels like a classic Black Swan event – the attack seemed to come from nowhere yet looking back the risks were obvious. Weak passwords, security patches not being updated, and tech teams being too thinly stretched to manage the continued threat of cyber-attacks are some of the most common and obvious reasons why systems are compromised.

Security is not, as Jim suggests, just a problem for IT teams to deal with but everyone’s responsibility. He advocates ongoing reviews and investment in the three pillars of ‘people, processes and technology’ as the best defence from cyber-attacks.

Clearly, it’s important to empower people to make good decisions and develop processes that everyone understands and adheres to, from senior managers to production teams wherever they’re based.

But what about the technology, so critical for operational and commercial success yet also a potential weak link in security? The problem is not the technology itself – rather the way IT infrastructure has evolved in many global pharmaceutical companies.

They might have a centralised IT service responsible for thousands of software solutions across different sites, or else the service will be contracted out. Some have also inherited risky legacy systems following the acquisition of smaller companies.

The technical team can’t possibly be an expert in all of these solutions. Applying for software licences and managing upgrades and security patches becomes time-consuming and unmanageable. One upgrade could take between six and nine months to plan and implement and involve dozens of people. Then you’ve got to align individuals, evaluate the risks and deploy at scale. Upgrades on a managed cloud-based system, in contrast, would normally take just half a day.

Often, the end-users, the people making the life-saving drugs, are left stuck in the middle. They can do their bit by following good security practices but they’re busy professionals who want their systems to ‘just work’ when they need them to.

Another issue is that pharma is a heavily regulated industry, and all production

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Technology significantly enhance a drug manufacturer’s cyber-resilience, and the time required for training is minimal compared to the disruption that follows a breach.

Technology firms, including cloud hosting providers, also have a responsibility to maintain the highest security standards and earn the trust of the pharma industry.

processes have to be validated, so it used to make sense to have their servers in data centres they owned and managed.

All that’s changed over the past five years though. What we’re now seeing is a growing appetite for cloud hosting because of the flexibility and scalability it offers but also the security.

During my conversation with Jim, he noted that it makes sense to store highly sensitive data on-premise, but this data must be carefully monitored. For example, who has access, how do they access it and when can they access it. However, migrating operations to the cloud can offer a level of security that’s difficult for internal IT teams to match.

“There’s nothing wrong with on-premise servers but you mustn’t forget to budget not just for the maintenance but also the security monitoring of those servers, which should be running every minute of every day,” he said.

“Few companies have the appetite to continually invest in high quality automated services for their servers 24 hours a day, 365 days a year, which is why they turn to a managed provider with the security already built-in. Secure cloud services are already being used for highly sensitive information by household brands, law firms and governments, and if it’s good enough for them, it can be good enough for pharma.”

Preparing Your War Room Pharma manufacturers, like any other, hope to never have to put their cyber-security response into action but not having a plan in place could be catastrophic. The industry lives under constant threat from ransomware attacks, which are becoming ever-more sophisticated and frequent.

42 INTERNATIONAL PHARMACEUTICAL INDUSTRY

What’s more, figures from IBM show that pharma companies take an average of 277 days to identify and contain a data breach, by which time valuable data could be irretrievably lost, so early detection is key.4 Should the worst occur, senior management need to mobilise their response and recovery teams quickly. Clear processes and a chain of command helps to prevent any hold-ups or errors made under pressure.

Internal and outsourced tech experts play a leading role in containing the threat but stemming the operational, financial, reputational damage requires a collective effort from a cross-section of teams.

Jim explained: “Response and recovery awareness is key. Creating a good plan means asking questions like which teams will come together and when; what controls are in place to categorise the attack, who’ll be accountable and empowered to take action?

“If a factory has to be shut down, you could wait for a senior manager to approve it, which is slow. Alternatively, you can train someone on site to pull the plug and limit the damage. When you’re against the clock, this person is a hero because they’ve saved the company millions.”

Conclusion As Jim asserts, the best form of defence against cyber-attacks is educating staff and creating a culture that promotes the right behaviours.

It’s important to measure people’s understanding regularly – could they spot a new type of phishing email; do they know why they need unique, long and complex passwords; and do they understand the enormity of the risk? All this could

Their infrastructure should support continuous back-up and fast recovery of data in the event of an attack. They’ll need dedicated cyber-security experts too, and hold relevant certifications, including ISO 27001 for information security management. A Tier 3 data centre offers protection against physical threats, such as fires or natural disasters, and high levels of security for personnel. By storing data in multiple high-grade data centres, the risk of downtime is reduced even further.

Even outside of a pandemic, pharma companies are under pressure to develop innovative treatments and meet their contractual obligations. In order to fully realise the benefits of data-driven technologies in drug research, manufacturing and delivery, they cannot afford to neglect the threat of cyber-attacks. While attempts may become more sophisticated, staying ahead of the latest trends will help to avoid the Black Swan events that can cripple entire organisations.

REFERENCES 1.

2.

3.

4.

Source: https://home.kpmg/xx/en/home/ insights/2020/05/rise-of-ransomware-duringcovid-19.html Source: www.ncsc.gov.uk/annual-review/2020/ ncsc-accessible-version/index.html#chapter-1 Source: https://investors.biontech.de/newsreleases/news-release-details/statementregarding-cyber-attack-european-medicinesagency Source: www.ibm.com/security/data-breach

Rod Schregardus Rod is the production planning and scheduling software specialist at The Access Group. He works with industryleading pharma and biopharma companies in the US, UK and Europe to help them to optimise manufacturing capacity while maintaining validated processes, within a highly-secure datadriven environment.

Winter 2021 Volume 13 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Technology

How Technology Can Make Pharmaceutical Packaging Design an Easier Pill to Swallow Packaging is one of the most vital components in modern commerce. It must define and promote a product and brand whilst being functional and provide relevant information. It should attract customers, augmenting their interest and confidence. It is an essential part of any product that should never be overlooked.

For the pharmaceutical industry, packaging is on a whole other echelon of importance. The strict regulations that govern the quality and standards of drugs also extend to its containment. This presents significant manufacturing hurdles, not present in other industries.

Pharmaceutical packaging has to be exact, for storage and transit and ultimately to saves lives. As well as protecting medication, it requires material traceability, good manufacturing practices, consistent quality and often child-resistance. The packaging must also support clear labelling to ensure customers fully understand what they’re taking, as the safe consumption of pharmaceutical products depends on how well a patient understood the instructions.

The tight regulations even relate to the label itself and the glue that’s used to attach it.

Drug packaging is also hugely influential in consumer decision-making, conveying trust in the safety and efficacy of the medicine provided.

Some pharmaceuticals are produced in small quantities to enable product diversity while others are manufactured in huge volumes. Some have patent protection while others are generic products with strict cost constraints. Pharmaceutical companies set aggressive and tightly co-ordinated schedules, with no room for error or miscalculations. Compliant packaging requires precise manufacturing management.

Achieving Sustainability in Drug Packaging Whilst safety, not environmental friendliness, is the top priority for pharmaceutical packaging, sustainability is a critical consideration for any sector in today’s society. Customers too now have a greater focus on sustainable purchasing, increasingly gravitating towards businesses and products that benefit the environment.

Embracing greener approaches has become a key strategic aim for drug developers and there is a tremendous opportunity within the manufacturing practices and processes for it to become more sustainable.

Sustainability in pharmaceutical packaging should be considered holistically to understand how a positive impact can be achieved throughout the supply chain and how to embrace technical, environmental and social practices in this endeavour. For example, this could include incorporating more sustainable and efficient design at the beginning of package development.

The resulting challenge is how to accommodate even more demanding production schedules and product variety in the most sustainable way possible.

Pharmaceutical manufacturers must find packaging solutions that minimise the environmental impact of expanding product lines.

Reducing environmental impact and footprint is a key priority for manufacturers in general. Indeed 1 in 4 manufacturers (26%) we surveyed1 are motivated to build a new factor or upgrade existing facilities to improve their sustainability practices. 9 out of 10 (89%) were confident of helping the UK Government to reach net zero emissions by 2050. Amongst shorter-term sustainability goals, almost half (42%) of manufacturers identified the reduction of power usage as a top priority in the manufacturing process, with 45% prioritising the reduction of consumables.

44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2021 Volume 13 Issue 4

Technology simulation software. Today, leading system integrators and original equipment manufacturer (OEMs) are using simulation software to design, validate, and sell pharmaceutical manufacturing solutions.

The simulation designs, optimises and verifies the packaging process and production feasibility while reducing time taken and cost incurred. It adds realism by highlighting how the actual process would work using the pharmaceutical company’s own products and tasks.

The question overall is how best to move towards more sustainable pharmaceutical production and packaging within a heavily regulated industry.

How Technology Accelerates Pharmaceutical Packaging Pharmaceutical companies distributing life-saving medications must be able to move more rapidly with the way pharmaceutical packaging is designed and commissioned. But long development and approval times present particular issues.

Manufacturers need to quickly plan and set up production but with care as process changes generally require approval. Process validation, documentation, and traceability requirements are onerous, and exacerbated by relentless price-down pressures, especially as patents expire.

When it comes to accelerating the time from lab bench to commercial use, technology can speed up and scale up production. Today it is revolutionising the way companies manufacture, improve and distribute their products. Manufacturers are integrating enabling technologies into

their production facilities and throughout their operations.

For example, using robots for preprogrammed packaging tasks is improving manufacturing rates, achieving uninterrupted production lines and saving money on wages. Now playing an irreplaceable role in pharmaceutical packaging sectors, they have become cheaper, smarter and more flexible. They can perform tasks around three or four times quicker than humans and be used up to 24 hours a day. Some robots have been specifically designed for reducing contamination.

Conveyors are also delivering a better and slicker workflow and minimising cross-contamination from the handling of different products. Precision, control and reliability make them a critical element in a pharmaceutical packaging line. Preprogramming of both conveyors and robotics is key to ensuring the unique demands of pharmaceutical production are met.

The Power of Simulation Software A more powerful tool is 3D manufacturing

These technologies can create an accurate and dynamic model of a production facility and allow experimentation with manufacturing processes in a virtual setting. Users can quickly move through the process of designing and building models. Importantly this improves project stakeholder understanding and builds trust, enabling faster, more informed decisions to be taken across different teams.

The use of automation can also allow businesses using simulation to increase production capacity and process flexibility.

Indeed, one of our pharmaceutical customers used our simulation capability to achieve a 35% gain in efficiency gains across two production lines, improvements of 34% in robot productivity and a 33% reduction in floor space requirements.

Another example of this was in our work with DHL. Their constantly changing nature and highly competitive world of supply chain and logistics meant that they must move quickly and at the lowest possible cost. Packaging in healthcare was carried out manually at many individual workstations across the UK. Using simulation, they were able to evaluate the automation of the non-value-added tasks to improve production line efficiency whilst balancing best practice. By being able to visualise the switch from individual workstations to a balanced flowline, they could validate efficiency improvements of 35%.

Manufacturing Mistakes Can Be Costly Whilst the pharmaceutical industry is flourishing, cost reduction strategies are crucial to support future growth. So, minimising costly mistakes in manufacturing is vital. In our recent study amongst UK manufacturers, almost all of the companies we interviewed (97%) had made at least one mistake in their manufacturing projects. The study revealed that mistakes and/or associated downtime in the manufacturing

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 45

Technology

process typically costs organisations £98,000 on average, with 2% of respondents saying they incur costs over £1 million. Staggeringly, for some, the cost of correcting errors was over £2.5million.

With the cost of failure so significant, the acknowledgement that 59% of mistakes or faults could have been avoided with the use of simulation software, shows the technology’s potential in helping organisations save significant sums of money.

The Right Technology is Imperative Pharmaceutical packaging is complex.

With ever-changing consumer demands, the manufacturing processes need better planning and flexibility. Virtual tools, supported by process and expertise, can identify performance flaws and production challenges. It can help pharmaceutical manufacturers accelerate the functional and design qualification of the production systems with easy-to-use simulation features. Additionally, production simulation helps with risk analysis by the visual testing and identification of bottlenecks.

The advanced technology can take ideas and convert them to viable production ready design. By using simulation to demonstrate the overall process with actual products and tasks it provides credibility, making production decisions faster compared to the cases without simulation. Put simply, it can 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

make the difference between success and failure.

required, less time is needed, and fewer types of equipment are used.

The appetite for supporting technologies is growing among organisations, with artificial intelligence (24%) viewed as important to building or redesigning the factories of the future. However, choosing the right solution is key as choosing the wrong one can delay progress. More than half of manufacturers (57%) feel that the simulation software they use to design new factories or upgrade existing sites is not easy-to-use, with two-thirds (66%) admitting to not using the software efficiently.

As healthcare treatments become more complex and the room for error gets narrower, simulation can support the pharmaceutical industry to merge technology and expertise to deliver the right packaging solution. These virtual tools can play a huge part in enabling the safe, fast and accurate production of medicines and its packaging, and supporting the pharmaceutical industry to deliver a higher quality of patient care.

Investment in the right simulation software will enable organisations to benefit from logical, simple workflows and a readyto-use library of manufacturing equipment.

Simplifying Processes in a Complex Industry Packaging is a science that is a major success contributor for pharmaceutical industries.

Whilst the pharmaceutical industry is continuously evolving, its advancement depends on the development in packaging technology.

Authentic simulation of real-life processes can greatly accelerate packaging design for pharmaceutical products, improving the speed to market. It can ensure materials are used more efficiently, fewer people are

Steve Morris Steve Morris is Country Manager for UK & Ireland at Visual Components and is knowledgeable on all things Digital/Data / AI/Machine Learning/3D Simulation.

Responsible for setting sales strategy and execution across geographic markets and industry verticals. Development of customer value propositions that solve complex operational problems by joining the dots and through advanced AI & ML algorithms and applications, software simulation producing positive outcomes and benefits that provide real return on ROI projects and programs.

Winter 2021 Volume 13 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 47

Manufacturing

Operational Readiness – The Precursor to Operational Excellence Following any tech transfer project, the subsequent startup of the manufacturing line is almost always full of challenges. The goal is to startup as soon as possible once the project is completed but also to achieve steady state throughput as quickly as possible after the startup begins. This type of startup is what is called a “Vertical Startup.” In practice, vertical startups are rare because management teams typically focus their attention on having the facility and the equipment qualified in time to meet the process qualification milestone. The consequences of this thinking is that a broad range of workstreams are often neglected or receive inadequate attention although they are critical to startup. Workstreams like staffing, training, procedure development, supply chain, analytical methods, etc. must all be ‘ready to go’ by this important milestone. The result can be like having perfectly tuned race cars lined up on the starting line of a Formula 1 race, but with untrained drivers, little gas, unpracticed pit crews, and no spare parts.

Vertical Startups do not happen by accident. The first step requires management teams to transition their focus from a process qualification milestone to an Operational Readiness milestone. Once this happens, operations departments can achieve a Vertical Startup by applying the principles of Operational Readiness, a proven methodology used across the spectrum of manufacturing industries.

Not only is it a proven methodology, it is central to the practice of technology transfer. Despite its importance, Operational Readiness is often not fully understood, not correctly applied, or is confused with the principles of Operational Excellence.

The primary objective of this article is to inform the reader (particularly those who are a part of management teams) about Vertical Startups and how Operational Readiness is the organisational state that needs to be reached in order for vertical startups to exist. The secondary objective 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

is to help the reader build an understanding of Operational Excellence in addition to Operational Readiness. The series will also highlight the need to: (1) design systems which are comprised of production-friendly equipment that is easy and safe to maintain and operate; (2) implement organisational systems to allow for the swift and smooth startup of new equipment recognising safety, product quality, and cost; and (3) decrease the Life Cycle Cost (LCC) of equipment and facilities.

Why a Focus on Readiness?

Getting off to a good start is the essence of Operational Readiness (OR). OR is a management approach widely used in the chemical production and energy sectors which has direct applicability to drug makers.

These industries use formal Operational Readiness and Assessment (OR&A) programs as a risk management paradigm to guide management practices for performing pre-startup reviews of (1) new processes regardless of scale, from big plants to small plant startups, (2) processes that have been shut down for modification, and (3) processes that have been administratively shut down for other reasons. However, being “ready” needs to go beyond just performing pre-startup reviews – particularly for the life sciences industry. It needs to include an analysis of the product input and output variances and the control strategy deployed – not to mention evaluating the actual startup afterwards, which is one of the best performance indicators of OR. For all engineering project startups, anything less than getting up to speed swiftly and smoothly should be considered a lack of preparedness. Considering these points and the definition used in other industries, we define OR as: Operational Readiness is the state of preparedness attained by an organization when they can safely and efficiently startup, achieve design throughput within the design timeframe, and operate that process in control,1 in a sustainable and environmentally friendly manner.

Whereas the idea of Operational Excellence is broader by nature and involves a focus on the value stream:

Operational Excellence is when each employee is commited to mastering their role, can see the flow of value to the customer, and works to continuously improve that flow.

This definition of Operational Excellence is insightful when considering the concept of the Pharma 4.0™ “holistic control strategy,” which is enabled by digitisation and targets all stakeholders along the value chain. “All the necessary data are managed in real time, fully transparent, and available for sound real-time decision-making, improving quality, manufacturing process efficiency, and accuracy. In sum, the holistic control strategy ties regulators, industry members, and patients together in an overall holistic value network structure driven by the Pharma 4.0™ operating model.”1 Given the different domains of both definitions, it is easy to see why it is necessary to separate the terms from one another.

To become operationally ready, leaders must begin working toward that objective early in the project – ideally at the beginning stages of the project during the preliminary design review (but no later than the Design Qualification). This early involvement may surprise most operations managers, but this effort is essential. The traditional approach at these design review stages is to evaluate design concepts for feasibility, technical adequacy, risks, and general compliance to requirements. However, with the ever more complicated equipment being introduced to the market, along with the complex processes being designed, organisations need to start evaluating how friendly the equipment and processes are to operate and maintain, and procuring resilient equipment which eliminates unplanned downtime.

Traditionally, these earliest design activities frequently overlook the operators and maintainers, which becomes evident during plant startup. Instead, the inputs received to the design in the early stages come from scientists who usually don’t have productionscale manufacturing experience. This is a typical miss and projects lose the opportunity to have people experienced in manufacturing provide early input into the process design.

Consider the following tale of two startups in two different imaginary companies: Winter 2021 Volume 13 Issue 4

Manufacturing

Figure 1 – Startup Profiles for Two Different Companies In Figure 1 above, the blue graph represents a company who has invested the time and energy early in the design and prepares its operators and supervisors to startup and operate the equipment.

Their startup is on time and it is “vertical.”

One could conclude that this company is “Operationally Ready” and they achieved that preparedness level prior to startup.

Whereas, the orange graph represents an average company’s attempt at readiness.

They have a “flat” startup, which is costly to patients and investors, and exhausting to their staff. Demand goes unmet or competitors launch competing products. Startup costs rise. And despite their best efforts to reach capacity, their startup period grows longer by the day.

Everyone’s been there, but it doesn’t have to be that way. There are three main areas for consideration by leaders that could ease the challenge of any startup regardless of the end purpose. These are: (1) problem prevention, (2) production friendly equipment and systems, and (3) an organisational approach that formalises operational readininess into an human organisational assessment system.

Systems Thinking for Problem Prevention First, the industry must change when problem identification occurs. Evidence shows that the earlier problems are identified in any engineering project , the better the project performs both in the short term and throughout the entire life cycle of the project. In most engineering projects, designers, project teams, and customers still more or less react and address wwww.international-pharma.com

problems when they arise during the postconstruction testing and startup stage as they rush to project completion. Instead, entering the project with a prevention mindset will tend to drive problem identification early “on paper.” This is not an easy activity since there is no physical equipment to look and the best you often have is preliminary drawings. This approach

succeeds when using multi-functional teams guided by a rigorous process that requires a “systems thinking” mindset before construction begins. “Systems thinking” can mean different things to different people but for this paper it simply means that one should always think in terms of the whole system rather than the parts of the system.

As an extreme example, thinking strictly about building a greenfield facility without thinking about getting ready to operate the new facility could reasonably result in a project that delivers ahead of schedule and under budget but without anyone who is ready to turn it on. Or more commonly, not thinking about how easy or difficult the plant is to operate when the design is on paper (and changes are less costly to make) and waiting on a “debugging” period to identify problems before, during, and after plant startup does not follow a “systems thinking” mindset.

Refer to Figure 2. In this figure, the number of problems identified are now included as a bar graph depicting a simple count of problems versus time. When comparing the timing to the startup, operationally ready companies eliminate problems through redesign, procedure development, and training prior to startup. The net effect is improved operability and maintainability.

Figure 2 – Operationally Ready Company – Problem Identification Timeline INTERNATIONAL PHARMACEUTICAL INDUSTRY 49

Manufacturing have historically recognised that an operational system is comprised of multiple elements: (1) People, (2) Procedures, and (3) Equipment. Consequently, an organisation’s preparedness efforts need to address these three areas individually as well as in an integrated fashion. Logic trees are frequently used for this effort as a visual diagnosis that lays out a problem and all its possible solutions, allowing you to choose the best course of action.

Figure 4 lays out the three key elements to achieving Operational Readiness through an “AND” relationship, which means all three are required. These three elements provide only half of the analytical picture, however. Consideration must be given to the interfaces among these elements.

Figure 3 – Not Operationally Ready Company – Problem Identification Timeline Whereas in Figure 3, problems with maintainability, operability, safety, and supportability are identified during testing and after startup. This delays the facility achieving full-scale operational output.

Moreover, overall life cycle costs increase as design changes become cost-prohibitive or are intentionally delayed.

The inevitable time pressures from this company’s poor startup will lead to “heroic,” uniquely designed fixes that are unsustainable operationally or financially, creating further waves of problems to solve long after startup.

Operational Readiness and User Friendly Plants Second, designers must begin adding a new function to the design team, someone skilled in the ways of operability – similar to the function of a user interface designer on a software engineering team – to maintain “production friendly” status throughout the project. Human-machine interface best practices can be used to greatly improve equipment operability. A properly designed interface solution not only enhances productivity of the operator, but also provides system insight to control and maintain the machine.

50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Much of the pioneering done in this area relied on carefully documenting lessons learned and constructing varying levels of mockups in advance of building the final product. Lessons learned would have the greatest impact when designs were repeated in “a cookie cutter” approach which is not as prevalent today. Similarly, mocking up designs were used when the technology tended to be more static and were not expected to undergo substantial changes throught the life cycle of the equipment.

The fast pace of change in the industry precludes much of this from being as effective as it was in the past. Nevertheless, the end goal of a vertical startup must incorporate human-machine interface development in order to improve plant operability, maintainability, and throughput.

User friendly equipment makes the condition of being operationally ready that much easier to achieve.

Formal Operational Readiness and Assesment Program Lastly, companies should develop and implement an OR&A program that anticipates problems and either eliminates them or puts management systems in place to mitigate them. OR&A programs

•

Do the people match the equipment?

Is the equipment properly operable for the people who have been selected and trained to operate it; e.g., have we selected people with proper color discrimination to deal with color-coded equipment elements?

•

Do the procedures match the equipment? E.g., have we avoided situations in which the operators have been given Version 1 procedures manuals to operate Version 2 equipment?

•

Do the procedures match the people who are to use them? Do we have selection procedures which assure a proper degree of functional literacy for people who must read and understand complex work procedures; e.g. have we written procedures that focus a person’s attention on the step-by-step task amid the distracting surroundings?

Conclusion The confusion that surrounds Operational Readiness is understandable. The ideal behaviors needed on the Operational Excellence journey are the same behaviors needed to achieve Operational Readiness.

Accepting that both have different contexts is critical to eliminating the mix-up. Operational Readiness requires a mindset of problem identification, anticipation, and elimination in advance of starting up. Operational Excellence is an obsessive focus on the value chain throughout the life of the product, which still requires the same identification, anticipation, and elimination of problems in addition to the other behaviors that drive continuous improvement.

Winter 2021 Volume 13 Issue 4

Manufacturing

Figure 4 – Logic Diagram for Operational Readiness Generally speaking, when it comes to OR&A programs companies have two choices: They may invest time and money to perform the extra early work to prepare as in the case of our imaginary company with the vertical startup, or they may accept the uncertainties and/or lack of system control that may result by waiting until the last minute. The evidence clearly favors the former (compare Toyota and GM’s approach and performance in the 1970’s and 1980’s); therefore, all parties involved in engineering projects and the subsequent startup need to be clear that the objective is to achieve Operational Readiness, as opposed to merely completing the project.

wwww.international-pharma.com

REFERENCES 1.

2.

The phrase “in control” is important because it brings together the guidance of ICH Q8(R2) through ICH Q12 which address the development of a control strategy to ensure that a product of required quality will be produced consistently.

ICH Q10 defines control strategy as: “… a planned set of controls, derived from current product and process understanding, that assures process performance and product quality.”

Heesakkers, H., C. Woelbeling, T Zimmer, N. AlHafez, L. Binggeli, M. Canzoneri, L. Hartmann.

“Applying Holistic Control Strategy in Pharma 4.0™” Pharmaceutical Engineering 40, no 1. (January — February 2020). https://ispe. org/pharmaceutical-engineering/januaryfebruary-2020/applying-holistic-control-strategypharma-40

Richard Tree As COO, Rich is responsible for CAI’s global operations. He is a hands-on senior leader with extensive experience leading operational excellence efforts in diverse types of businesses. He is dedicated to helping companies achieve readiness and resiliency in their operations through highperformance teams. As a lean operations expert and leader, he is personally credited with the lean transformation of 9 manufacturing sites and coaching over 34 manufacturing sites in advanced lean and six-sigma techniques. Rich’s professional career began in the US Navy where he served over twenty-two years on active duty supervising nuclear power operations on four submarines. He has since served in multiple leadership roles from Engineering Director to COO in three manufacturing companies prior to joining CAI. He is currently working on his dissertation for a Doctor of Engineering from George Washington University where his research focuses on multicriteria decision analysis. He holds an MBA from Southern Methodist University and a Bachelor of Science degree from Columbia College.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 51

Manufacturing

The Case for Smart, Real-time Quality Monitoring in Life Sciences Manufacturing The more fragmented that processes become, the more critical it is that they can be assessed and managed for consistent quality. During the peak of the pandemic, as drug and medical device production continued at pace, manufacturers experienced a deepening challenge of how to monitor, analyse, report and act on quality performance and any emerging deviations. Siniša Belina, senior life sciences consultant at Amplexor, delves deeper into the potential of modern tools and holds up examples of emerging best practice.

Across a whole swathe of industries, the Covid-19 pandemic has shone a light on restrictive business processes, information silos and poor supply-chain visibility. In life sciences manufacturing, for instance, a range of challenges linked to quality management have been exposed and starkly felt.

52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

On the one hand, public safety measures over the last 18+ months have put physical distance between team members – hampering the usual form-filling, manual signoffs and Excel-based record-keeping associated with monitoring traditional manufacturing processes. And informal discussions at the watercooler, in which patterns of emerging problems might have surfaced, have simply not happened.

best chance of accurately processing reams of incoming adverse event data, and meeting deadlines – with the confidence that nothing critical will be missed.

Anticipation is Everything Increased practical barriers to quality assurance, added to the missed opportunities to spot and pre-empt issues along the supply chain using data analytics, have helped drive a renewed business case for intelligent, joined-up quality monitoring based on a single, global, real-time graphical view of all aspects of production.

The case for harnessing smart, real-time quality analytics is strong and growing.

Particularly where artificial intelligence/ machine learning is involved, this is about being able to spot emerging patterns very early on – at the first sign of deviation/ non-conformance. Issues might range from recurring problems with equipment to varying impurity levels/product instability whose cause needs further investigation.

In the meantime, other parts of pharma organisations have seen first-hand the benefit of pre-emptive signal detection. This is most visible in pharmacovigilance, where use of smart systems present a department’s

Proactively monitoring and establishing alerts for potential manufacturing quality issues/product deviations, or process nonconformance, would be another logical use case for the same kind of software solution.

Missed Opportunities to Act Up to now, the tendency has been to view quality monitoring as a compliance activity, linked to the regulatory requirement for

Winter 2021 Volume 13 Issue 4

Manufacturing in a centralised, cloud-based repository that underpins multiple use cases.

As long as contributing data continues to exist in Excel spreadsheets and individual Access databases, the scope for viewing and acting on the complete, evolving picture – or any particular part thereof – will be severely limited.

Beyond an integral master data source, the ability to configure the analytics, viewing, and reporting experience to fit the particular user requirements will be important, as well as the ability to set thresholds or parameters to trigger push notifications or alerts to the relevant people if these are approached or exceeded. a periodic Product Quality Review. Yet this approach doesn’t necessarily invite continuous, real-time quality monitoring, nor with it the chance to stave off production line issues before avoidable risks and costs are incurred. If issues do surface during preparations for a review, these are likely to be fairly established and now require retrospective investigation to determine what has gone wrong, the likely root cause, what the impact may have been, and what remedial action is now required.

This is a wasted opportunity, especially as much of the data to support more continuous and timely quality tracking is being gathered anyway – with a view to creating that annual review report at some later date.

The issue is that this data is not being amalgamated, compared, or processed in the moment – to produce actionable insights and/or to trigger alerts.

Transcending System Silos to Build the Big Picture Moving to a situation that enables continuous, active quality monitoring does not require a major upheaval. The main criterion is that systems are able to draw on data from across functional or departmental silos, so that deviation details, environmental data, complaint information, and Corrective and Preventive Action (CAPA) records can be combined and cross-checked on the fly.

Better still, analytics and reporting tools should be able to call on historical data too, allowing live comparisons to be made and enabling immediate smart signal detection wherever incoming data deviates from current parameters and past patterns.

All life sciences manufacturers are on a drive to be more effective and efficient with wwww.international-pharma.com

resources, driving up quality without overextending internal resources – and smart, real-time quality monitoring and reporting plays directly to this requirement.

What’s more, it is much easier to implement such capabilities in the current ‘cloud-first’, ‘platform-based’ enterprise IT environment. Here, adding new capabilities and use cases is often simply a case of switching on additional features, or user groups who are able to draw on alreadycentralised, pre-integrated data, for tailored display and application for their own particular purposes.

Hindsight isn’t Always a Wonderful Thing Given that, as already noted, much of the data exists or is being captured already, adding in smart analytics and reporting capability can elicit an immediate return – by saving resources/reducing waste, and ultimately by preventing a sub-standard product batch from leaving the production line.

Rather than conducting quality reviews and further investigations in hindsight, smart on-the-fly reporting gives manufacturing teams a chance to explore emerging issues and perform root-cause analyses in real time. If impurity levels are seen to exceed accepted norms, for instance, teams can swiftly move to determine whether the issue might be a variance in the air humidity. This in turn might be traced back to a change of heating/ventilation/air conditioning (HVAC) system.

Creating New Clarity via The Cloud The starting point for the shift of emphasis towards continuous quality monitoring must be an amalgamation of data sources, ideally

The good news is that all of these capabilities are well within companies’ reach and can often build on the data sources teams have already established. Once those responsible begin to think beyond compliance toward the efficiency, cost and risk reduction benefits that come from being better informed, the business case for smart real-time quality analytics in life sciences manufacturing tends to write itself.

Siniša Belina Siniša Belina is a Senior Life Sciences Consultant at Amplexor, where he has worked for the last 13 years. He is an experienced consultant with history of working in the pharmaceutical and IT industry, with particular skills in Pharmaceutics, Quality Management, Regulatory Affairs, and Document Management. Siniša applies this detailed knowledge to the areas of business process analysis, optimisation of software solutions, and demonstration of their capabilities. He possesses a Master of Science in Pharmacy from Zagreb University. Amplexor helps life sciences organisations ensure quality, efficacy, and safety through efficient, end-to-end support for product lifecycle processes, data, and content management.

Email: sinisa.belina@amplexor.com Web: www.amplexor.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 53

Manufacturing

Understanding the Challenges of Highly Potent Actives Mario Di Carmine, Pfizer CentreOne Lead at the Pfizer manufacturing site at Ascoli, Italy explores the challenges facing pharmaceutical companies when using highly potent active ingredients (HPAPIs) for the first time.

A rising number of active pharmaceutical ingredients (APIs) are classed at “highly potent”.

They are being increasingly harnessed by pharma companies developing oral solid dose (OSD) treatments to treat a variety of chronic conditions. For instance, they are being explored as potential new cancer therapies, and as treatments designed to block immunological response to prevent organ rejection following transplants. They even have the potential to provide enhanced contraception capabilities, as well as to manage a range of other disease states and chronic conditions, such as heart disease.

The popularity of HPAPIs is due precisely to their high potency. They elicit a more targeted pharmacological effect at a lower concentration than standard APIs, which results in smaller dosage requirements.

For OSD products in particular, this key benefit can significantly enhance the patient experience in a number of ways: •

•

Allows for smaller pills – a significant advantage when creating medication for patients who may have difficulty swallowing Allows for less frequent dosing – enhances convenience for patients as they don’t have to interrupt their routine as often to administer.

HPAPIs don’t just have benefits for patients, they offer advantages for drug developers as well. In many cases, such ingredients are being explored for their potential to treat the currently unmet needs of patients with serious, life-threatening conditions. As a result, for many drug applications, HPAPIs can receive fast-track designation or accelerated approval from regulatory bodies, significantly speeding up time-to-market.

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With all of this in mind, it is no surprise, then, that the global market for these highly potent APIs (HPAPIs) is expected to reach nearly $27.9 billion by 2027, growing at a CAGR of 6.1%.1 Challenges to Developing with HPAPIs However, harnessing HPAPIs does have its challenges when it comes to developing and manufacturing OSD products. Their potency means they pose a serious health and safety risk for employees that must be considered at all stages of the development and manufacturing process, as well as during tech transfers that must be addressed to safeguard team members.

Adding to the complexity, HPAPIs encompass a wide range of compounds of varying strength and varying safety risks, meaning one size does not fit all when it comes to control measures. Expert support is needed to address these issues and to ensure efficient and effective development and commercial manufacturing of OSD products.

So, what must pharma companies bear in mind in order to harness HPAPIs for their OSD products successfully? Here are the four key challenges that need to be considered and overcome both during the development process and during commercial manufacturing of finished products: Challenge 1: Classifying Potency Effectively As we have mentioned, HPAPI is a large and diverse category of ingredients, each with its own features, benefits, needs and hazards.

It is crucial to understand the potency and toxicity of the API being used in the OSD product, in order to establish the most appropriate production line measures to minimise safety risks for employees.

Broadly speaking, an API is classed as “highly potent” if it – or the intermediates that are used to make it – falls into one of the following categories: •

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 dose of 1

•

•

milligram (mg) or below per day.

An API or intermediate with high selectivity, meaning the ability to bind to specific receptors or inhibit specific enzymes, and/or the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses.

A novel compound of unknown potency and toxicity.

APIs can be further classified into four categories under the performance-based exposure control limits (PBECL) system according to their potency and toxicity: • • •

•

Category 1 compounds: are low potency with higher dosage levels.

Category 2 compounds: moderate acute or chronic toxicity, but their effects are reversible.

Category 3 compounds: have elevated potency, with high acute or chronic toxicity; these effects may be irreversible.

Category 4 compounds: have high potency and extreme acute and chronic toxicity, cause irreversible effects and are likely to be strong sensitisers, with poor or no warning properties and a rapid absorption rate.

All highly potent products are category 3 or 4 in this system, based on their cumulative risk factors; regulatory requirements for containment and protection vary depending on the category.

In order to address the next three challenges, it is crucial to understand exactly where the API in question sits in each of the above categories. The higher the category, the more stringent the containment and safety processes have to be in development facilities and on manufacturing lines to safeguard employees and to minimise the risk of cross-contamination between products. Support from experts in HPAPI handling is crucial to identify and understand the category the ingredient in question should be placed in.

Challenge 2: Establishing the Most Effective Approach to Containment for The OSD Line Once the potency, the toxicity and Winter 2021 Volume 13 Issue 4

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Manufacturing precise nature of the safety risk is firmly established, it is crucial to identify and develop appropriate containment measures for the OSD production line. A number of key elements must be considered to develop an effective safety strategy: • The criticality of the HPAPI in question – meaning the precise risk posed by the chemical.

• The layout of the production line – OSD production lines in particular feature a number of areas where potential containment issues can occur, requiring stringent control measures. Points where operations take place that have a high probability of dust dispersion, such as dispensing, granulation or sieving, may be designated High Contamination Areas, requiring the most stringent controls. Areas with operations that have a low probability of dust dispersion, such as tablet collection, in-process control (IPC) testing and primary packaging, may be designated Low Contamination Areas, requiring less rigorous measures. Normal Pharma Areas, such as secondary packaging lines, require no special controls, as there is no probability of dust becoming airborne.

• High containment equipment – such as isolators to minimise the risk of containment breaches occurring.

• Material flow – OSD production often requires the processing and handling of dry powdered materials, which can be a particular concern due to their ability to become airborne.

If appropriate containment and cleanroom measures aren’t taken – and if portable equipment containing the HPAPI isn’t handled correctly – airborne particles can easily escape the confines of the production line, or even enter air ventilation systems to circulate throughout the wider facility, with repercussions for employee safety.

• Personnel flow – it is not enough to consider the layout of the production line and the flow of material to establish control measures. It is also important to take into account employee behaviour and the way they move through the production line. This is crucial to establish points on the line and the times where they need to be in contact with production equipment, such as during cleaning or production changeovers. Understanding such factors is key to establishing measures to minimise contamination and optimise safety.

56 INTERNATIONAL PHARMACEUTICAL INDUSTRY

•

•

•

•

Personal protective equipment (PPE) – is crucial to ensuring optimum employee safety. The type of PPE – protective suits or fitted masks – required will depend on the nature of the material – whether it is dry and easily made airborne – as well as the nature of its toxicity.

Environmental management – the waste products from HPAPI processing can have negative implications for the surrounding environment, wildlife, and local communities too. This means they need to be managed and disposed of carefully after use.

Procedures and training – in addition to all of this, it is crucial to establish training and safety protocols for employees to ensure they understand the risks involved on the production line and know what they need to do to manage and safeguard their own health and that of their colleagues.

Monitoring – continuous monitoring of safety systems should also be included in order to ensure control points continue to offer optimum performance, maximising safety for employees.

To optimise containment and minimise safety risks, it is advised to develop a strategy covering all of these elements in line with local regulatory requirements.

Building a dedicated HPAPI-handling facility within a larger site – the so-called “plant-inplant” concept – can go a long way towards streamlining the requirements within such a strategy. Such an approach can minimise the risk of cross-contamination by isolating HPAPI production from other manufacturing projects. It can also reduce training and PPE requirements, as it will only be necessary to train the individuals working in the HPAPI facility itself, rather than the entire workforce.

Challenge 3: Effective Technology Transfer Strategies It is often the case that HPAPI OSD projects have to be transferred either between the drug developers’ own facilities, or from the drug developer’s site to that of a trusted contract development and manufacturing organisation (CDMO). Not only must the new facility be adequately prepared to ensure containment of the HPAPI prior to the start of operations, but steps must also be taken during the transit of the HPAPI material to minimise contamination risk.

To ensure optimum containment throughout, an accurate preliminary strategy

can be crucial. It can help intercept and anticipate any and all possible issues that may be encountered. These include process robustness, regulatory and environmental health and safety aspects, and last, but not least, equipment classifications.

Equipment classification is as critical as any other aspect of the technology transfer, in order to ensure the equipment at the receiving site is comparable to that at the donor site. Classification must be done according to the requirements of the Scale-Up and Post-Approval Changes (SUPAC) guidelines drawn up by the US Food & Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER). This guidance offers a comprehensive list of comparable equipment, allowing companies to determine whether adjustments need to be made to the receiving site prior to any transfer, saving time and resource, while also ensuring safe handling of any APAPI. The features of an effective strategy include: • • • • •

Site segregation assessment Process robustness verification Process optimisation Regulatory considerations Environmental health and safety considerations

Experience is the key to understanding the needs of the HPAPI and the drug formulation in all of these areas. This will help ensure the HPAPI and its accompanying materials are transferred smoothly and safely.

The specific type of technology transfer will also dictate what is contained within the strategy. There are two different types of technology transfer: •

•

Primary – where the product is transferred from research & development (R&D) to the Receiving Site, such as a CDMO or contract manufacturing organisation (CMO).

Secondary – where the product is already on the market and its production is transferred from the Sending Site to the Receiving Site (site-to-site).

The secondary transfer of a project, given that it takes place within a company’s own operations, should be reasonably straightforward as communications channels between the two sites should Winter 2021 Volume 13 Issue 4

Manufacturing contained production lines quickly and efficiently, streamlining project timeframes while ensuring optimum health and safety.

Reconciling Efficiency with Safety in HPAPI OSD Production Given the potential of HPAPIs not just to enhance patient convenience, but to treat a wide array of serious, previously untreatable conditions, it is no surprise that so many new highly potent drug candidates are entering development all the time.

As a well-established, effective, and highly convenient dosage form for systemic drug delivery, OSD offers a number of unique benefits that complement the patient convenience advantages of HPAPIs. As such, we can expect the number of HPAPI OSD development and manufacturing projects to continue to grow into the future.

already be well established. Primary transfers may be more complex, as lines of communication between the company and its outsourced CDMO partner may need to be built from the ground up if the relationship is new. With this in mind, it is crucial to engage expert partners that have experience in HPAPI transfers in order to ensure the process takes place smoothly, with minimal risk of containment breaches or delays.

Challenge 4: Safe and Effective HPAPI OSD Production and Packaging Lines Finally, regardless of whether a transfer has taken place or not, it is important to ensure that the production and packaging lines are suitable for safe and effective HPAPI OSD production.

An ideal HPAPI OSD manufacturing and packaging line should include: •

•

•

High containment processes in a closed system with control measures throughout in line with the requirements of the category classification of the HPAPI being handled.

HPAPI dispensing and milling equipment contained in a segregated area or isolator staffed only with qualified personnel to minimise contamination and safety risk for employees.

If producing tablets, dry granulation with pre-tabletting, sieving, and tabletting in a segregated cleanroom

wwww.international-pharma.com

•

• •

area again to optimise containment and safeguard worker wellbeing.

For capsules, high or low-shear wet granulation and drying with capsule filling in a segregated cleanroom environment.

Tablet visual inspection systems to allow safe, remote quality control processes.

Contained packaging lines to minimise containment breach risks as the finished tablets or capsules are dispensed into their primary packaging.

The containment protocols depend on the nature of the chosen packaging – the containment equipment needed for a bottle presentation necessarily differs from that required for blister packs.

The inclusion of technologies can help further minimise safety risks on HPAPI OSD lines. For example, housing HPAPI manufacturing and packaging processes within "pressure cascade" systems can prevent contamination of external areas. A nitrogen inserting system can be installed to provide protection for team members handling hazardous compounds with solvents.

The measures needed to create a secure and contained HPAPI processing line takes considerable time and investment to put in place. Outsourcing processing and packaging of HPAPI OSDs can help pharma companies access effective, high-quality

Nevertheless, the potency and toxicity of HPAPIs means that careful consideration needs to be taken to the facilities and processes in place at the site intended to handle manufacturing and packaging.

Failure to take appropriate steps can have negative ramifications for employees, as well as the surrounding environment and neighbouring communities as well.

By taking into account the challenges we have discussed, and taking steps to address them as early as possible, pharma companies can be confident they have the measures in place to optimise containment throughout every step of their development and manufacturing process. In doing so, they can ensure optimum health and safety, in line with stringent safety regulations.

Mario Di Carmine After joining Pfizer in 2001 as a Finance Analyst, Mario progressed through the ranks as Finance Manager, Ascoli Finance Lead, and Supply Chain Lead.

He now heads up the Ascoli site team as a Pfizer CenterOne Lead. Mario holds a master’s degree in Economics and Business Administration and an APICS Certification. In his role, Mario manages business development, introduces new products, and oversees all CDMO activities at the Ascoli site.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 57

Packaging

Product Protection via Primary Packaging – Screwcaps to the Rescue The use of screw caps to seal bottles for consumer use varies greatly from region to region. However, in North America, as in Europe, many medicines are sold in containers with screw caps.

An important component and part of the packaging of many dosage forms, screw caps are employed to securely close containers holding powders, pastes, liquids and other products.

The tightness they offer, i.e. the low permeability of gases, vapours and aromas, which is guaranteed even after re-closing, is unrivalled. Compliance with regulatory requirements and functional reliability aside, innovative manufacturers of medicinal products are increasingly using screw caps as an additional feature to offer added value to customers, patients or the pharmaceutical filler. Our article presents various possibilities of product protection with the help of innovative screw caps.

In the production of screw caps, plastic injection moulding is favoured for the freedom of design offered. After a onetime investment in an injection mould, the manufacturer is very flexible when it comes to the choice of plastics and colours.

Identical articles in several colours can be produced from one mould without much effort. The plastics can also be varied with each run, an important consideration for differing regulatory requirements.

A batch can be made from a particularly temperature-resistant plastic, for example, or additives that optimise features such as opacity, UV-resistance or barrier properties added.

Recently, innovative brand owners have been focusing on enhancing primary packaging with additional benefits for consumers, patients, and bottlers, such as more information on the bottle. Brand owners can benefit from the generation of data for marketing. Beyond protecting the product from leakage and spoilage, the screw cap as primary packaging material can serve to prevent tampering and counterfeiting of the contents. The WHO 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

assumes that 1 in 10 medical products or medicines in low- and middle-income countries are falsified or substandard.1 Steadily growing online trade ensures the global spread of such counterfeits.

Counterfeiting and manipulation take different forms. Unlike lifestyle items such as sunglasses, the packaging of the medicinal product is the most important clue to its authenticity. The packaging is often the only thing that laypeople, i.e. users and patients, can check for authenticity.

With few possibilities to attach anticounterfeiting protection directly to the product, its primary packaging must take over this enormously important task. There are documented cases where the original packaging of cancer drugs was refilled with an ineffective substance and reintroduced to the market through criminal channels. Unfortunately, undamaged original packaging makes it possible to repackage expired drugs or to circulate drugs that were originally intended for a different target market.

This article presents the various ways in which the screw cap, as the primary packaging material, can contribute to the protection of the contents. It is not only a question of protecting the product from manipulation, it also includes protecting the consumer from counterfeit products. Manufacturers, distributors, and pharmacists are also protected by adequate packaging. Tamper-proof packaging can

protect against unjustified refunds or claims. It can also reveal which part of the supply chain has been tampered with.

Initial Opening Protection as a Base There are a variety of ways to ensure the protection of the products, both visible and hidden. The basis of product protection is to ensure that the packaging and the product belong together. This means that hidden refilling, replacement, etc. of the contents must become impossible. At the same time, the packaging must not have limitless negative impact on usability; senior citizens and physically-impaired persons must also be able to open the packaging easily.

Sealing Foils on The Bottleneck Sealing bottle openings with foil is a widespread, established way of protecting the contents. Consumers know this principle from their everyday lives, e.g. ketchup bottles or milk cans are sealed with foil under the cap. Before consumption, the sealing film must be removed. There are films that can be peeled off in one piece to enable the user to remove them easily.

Films that cannot be removed in one piece and thus make resealing impossible offer a higher level of protection.

Induction and conduction sealing inserts are complex multi-layer sealing discs (see figure 1) which are mounted in the closure.

After capping, the sealing insert is heated in a special sealing unit. An adhesive is activated and bonds to the neck of the

Figure 1 – Structure of the induction insert Winter 2021 Volume 13 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 59

Packaging bottle. Sealing usually takes place directly on the filling lines. This means that another work step must be integrated into the line and corresponding investments have to be made in the sealing equipment. In addition, there are sealing foils that are mounted in the closures, like the induction inserts. With these special inserts, however, the adhesive is not activated by induction heat, but by the pressure generated during the screwing process. These sensitive liners are only used for a few special applications.

When the bottle is opened for the first time, the film must be removed from the bottleneck to allow access to the contents. With sealing foils, a high degree of individualisation is possible through printing. The sealing creates a firm bond between the bottle and the film, providing additional protection for the contents.

However, sealing on the bottle is not the best solution for all applications. For example, induction lines that seal on untreated glass bottles are only available for a few liquid substances.

Screw Caps with Tamper-evident Rings Another possibility to protect the product from fraud is a tamper-evident ring on the closure (Figure 2). When the closure is screwed on, the tamper-evident ring grips behind the retaining ring of the bottle. When the bottle is unscrewed, the ring expands at the retaining ring and either tears off completely (also called "tear-off ring") or merely breaks, as is usually intended for beverage bottles. Consequently, the system only works if the closure and bottle are matched. The bottle must offer retention possibilities for the ring. After opening the closure, the tamper-evident ring remains either on the bottle or on the closure. There is no part to be disposed of separately, as in the case of an induction insert, which has to be removed and then disposed of.

A major advantage is that the closures with tamper-evident rings can be activated without any further technical infrastructure.

The closures can be screwed on manually, which is particularly attractive for bottlers with small batch sizes and budgets, or mechanically on a filling line. Unlike sealing film, the integration of additional technology is not necessary here. In contrast to bottlenecks protected with sealing film, it is possible to check the integrity of the closure while it is still screwed on. This means that the integrity of the packaging, and thus of the contents, can be checked throughout the supply chain. The tamper60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2 – Tamper-evident closures evident ring does not come into direct contact with the contents. Therefore, when designing a closure with a tamper-evident ring, the components that come into contact with the product can be manufactured unchanged from proven materials that may be approved of for product contact. The ring itself can, if necessary, be made of other materials than the closure. In the case of multipart closures, the colour of the ring can be contrasted.

Shrink Sleeves/Labels It is also possible to guarantee the integrity of the packaging with the help of shrink sleeves or labels. In both cases, after filling, the closure is connected to the bottleneck or bottle from the outside with a paper or film. Before the first opening, the connection must be separated. These security measures are popular for small batch sizes and direct sales, such as wine sales in estate bars, because shrink films are easy to apply using a hot air dryer and labels can also be produced in very small runs on office printers. Integration into existing technical processes, on the other hand, is time-consuming and the result is not particularly tamper-proof. Therefore, this option is only mentioned in this article for the sake of completeness.

VISIBLE SOLUTIONS When product protection is visible, no tools are needed for checking. This means that everyone in the supply chain down to the customer can check whether the packaging is original and whether the product has been tampered with. The visible additional feature simultaneously increases the value of the product and the confidence of the users in it. It is vital, therefore, that the responsible persons are educated about the presence of the features.

Laser Marking of the Closures The principle of laser marking of plastics is an established process that has been used in the beverage industry for many years. It is now also being used for primary packaging for pharmaceuticals, diagnostics, and analytics. Closures can be supplied with any desired laser marking. Important information such as the manufacturer, brand and product name or batch number can be lasered on. This makes it easier to identify the contents and avoids confusion.

Other information such as thread size, temperature resistance or hazard symbols can also be lasered. The entire surface of the closure can be used for the inscription, not just the top plate. There are no costs for changes to the injection mould, embossing Winter 2021 Volume 13 Issue 4

Packaging die, or printing plate. This important marking of the closures can be done by the manufacturer as part of an extended service. Alternatively, with the appropriate equipment, customers can also carry out laser marking directly on their premises, for example, on the filling line. This makes for a considerable gain in flexibility in labelling.

Each closure can be individually marked with the batch number or a data matrix code quickly and permanently, details which improve traceability. A data matrix code can hold a wide range of information, such as individual medication intake schedules, which users can transfer to their calendars.

With laser marking, very fine markings are possible, even on smaller areas. This means that a high-information density is achieved.

Since lasers only write with light, no materials other than electricity and suction are needed in the marking process. There is also no need for pre-treatment of the caps. With products such as ink and solvents made superfluous, there is no smearing or drying, and set-up times or downtimes for cleaning are eliminated. Experience from the food and cosmetics industries has shown that this reduces maintenance costs to a minimum.

Injection-moulded Holograms Applying holograms to packaging using foils is an established process. In principle, there are no limits to the design. However, additional processing steps are necessary

either in the filling line or after injection moulding of the closure, which means that the benefit is offset by a corresponding effort in terms of plant technology, integration effort, and thus, costs. An alternative to the classic application, which also promises lower costs in operation and maintenance, is the treatment of the mould surface with nanotech-patterns. The treatment gives the tool a structure (Figure 3); when hot plastic flows onto this surface, this plastic gets the imprint of the surface. Due to the precisely calculated refraction of light, the hologram appears on the surface of the closure when cool. In addition to the firm bond with the closure or primary packaging material made of plastic, this hologram has the advantage that no additional films, additives, or adhesives need to be used to apply the hologram. Established standard colours and plastics can be used to produce the closures, and no adaptation of the raw materials is necessary.

authorised entities in the supply chain with appropriate verification devices. This technique is ideal for detecting supply chain vulnerabilities, to guard against unjustified claims for damages, and to protect brands.

The design of the hologram can either be taken from a database of existing and protected holographic images or created according to individual specifications and adapted to the customer's wishes.

Fingerprint on the Surface of The Closures One surface of the mould is given a special structure that can only be seen with a special camera. The injection mould thus leaves a fingerprint that appears on all parts produced from the mould. The unit costs remain unchanged and there are only one-time costs for coating the mould. The principle is comparable to the hologram technique presented earlier, with the difference that the hologram can be seen with the naked eye. This process is particularly suitable for applications with larger quantities where an identical marking is desired on all parts produced.

HIDDEN SOLUTIONS Unlike with visible solutions, special tools are needed to check packaging with invisible anti-counterfeiting devices. Depending on the desired purpose of the invisible solution, investments need to be made to equip the

Fluorescent Pigments, Printing Ink With a special inkjet printer and security inks invisible in daylight, parts made of plastic can be printed with almost any image. The printing can take place after filling, for example, and contain production-related information. Simple identification with a UV lamp, such as those used for checking banknotes, is possible. If necessary, the form of the closure must be adapted to the printing process for an optimal printing result. Besides the investment in the printer, there are costs for an additional work-step and for the care and maintenance of the printer. The introduction of inks into the filling process is considered a risk in some industries.

Taggants Incorporated in The Plastic Taggants in the closure are microscopic particles that are invisible to the human eye but can be detected by using a detector device. These particles can be finely dispersed throughout the plastic granules.

This technique can be used to authenticate the original container. Closures with and without the taggant are indistinguishable to the human eye, but when excited by a laser, produce a glow.

Figure 3 – Hologram cap wwww.international-pharma.com

The cap with taggant might show, for example, a green dot when a special laser pen shines on it, while the cap without shows no corresponding signal. This distinction now makes it possible to quickly recognise a cap equipped with a taggant as a security feature and the associated container as an original. This authentication can be done by human control using a detector device (e.g. laser pen). Alternatively, detectors can INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Packaging be integrated into machines so that the authentication of containers can also take place in-line in production lines or process plants.

developed apps can be opened through communication between the closure and the smartphone. Therefore, in many cases, this hidden solution is actively promoted by the distributor.

Closures with Integrated NFC Tag One exception to the invisible solutions category are closures with integrated NFC tags. NFC or "Near Field Communication" is the same technology used for contactless payment with credit cards or key cards, and as a result, customer familiarity with this technology is steadily increasing. The closures are equipped with a tag that can be read at a distance of up to 15 cm. The level of security is very high. All chips have a unique serial code, and even the simplest chips can be blocked from being overwritten.

The tags are not visible from the outside, but their presence is often communicated by the brand owners. Special closures offer contactless communication with any NFCenabled smartphone. NFC readers are built into almost all modern smartphones. There are also devices that can be connected to computers, laptops, or tablets. As with the data matrix code, the product can be verified via the manufacturer's website.

This technology can be incorporated into most closures. This avoids costs for new injection moulds or mould changes.

The closures keep their design because the chip is not visible from the outside. The fact that the chip does not come into contact with the product is an advantage for users Technology

Initial outlay

Conclusion Counterfeit protection is an important component in ensuring product safety and makes packaging more attractive. However, the best anti-counterfeiting protection only works if patients and customers are properly trained.

in the food, chemical and pharmaceutical industries.

A wide variety of information or commands can be programmed onto the chip. With corresponding applications, it can be verified that the product is not a counterfeit. This technology can also be used to communicate with a technicallysavvy target group. For example, links to websites, product data sheets or specially

Unit cost

Authentification Method

Expenditure none

Laser marking

very high

high

visual without additional aids / tools

Holograms

high

very low

visual without additional aids / tools

UV colours

high

Nanocoating

none

high

visual with UVlamp

middle

very high

very low

Special highresolution camera

high

Polymerbased solution

middle

high

Optical analysis with special tools

high

NFC tag

low

very high

NFC reader (smart phone)

low

Table 1 – Solution overview 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

While this article is a brief overview of the most common options for product protection via primary packaging, in most projects, a combination of solutions is used. The optimal solution is as varied as the different areas of application of the closures. To choose the right one, a comprehensive examination of the project is necessary. Batch sizes, existing fillings and packaging technology, the product to be filled and the goal of individualization are important criteria in choosing the appropriate or unique design. The higher the level of customisation, the more difficult it is to counterfeit a product.

REFERENCES 1.

https://www.who.int/news/item/28-11-20171-in-10-medical-products-in-developingcountries-is-substandard-or-falsified, visited on 7 Oct 2021.

Clemens Börner As Head of Technical Sales at KISICO, Clemens Börner´s work focuses on advising packaging developers from the pharmaceutical and analytical industries. A business economist and MBA from the University of Mainz, he looks back on more than ten years of experience in his current position.

He supervises new developments and projects with a focus on tamperevidence and anti-counterfeiting.

Solving problems with existing packaging is another important part of his work, and for this, he can draw on the knowledge that KISICO has garnered for over 70 years.

Email: clemens.boerner@kisico.de Winter 2021 Volume 13 Issue 4

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 63 NIPRO PHARMAPACKAGING INTERNATIONAL Blokhuisstraat 42, 2800 Mechelen, Belgium | pharmapackaging@nipro-group.com | www.nipro-group.com

Packaging

Ensuring Complete Product Packaging Quality

Liquid pharmaceutical manufacturers operate under great scrutiny and must set high standards of product quality.

In three steps, Jürgen Kress, General Manager for Checkweighing and Vision Inspection, Mettler-Toledo Product Inspection, outlines how sophisticated weighing technology helps ensure that liquid pharma products are safe for consumers and compliant with regulations. He also examines the importance of serialisation and aggregation, and how product inspection helps drive transparency in the digital supply chain. Finally, he explains the importance of software connectivity as a critical part of making product packaging quality happen.

Step 1: Safety First – Getting Dosage Sizes and Pack Completeness Right It’s no exaggeration to say that quality assurance in liquid pharmaceuticals is a matter of life and death: give a patient too much or too little of a dosage, and the results might prove fatal.

Such potential consequences are bound to keep liquid pharmaceutical manufacturers on their toes. Their responsibility is to drive high standards in product quality, and to maintain these standards through the filling and packaging processes that ultimately deliver the finished product – be it a bottle, vial, ampule, or other vessel – to the patient or health sector organisation that will use it.

of bottles, if not securely supported on the conveyor belt, are liable to tip over during processing. If a container breaks, there is spillage and possible glass fragments that can cause a line to shut down for clean-up, along with waste from the affected products on the line.

Getting the Sensitivity Correct A checkweighing system based on highperformance Electro-Magnetic Force Restoration (EMFR) load cells has the required level of sensitivity to work with such lightweight products. It is not, however, just that the dosage amount might be under – or over – filled; there is also the issue of whether the bottles or vials themselves are of a uniform weight when empty. Even slight fluctuations in the tare weight of the vessel can have a profound impact on the gross weight of the product once filled. Therefore, each individual bottle’s tare weight must be determined first, so that the correct dosage size leads to a predicted gross weight of product.

If fragile glass bottles and vials are not handled carefully during processing, they may break, leading to machine downtime while the problem is rectified. Therefore, checkweighers must have sophisticated product handling capabilities, including sorting and rejection mechanisms, to minimise this risk.

Optimising Productivity This brings us to further benefits that fill level control of liquid pharma can deliver.

Less downtime equals greater productivity and speed to market. Eliminating the risk of over-filling and product give-away ensures that the stock of medicine the manufacturer holds is optimised for the maximum number of bottled products, making the manufacturer more profitable.

The avoidance of serious safety incidents preserves the brand’s good name in the market. All of these dimensions are of an economic benefit to the manufacturer.

Alongside this control of fill level, another key part of quality assurance is the product completeness check. This can relate not just to the liquid itself, but to other things – typically a folded leaflet with medicine information and instructions for use – that must also be included within the product packaging to meet compliance requirements. Once again, these are very lightweight components of the package, but a sensitive checkweighing system can determine whether a pack has a leaflet inside or not by detecting subtle weight differences. An additional countercheck function in checkweighers can also help to ensure that rejected products are indeed off-weight and were correctly rejected. These processes can usually be carried out without disrupting production speeds.

The Technology Solution The solution for liquid pharma manufacturers lies is technical automation.

Product inspection systems can perform the required technical tasks, in a fail-safe manner, and at the production speeds that manufacturers need to operate at to be profitable.

In this specific field, an advanced checkweigher is the best option to check that dosage sizes are correct within primary packaging. The system must be capable of extremely accurate weighing and of careful product handling. These products are very often small, light, fragile, and, in the case 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Packaging

In summary, the checkweigher can inspect the fill level, comparing tare weights with gross weights to make sure the right dosage size has been filled. It can also identify that a packaged product has been completed with all the components that need to be included. Aside from the safety of the patient or consumer, the benefit to the liquid pharma manufacturer of product inspection being able to detect these issues before a product is shipped to market is that they can avoid the significant financial and reputational costs that are the result of product recalls.

With fill level and completeness control, however, the case for the importance of high performance checkweighing becomes more apparent: patient safety is the main priority, but there are financial benefits for the manufacturer too.

Compliance Then there is compliance. Product inspection systems such as checkweighers constantly gather and share production line data.

This can be used to demonstrate that the manufacturer is operating in compliance with governmental regulations such as FDA 21 CFR Part 11 (which requires an audit trail of processing changes to be created and stored electronically), as well as those contractually set down by retailers.

Next Steps As supply chains have become increasingly digitalised, the collection of data has been linked more and more to individual products, each with a unique serial code, enabling it to be instantly identified. This is critical in liquid pharmaceuticals and forms the basis of the second step: Serialisation and Aggregation.

Step 2: Serialisation is The Key to The Digital Supply Chain The pharma supply chain is a digital one, driven by the electronic exchange of data.

It cannot operate without serialisation – giving each product its own unique and verifiable code – and aggregation of batches

66 INTERNATIONAL PHARMACEUTICAL INDUSTRY

of products under a similarly verifiable code.

Context is especially important here. A worrying trend in the pharma market is that of counterfeit medicines, with unscrupulous suppliers seeking to make money from copycat medicines, where the standards of product quality and therefore safety are extremely dubious.

Serialisation The digitalisation of the pharmaceutical supply chain has helped to tackle this problem, and serialisation of products is required in marking out the legitimate products from the fakes. Far more than this though, serialisation also paves the way for digital transparency and traceability throughout the supply chain of individual packs, and manufacturers can benefit from that in many different ways.

For example, it is a fact of life in the pharma business that occasionally there are problems with a product, e.g. a single vial, and it needs to be recalled. With serialisation in place, the manufacturer can utilise the serial code and access an audit trail of events and stages in an individual product’s progression through manufacturing and packaging to distribution. If a recall must be made, the manufacturer can therefore be much more targeted in the scope of its recall, calling back just the specific products that it knows have been affected, rather Winter 2021 Volume 13 Issue 4

Packaging than entire batches, many of which might be perfectly good products.

Aggregation Serialisation is followed by aggregation, where large batches are grouped together in a box, case or pallet for global or regional distribution of products. Aggregation can also serve as an anti-counterfeit measure offering additional assurance by checking these secondary boxes at key distribution points. Aggregation is becoming a mandatory requirement for compliance in many countries.

Whether we are talking about the unique serial code on an individual product or that on aggregated batch, the existence of a verifiable code immediately suggests quality and legitimacy. It reflects positively on the pharma manufacturer. However, an important word here is “verifiable”: the application of the code itself needs to be carried out with high quality, so that it is readable, with no smearing or skewing.

Partly, this is an issue of labelling and printing, in that printing onto labels or directly onto the side or top of a package, must be approached with a view to producing a code that is both clear and legible. That is only half of the story, though – inspection of the code is the second part.

Vision Inspection Vision inspection systems are responsible for reading and quickly identifying packs with incorrect or poor-quality codes. This can save a great deal of time, money, and resources in allowing line stops so that any faults can be quickly rectified, and good quality coding can begin again.

A common practice with aggregated products is to use “helper codes”, printed on top of the products, so that the code can be read even when the product is packed into a container with other products. This still requires some forethought and coordination, since not every vision inspection system is able to read codes on the top of products.

It is important for liquid pharma manufacturers to make an analysis of their applications, bearing in mind the type of packaging they want to use at the final point of sale. Understanding this will aid in the setup of serialisation and aggregation processes so they can assess what their vision inspection requirements will be.

For instance, in liquid pharma, equipment should be able to handle different types of round containers, can read top or helper codes, and can verify small detail datamatrix codes or codes of various sizes.

Sharing Data The analysis must stretch beyond the factory walls too. Serial and aggregation data needs to be shared with the supply chain, so it is also critical that the technology deployed to read and verify codes can also communicate this information to the next links in the chain.

That communication comes about through digital connectivity, requiring software systems that can talk to each other, and that's what the third step will look at: the role of software connectivity in quality assurance for packaged liquid pharmaceutical products.

Step 3: Connectivity Gives Product Data its True Digital Meaning In the previous two steps, we have looked

at ways in which product inspection equipment such as checkweighers and vision inspection systems can help liquid pharmaceutical manufacturers to manage the quality of their products.

In this third step, we move onto the importance of software connectivity to bring this all together. It is a technical challenge to integrate software, but one where pharma manufacturers and their technology suppliers must not cut corners, because the benefits of getting this right can reach into every aspect of a manufacturer’s operation.

Connectivity Equipping product inspection systems with the right software connectivity gives manufacturers a chance to gain a realtime picture of production, processing and packaging lines, allowing them to spot potential problems in advance. It might help them to avoid issues arising in the first place, but at the very least, they will be able to mitigate the damage and costs that they might incur. Being able to quickly pinpoint where something went wrong, and then quickly taking the action required to put it right, will also be appreciated by supply chain partners.

If we consider the word “connectivity” itself, we can gain a greater appreciation of why software connectivity is so important. We exist in a marketplace that is increasingly inter-connected; where the supply chain is transforming towards a fully digital utility that every partner both feeds into and taps into. To achieve true transparency, such a supply chain requires data to be automatically gathered and shared by each partner and passed on via an efficient digital

In liquid pharma, the shapes, and sizes of the primary packaging – bottles, vials, ampules – present their own problems for serialisation and aggregation. For a start, since these kinds of vessels are typically round, they will rotate on the conveyer without a clear orientation of the package label visible at any time. Good product handling is going to be required in printing or applying serial codes directly onto pharmaceutical bottles, if that is the application. In vision inspection, it may be necessary to have technology that provides a full 360-degree view of the product surface, so that serialisation codes can be verified. Such a system would be able to view the product from all sides, regardless of the orientation and thus verify the serialised codes on the package. wwww.international-pharma.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 67

Packaging Compliance, digital supply chain transparency, managing production issues and operating more efficiently and cost effectively are benefits that liquid pharma manufacturers stand to gain by taking a proactive view of software connectivity.

All of these have a bearing on overall product quality – a multi-faceted aspiration for manufacturers in liquid pharma, incorporating the medication and the many processes by which that medication comes through the supply chain to market.

handshake from machine to machine, partner to partner.

Neither the handshake, nor the exchange of data can happen efficiently without software connectivity. In the areas of serialisation and aggregation, in particular, it is crucial. The point of these activities, after all, is to enable easy tracking of products, whether individually or as batches, through the supply chain. The data and the codes are pointless if they go nowhere. Building and sharing an audit trail of actions linked to serial codes serves multiple purposes.

Importance of Data Firstly, it is a record of actions taken during manufacture and onward processing of a product – information that might need to be referred back to in the event of a problem with the product and as reference against attempts by counterfeit operations. Secondly, the data gained is useful for proving good manufacturing practices are being followed and meeting the compliance requirements of different levels of regulations. Thirdly, without this access to digital data, real-time process monitoring, and inventory management cannot meaningfully happen.

Role of Product Inspection Pharma manufacturers will typically deploy checkweighing (for fill level and completeness checks) and vision inspection, to make additional quality checks as needed. Track and trace is a requirement for serialisation and may be optional for aggregation (depending upon the region).

Utilising all three of these technologies will help in supporting top-quality production methods and compliance.

68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Modern checkweighers and vision inspection systems should have advanced software already integrated, with robust security levels and process monitoring capabilities built in. This should be aligned to global and local regulations that follow Good Automated Manufacturing Practice (GAMP 5) guidelines. For track and trace systems, integration into MES- or ERPsystems (Level 5 software) ensures connectivity across single or multiple production sites and provides transparency into the production line data. Exchange of data should be managed through industry standard protocols and software architecture such as OPC UA, PackML and Fieldbus, which supports developments around the Internet of Things and Industry 4.0 initiatives.

Compliance For European manufacturers, compliance with the EU Falsified Medicines Directive (FMD) requires reporting of serialisation data to the European Medicines Verification Organisation (EMVO). Solutions for tracking and tracing the data must also include connectivity to Level 5 software, which in turn reports the data to the EMVO. Partner organisations must be technically certified to do the reporting as they have demonstrated that they meet the technical feasibility to do so.

Additionally, the need to comply with requirements such as those set out by the US FDA CFR 21 Part 11 regulations must also be supported. This FDA clause specifically calls for machinery to create a local electronic audit trail, recording activity such as user logins and machine set-up adjustments.

Conclusion The key point to understand quality assurance for liquid pharma packs is that strong product inspection capabilities are at the centre of any effective quality assurance program. They help in making the production of liquid pharma products safe, complete, trackable, and compliant with all levels of regulations. They play a critical function in creating and maintaining a transparent and connected digital supply chain.

Crucially, product inspection systems do this while supporting manufacturers in meeting productivity and profitability objectives, by keeping production lines running at the speeds required with minimal downtime. Robust and thorough product inspection solutions are a requirement for liquid pharma manufacturers, helping them to overcome some of the many challenges they face today.

For more information: www.mt.com/pipharma-liquid-pr

Jürgen Kress Jürgen Kress studied Physics at University Wuerzburg and SUNY Stony Brook and graduated as Ph.D. in Medical Physics at University Heidelberg. His professional career includes various roles at The Boston Consulting Group, Siemens and Leica Biosystems, where he has worked in Healthcare IT and Diagnostics fields with a focus on Radiology, Cardiology and Pathology information management.

Jürgen joined Mettler-Toledo in 2019 as General Manager of the Checkweighing and Vision Inspection business within the Product Inspection Division.

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Packaging

Delivering Efficiency on The Packing Line

Equipment suppliers can play a key role in ensuring pharmaceutical manufacturers can take a Right First Time approach to their packing requirements, says Richard Aitchison of ATS Packaging Machinery.

To the lay person, the pharmaceutical industry may appear to be bullet-proof, a sector that can survive and prosper whatever the economic climate. Just as the fact that we still have to eat, even in more straitened times, benefits food manufacturers, illness takes no notice of current market conditions. This means that, whether we are seeking treatment for a common cold or a more serious ailment, the pharmaceutical industry will always be needed to provide the remedy.

Even the unprecedented situation of the Covid-19 pandemic has brought about opportunities for the sector. In the USA, for example, a survey undertaken last year

by The Harris Poll on behalf of Samueli Integrative Health Programs found that many adults planned to be more mindful of their self-care habits, with 80% of respondents saying that they would be more likely to practise regular self-care once the pandemic is over.

Sales of vitamins and minerals have also seen huge increases as consumers seek to boost their health and immunity. According to market researcher Kantar, UK sales reached record levels in 2020, with more than half the population having bought a supplement of some type in the past year.

That the pharmaceutical sector is relatively shielded from normal business pressures is of course a huge over-simplification and does not take into account the many challenges that pharmaceutical manufacturers continue to face. The speed of the development of the Covid-19 vaccines has been hugely impressive, but the fact remains that for the vast majority of new drugs, the path from formulation to regulatory approval is usually long and arduous. On average, it can take around ten years for a new medicine to 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

complete the journey from initial discovery to the marketplace, with clinical trials alone taking six to seven years.

The costs are eye-watering as well. A study last year estimated that the median cost of getting a new drug into the market was $985 million, and the average cost was $1.3 billion, although this was much lower compared to previous studies, which have placed the average cost of drug development at $2.8 billion.1 Nor is success guaranteed. Indeed, an article in Scientific Reports in 2019 reported an overall failure rate in drug development of over 96%, including a 90% failure rate during clinical development.

I realise that much of the above is preaching to the converted here, but for equipment manufacturers supplying the pharmaceutical industry, it is vital to be aware of the pressures and challenges that the sector has to face, as it is through these that we can best develop the most appropriate solutions to support our customers.

One thing that has become clear in our own dealings with pharmaceutical companies is that they are just as susceptible to commercial pressures as any other industry. Although, even with the huge development costs involved, the rewards for

finding the next ‘breakthrough’ drug can be immense, there is nevertheless still only a small window of opportunity for pharma businesses to recoup their investment before competitive products and generic alternatives start to come onto the market.

At the same time, the commercial environment is becoming tougher, with consumers now more aware and demanding, seeking improved treatments and therapies but at lower or more affordable prices.

Healthcare payers are also imposing greater cost constraints on healthcare providers and scrutinising more carefully the value offered by each medicine.

Such pressures mean that pharmaceutical manufacturers need to be as agile and flexible as possible, able to respond quickly to changing customer demands and market requirements.

This is particularly important to meet an emerging trend in the sector for personalised medicines, which are customised to the precise requirements of individual patients. This is creating an increasing need for the production of smaller batches of medications which has in turn led to the introduction of modular manufacturing that allows pharmaceutical processing companies to produce multiple batches of different drugs from the same facility.

Winter 2021 Volume 13 Issue 4

Packaging The need for greater flexibility has also led companies to streamline their production processes from start to finish, for example moving from batch-to-batch production to continuous manufacturing.

The more dynamic nature of this process allows pharmaceutical producers to introduce changes with greater ease and efficiency and can help to avoid excessive downtime.

This in turn is leading to greater integration throughout the packing line in order to help increase efficiencies and throughput. The ability of machines to be linked and able to feed information from one to the other helps to ensure that the performance of each piece of equipment can be optimised. For example, container or tube unscramblers can control and regulate the supply of containers to the filling system, and this can then ensure a consistent feed into the capping machine.

In this way, speeds can be maximised, and any bottlenecks avoided for a smooth and continuous filling and packing operation.

Another of the benefits of automating the packing line as much as possible is that it allows shopfloor personnel to be deployed to other parts of the operation where they may be more needed. However, the reduction of people on the line, who can intervene quickly in the event of any problem, means it is all the more essential that the equipment continues to function reliably and consistently. Remote monitoring systems can play an important role here.

Such systems allow individual machines, as well as complete single and multiple packing lines, to be monitored by both the equipment supplier and the pharmaceutical manufacturer and packer. This provides a high level of preventative maintenance where potential issues can be identified and even anticipated, so that action can be taken before machines and packing lines suffer any significant downtime.

The phrase ‘To err is human, to forgive divine’ is a well-known phrase and a very worthy sentiment but in the high-risk area of pharmaceutical production, where the effects of human error can be catastrophic, any mistakes can be ill afforded. For automated systems, therefore, ensuring the correct set-up procedures are implemented is critical. Here, intuitive touch screens can provide step-by-step instructions and prompts, and these can also incorporate different levels of authorisation access for individual employees.

pharmaceutical companies manage their operations more profitably. Businesses need to know exactly how much it costs to get a product or pack out of the factory and be able to easily identify areas where there are opportunities for improvement.

Capturing data allows companies to monitor remotely rather than deploying staff simply to monitor the systems. And the information gathered gives businesses the competitive advantage of being able to optimise production and work as efficiently as possible.

Just as the integration of equipment streamlines processes in order to deliver greater efficiencies, the capture of data from multiple areas of the production line enables the building of a more complete picture. This allows companies to be proactive rather than reactive when it comes to improving practices or methods, by using comprehensive reporting to give them the breadth of information to make informed decisions.

Increased integration and the availability of real-time reporting and data are key parts of the digital transformation of manufacturing that is being achieved through Industry 4.0 and the emergence of the smart factory. Among its many benefits, the adoption of Industry 4.0 principles will further help pharmaceutical manufacturers to increase productivity and quality and minimise risk.

The pharmaceutical industry is of course heavily regulated, and it is essential that all equipment is manufactured in line with the relevant requirements of each product or application, with accreditations such as FDA, CGMP, CE, UK, and Ex. It is also important for equipment manufacturers to keep abreast of changes to regulations as well as how requirements can vary from country to country.

Packing operations will usually take place in cleanroom or high care environments and the design of equipment needs to reflect this, for example machines that are easy to clean with no dust or dirt traps.

This also helps to avoid the need for unscheduled engineer call outs, something which will have been of particular benefit during the current pandemic. Equally important, remote monitoring enables service visits to be planned in line with machine usage rather than to a fixed schedule.

In addition, the data capture and analytical abilities of these remote monitoring systems are able to help wwww.international-pharma.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 71

Packaging Many complex APIs and formulations may require specialist handling such as Aseptic Manufacturing and Sterile Fill Finish. Aseptic Manufacturing is a process where a drug or medicine and its container and closure are first subjected to separate sterilisation and then brought together. Because there is no process to sterilise the product in its final container, it is vitally important that the container is filled and sealed in the extremely controlled environment of Sterile Fill Finish As part of the regulatory process, there is also the need to be able to track a product throughout the supply chain and also trace it back to its original manufacture.

Indeed, the national regulations on the serialisation of drugs are perhaps the most important criteria in the global marketing of pharmaceuticals and other pharmaceutical solutions, requiring up-todate knowledge and understanding of the various obligations from country to country.

To deliver these requirements, serialisation machines are able to print the packs with the relevant information which, depending on individual guidelines, can be machine readable matrix codes or alphanumeric character strings. More advanced systems are also able to provide additional benefits beyond simply printing and verifying codes. For example, they can also weigh the pharmaceutical product on the same installation surface and thus carry out a completeness check. In addition, each individual pack can have tamper-evidence incorporated.

Another enhancement that some systems offer is the ability to perform aggregation, which is the documented combination of product packages into larger packs, from bundles and shipping boxes to cases and pallets. This ensures complete serialisation at every level.

Such track and trace systems and serialisation solutions are also examples of Industry 4.0 in action.

There are other regulations that pharmaceutical packaging is subject to, notably that it provides suitable protection for the drugs or medicines, in particular ensuring that they cannot be unintentionally accessed, especially by children. Such requirements have to be balanced with the need for the pack to be easy enough to open, especially for seniors or those who are less dextrous.

72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

For caps and closures therefore, the challenge is to ensure that the closure is affixed and tightened correctly during the filling and packing process so that containers can be transported safely throughout the supply chain, without making them too difficult for the end-user to open.

Latest capping technology can play an important role here, using fully programmable torque, speed, applied force and vertical positioning of the capping head to ensure more precise placement and turning. The new systems also offer greater flexibility in terms of the types of closures that they can handle compared to capping machines that rely on mechanical cams and clutches and which are more limited.

One of the implications of all the regulatory frameworks that pharmaceutical products must adhere to and the high care manufacturing process that these often involve is that pharmaceutical products require some of the most expensive production areas in the world. As a result, space is usually at a premium. For equipment manufacturers, therefore, the focus in our new machinery development process is to minimise the footprint of each new model, with the aim of achieving increased functionality, speed and efficiency in the smallest possible space.

The pharmaceutical industry has to deal with many of the same commercial pressures as other industries, and in many cases the nature of the products mean companies are subjected to much greater control and regulation. For the filling and

packing process, the need to maximise efficiencies and productivity, to be agile and flexible and able to respond quickly to customer demands are all the more essential. Selection of the most appropriate equipment is key to achieving the Right First Time approach that will help companies to meet customer requirements and make the most of all opportunities.

REFERENCES 1.

Wouters, Olivier J.; McKee, Martin; Luyten, Jeroen (2020-03-03). "Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009–2018

Richard Aitchison Richard Aitchison, Technical Sales and Product Manager at ATS Packaging Machinery. Richard has over 25 years’ experience in capital equipment sales, with the past ten dedicated to the development and sales of a variety of packaging machinery throughout the world including Europe, India, China, and North America. At ATS he heads up the company’s specialist Packaging Machinery division, which designs, supplies and installs a wide range of packing equipment and complete packing line solutions for a number of end markets including the pharmaceutical sector.

Winter 2021 Volume 13 Issue 4

MORE THAN 35 YEARS OF EXPERIENCE ACROSS 5 CONTINENTS

Industriepark-Zwijnaarde 3 9052, Ghent Belgium +32 9 329 23 29

Clinical Laboratory and Diagnostic Solutions wwww.international-pharma.com

info@cerbaresearch.com www.cerbaresearch.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 73

Packaging

Prefillable Syringes in Deep Cold Storage: Is This The Way Forward for Mass Vaccinations?

The world has just witnessed the fastest vaccine rollout in modern medical history.1,2 This undoubtedly saved lives – but it placed intense pressure on our healthcare systems, workers, and supply chain. This begs the question: is there potential to make future vaccination programs even more efficient? The solution may lie in prefillable syringes (PFS) which have the potential to minimise the many challenges involved in vaccine production and administration.

PFS have become an increasingly valuable option for the packaging and delivery of vaccines, as opposed to the traditional method of obtaining the contents of a vaccine from a vial via a syringe. PFS contain the vaccine which can be administered to a patient through the PFS itself, making them a ‘ready-to-use’ method of vaccine administration.

Prefillable Syringes vs. Vials Over the years, PFS have become wellestablished in medicine thanks to their many benefits. Compared with vials, PFS provide benefits in terms of efficiency3 and patient safety,4 as they support many aspects of vaccine administration – from decreasing the time required to perform vaccinations,3 to minimising the occurrence of handling errors5 – and supporting dose sparing.6 Efficient workflows in vaccine administration are crucial. At the height of the COVID-19 pandemic, it became paramount that there was no time lost in vaccinating large numbers of society’s most vulnerable people. This is where PFS would be valuable to a mass vaccination program. Efficient and simple workflows may also help integration of COVID-19 immunisation into the possible future roll out of regular immunisation programs, such as flu or pneumococcal immunisation, in the coming months.7 PFS are ready-to-use; they are prefilled during the fill & finish operation at pharmaceutical companies under Good Manufacturing Practices (GMPs) quality 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

controls, with the exact dose required for a patient. Preparation steps at point of care are thus avoided, in contrast to vaccines supplied in vials, whereby the health care worker has to withdraw the proper dose from the vial with a disposable syringe.

Such prefilled single dose presentation provides the potential for faster vaccine administration.3,4 In fact, there are many evidence that support the quick administrative nature of PFS. It has been calculated that in a pandemic situation, the use of PFS to vaccinate 300 million people in the US could save over 3 million hours of HCP’s time, in which more people could be vaccinated.8 PFS Provide Patient Safety Benefits The administration process is likely to be more sterile when using PFS. Even with the most experienced HCPs, human errors can occur through the process of withdrawing a vaccine dose from a vial to a syringe.

Microbial contamination during the syringe preparation process is reported to be reduced with PFS.9 In addition, as vaccines in PFS are predosed for a single injection, the risk of human error in dosing the vaccine is reduced.

Reduced Wastage Through Dose-sparing Typically, the difficulty to extract the whole content from a vial leads to overfill of vials by the pharmaceutical manufacturers.

Also, as you often need to open a 5or 10-dose vial to immunise even one person,10 it is common that doses are left over in multidose vials. In the absence of preservative in the solution, multi-dose vials need to be discarded a few hours after opening, even if all doses in them have not been administered. Additionally, once predawn from a vial and stored in a standard disposable plastic injection syringe, any remaining vaccine must be discarded at the end of the workday resulting in waste if more is drawn up than needed.11 These combined issues lead to 5–25% of vaccine product being wasted, if packed in single or multidose vials.12,13,14,15,16,17,17,18 Some additional waste may be generated by the inability to completely empty disposable syringes used for vaccine

reconstitution or administration from a vial: this is due to their “dead space”, i.e., the volume between the fully pressed plunger and the end of the needle. It may reach up to 20% of a 0.5 mL standard vaccine dose.

Of note, the dead space may be reduced by a factor of 10 with special syringes designed to this end.8,9 The dead space of the PFS and its needle may be significant but can also be reduced by the choice of the appropriate needle and the specifications of the PFS. This is an area where there is strong value for dialogue between the vaccine manufacturer and their supplier. In the glass PFS typically recommended for vaccines, the dead space is estimated to be only ~ 0.04 mL18 i.e., less than 10% of a standard vaccine dose of 0.5 mL. Moreover, there is little overfill in PFS due to the precision of filling machinery. As a result, PFS may help reduce vaccine waste and support dose sparing.

The Rising Demands of Deep Cold Storage For the past few decades, there has been increasingly innovative research into scientific vaccine technology worldwide.

In what was dubbed as a ‘new era in vaccinology’, the development of mRNA vaccines was proof of such pioneering research. Compared to traditional proteinbased vaccines, mRNA vaccines are faster and easier to create.19 Despite these advantages, there are some challenges in the handling of mRNA vaccines. Traditional, protein-based vaccine formulations are commonly stored up to about 2°C–8°C. On the other hand, mRNA-based vaccine formulations require much colder storage temperatures. This is because these formulas are typically more unstable, and much colder storage temperatures are needed to ensure drug-product shelflife and potency.20 In fact, temperatures required for the storage of mRNA vaccines can go down to -40°C, and even further down to -80°C.21 In the case of new vaccine technologies requiring deep cold storage, the final primary packaging configuration should be carefully investigated to ensure that the container is compatible with such deep cold temperatures.

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Packaging

The Suitability of PFS in Deep Cold Storage Ultralow temperatures can, however, induce changes in the container behaviour due to thermal cycle. The materials of a filled PFS system can be subject to several thermodynamic transitions and cycling mechanical stresses during the thermal cycling from room temperature to low negative temperatures. As a result, deep cold storage could compromise the functional performance of the delivery system and the vaccine contents.22,23 Understanding the behaviour of PFS components and interfaces is crucial to assess if PFS can sustain deep cold storage temperatures.

Glass PFS for Deep Cold Storage Glass PFS systems are composed of several materials and interfaces which will face various challenges. Of these key challenges, several solid materials, such as the plunger stopper, barrel and tip cap, will shrink. Elastomer components such as the plunger stopper and tip cap may cross their glass transition between -40°C and -65°C. Water and silicone components will also freeze and, in addition, the stopper may move due to the variation of the energy of the air trapped within the headspace and following the ideal gas law.24,25,26 With these challenges, the device could be susceptible to leakage or weakness before or during injection. The integrity of the device is 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY

crucial to ensure the components with which it is filled remain stable throughout the manufacturing and handling process.

BD recently completed a preliminary study investigating the performance of glass PFS in handling the rigors of frozen chain storage. BD researchers conducted a comprehensive analysis of approximately 2,000 PFS, of several combinations of glass barrel coatings, with or without needle for injection, or nozzle for nasal administration, after deep cold storage at -20°C and -40°C.27 Different tip and flange designs, and multiple elastomeric closures were also tested. In the study the PFS functions were unaltered when stored at these deep cold storage temperatures and then thawed. Moreover, the container closure integrity of the PFS remained unchanged compared to those stored at room temperature, indicating great potential for maintenance of sterility.

Following this study, it is anticipated that the glass barrel PFS systems tested should be suitable for use when storage temperatures of -20°C and -40°C are required.

The Future of PFS and Deep Cold Storage Going back to the initial question: how can the vaccine injection system contribute to the efficiency of future vaccination programs?

PFS are known to simplify and better secure vaccine administration. The cumbersome and potentially wasting drug preparation process with vials is significantly reduced with PFS use.28 In fact, according to recommendations from the British Royal Pharmaceutical Society guidance on the safe and secure handling of medicines, injectable medicines should be in PFS wherever possible, to minimise manipulation of medicines.29 Furthermore, PFS avoid the need for sourcing and distributing disposable syringes, which may be a challenge for policy makers and providers in pandemic situations.30 Naturally, there are concerns on how PFS would perform in deep cold temperatures – including for those containing mRNA vaccines. With recent studies showing that glass PFS can be appropriate for use in such ultralow temperatures, PFS in deep cold storage may be the way forward for vaccination purposes. Take for example the Moderna and Pfizer–BioNTech mRNAbased vaccines developed for COVID-19, which are best stored in a deep freeze condition. Being able to store them in glass PFS in such conditions could significantly improve the efficiency by which they could be administered to the masses.31 These applications for PFS in deep cold storage go beyond COVID-19. The use of mRNA Winter 2021 Volume 13 Issue 4

Packaging vaccines against many other viruses – for example influenza – is being investigated.

Notably, following the success of Pfizer’s mRNA vaccine in the fight against COVID-19, they have recently launched a mRNA influenza vaccine trial to test its potential ahead of the predicted winter flu crisis.32 Collaboration is Key Developing vaccines for new diseases is only half the challenge – delivering them correctly is equally critical. The recent findings on glass PFS in deep cold temperatures are indeed promising. To further the significance of these findings, it is imperative that investigations on the stability of the medicines contained in glass PFS in deep cold storage continue.

Suppliers of PFS should collaborate with pharmaceutical companies. Pharmaceutical companies will be able to provide the drugs which will be contained in PFS. Such collaboration will help to better understand the interactions between the drug and the container in deep cold temperatures, ultimately enabling us to accelerate and optimise the use of glass PFS in deep cold conditions.

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CARROLL, R. (2020). COVID-19 vaccine is the fastest ever to roll out, according to Humboldt health official. [online] KRCR. Available at: https://krcrtv.com/north-coast-news/eurekalocal-news/covid-19-vaccine-is-the-fastestever-to-roll-out-according-to-humboldthealth-official Cohen, S. (2020). The fastest vaccine in history. [online] https://connect.uclahealth. org/. Available at: https://connect.uclahealth. org/2020/12/10/the-fastest-vaccine-inhistory/.

Vaccine Presentation in the USA: Economics of Prefilled Syringes versus Multidose Vials for Influenza Vaccination – Claudia C Pereira; David Bishai – Expert Rev Vaccines. 2010;9(11):13431349.

Preferences of healthcare professionals regarding hexavalent pediatric vaccines in Italy: a survey of attitudes and expectations.

Icardi 2020 What are the preferences of health care professionals in Germany regarding fully liquid, ready-to-use hexavalent pediatric vaccine versus hexavalent pediatric vaccine that needs reconstitution? Lloyd 2015 (Patient Preference and Adherence) Makwana, 2011, Prefilled syringes: An innovation in parenteral packaging.

Nature – The coronavirus is here to stay — here’s what that means – Nicky Phillips – vol.

590 382-384 - Feb. 2021 Claudia C Pereira; David Bishai. Vaccine

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24.

Presentation in the USA: Economics of Prefilled Syringes versus Multidose Vials for Influenza Vaccination. Expert Rev Vaccines.

2010;9(11):1343-1349.

Prefilled syringes versus vials: Impact on vaccination efficiency and patient safety in Indian private market S.G. Kasi a, *, S.V. Prabhu b, S. Sanjay c, A. Chitkara d, M. Mitra - 2013 Estimating Cold Chain Requirement.

Immunization Financing Toolkit. The World Bank and GAVI Alliance. December 2010 CDC Vaccine Storage and Handling Toolkit – Jan 2020 U.S. Pharmacopeia dosage forms – Injections.

Available from: http://www.pharmacopeia.cn/ v29240/usp29nf24s0_c1151s34.html World Health Organisation (2010). Appendix: Additional Information: Estimating Cold Chain Requirements. [online] Available at: https:// www.who.int/immunization/programmes_ systems/financing/Appendix_Cold_Chain_ Costing.pdf.

Food Drug Administration (2019). Emergency Use Authorization (Eua) Of The Pfizer-Biontech Covid-19 Vaccine To Prevent Coronavirus Disease 2019 (Covid-19). [online] Available at: https://www.fda.gov/media/144413/download.

Food Drug Administration (2019). Fact Sheet For Recipients And Caregivers Emergency Use Authorization (Eua) Of The Moderna Covid-19 Vaccine To Prevent Coronavirus Disease 2019 (Covid-19) In Individuals 18 Years Of Age And Older. [online] Available at: https://www.fda. gov/media/144638/download.

U.S. Pharmacopeia dosage forms – Injections.

Available at: http://www.pharmacopeia.cn/ v29240/usp29nf24s0_c1151s34.html World Health Organisation (2010). Appendix: Additional Information: Estimating Cold Chain Requirements. [online] Available at: https:// www.who.int/immunization/programmes_ systems/financing/Appendix_Cold_Chain_ Costing.pdf.

BD, Internal data analysis, TR20213895, BD Medical – Pharmaceutical Systems Le Pont de Claix, France.

How COVID unlocked the power of RNA vaccines - Elie Dolgin– Jan 2021 - Nature 589, 189-191 (2021) - https://www.nature.com/ articles/d41586-021-00019-w.

Rathore, N. and Rajan, R.S. (2008). Current Perspectives on Stability of Protein Drug Products during Formulation, Fill and Finish Operations. Biotechnology Progress, 24(3), pp.504–514 Reuters (2020). Fact check mRNA vaccines kept at very cold temperatures so that they do not break apart; COVID-19 vaccines will not genetically modify humans. Reuters. [online] 4 Dec. Available at: https://www.reuters.com/ article/uk-fact-check-mrna-vaccine-storagetemp-idUSKBN28E28D. Kohoutová, M. et al., How ionic liquid changes properties of dense polydimethylsiloxane membrane? Desalination and water treatment., 2010, 14. 78-82. 10.5004/dwt.2010.1013.

C. Michael Roland; GLASS TRANSITION IN RUBBERY MATERIALS. Rubber Chemistry and Technology 1 September 2012; 85 (3): 313–326 Kohoutová, M. et al., How ionic liquid changes properties of dense polydimethylsiloxane

25.

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membrane? Desalination and water treatment., 2010, 14. 78-82. 10.5004/dwt.2010.1013.

C. Michael Roland; GLASS TRANSITION IN RUBBERY MATERIALS. Rubber Chemistry and Technology 1 September 2012; 85 (3): 313–326 BD internal study - Eloise Perrin “Investigation on impact of deep cold storage on Glass PFS – A risk assessment study - Extract of EF20202208, EF 20202618 and EF20203052” SD20212919 BD. (n.d.). BD Completes Study Investigating Performance of Glass Prefillable Syringes (PFS) in Deep Cold Storage. [online] Available at: https://www.b3cnewswire.com/202109222267/ b d - co m p l e te s- s t u d y- i n v e s t i ga t i n gperformance-of-glass-prefillable-syringespfs-in-deep-cold-storage.html Vaccine Presentation in the USA: Economics of Prefilled Syringes versus Multidose Vials for Influenza Vaccination- Claudia C Pereira; David Bishai Posted: 12/15/2010; Expert Rev Vaccines. 2010;9(11):1343-1349.

Royal Pharmaceutical Society (2019).

Professional guidance on the safe and secure handling of medicines. [online] Rpharms. com. Available at: https://www.rpharms.com/ recognition/setting-professional-standards/ safe-and-secure-handling-of-medicines/ professional-guidance-on-the-safe-andsecure-handling-of-medicines.

Surmounting the insurmountable: four keys to success in deploying a COVID-19 vaccine at scale – Oct. 2020 https://www.ey.com/ en_us/workforce/four-keys-to-successfullydeploying-a-covid-19-vaccine-at-scale Vaccine Presentation in the USA: Economics of Prefilled Syringes versus Multidose Vials for Influenza Vaccination- Claudia C Pereira; David Bishai Posted: 12/15/2010; Expert Rev Vaccines. 2010;9(11):1343-1349.

Pfizer (2021). Pfizer Starts Study of mRNABased Next Generation Flu Vaccine Program | Pfizer. [online] Pfizer.com. Available at: https:// www.pfizer.com/news/press-release/pressrelease-detail/pfizer-starts-study-mrnabased-next-generation-flu-vaccine

Guillaume Lehée Guillaume Lehée is an entrepreneur and convinced scientist, acting as Innovation Leader for BD since 2017, focusing on problem solving, need understanding and technology and solution enablement, mainly for pre-filled drug containers. Guillaume holds a MBA from Grenoble Alpes University and a PhD thesis in Micro and Nanotechnology from University ParisSaclay. Guillaume is also co-founder of PhDTalent, a start-up facilitating collaboration between scientists and industrials to accelerate innovation.

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Packaging

The Importance of Clinical Trial Packaging and The Benefits in Outsourcing Your Small Molecule Packaging to a CDMO Operating a clinical trial in what is a tightly regulated industry requires comprehensive, big picture thinking.

Risks remain at all stages of the clinical supply chain, and they can make the difference between a successful study, or no study at all. Whilst businesses are continuing to navigate the COVID-19 pandemic, sponsors face challenges that require strategic planning and should avail of appropriate assistance, particularly in one area of clinical trial expertise – clinical packaging.

the stakes for sponsors when it comes to achieving return on R&D investment.

Increased competition, coupled with mounting study complexity, targeted patient populations and investor-driven need for speed makes optimising the processes that underpin successful clinical trials management, mission critical. One way to achieve this, while reducing risk and accelerating time to market, is to outsource vital components, such as clinical packaging strategy and implementation, to Contract Development and Manufacturing Organisations (CDMOs).

With so much focus on the emergence of biologics in recent years, it would be easy to surmise that the demise of small molecule drug development is imminent.

That, however, is not the case. Undoubtedly, biologics and biosimilars are among the most advanced therapies available and have had a game changing impact across multiple therapeutic areas, from oncology to arthritis and to autoimmune diseases. Yet, while the biologics market growth is predicted to increase at a CAGR of 11.9% to USD 625.6 million by 2026,1 a renaissance in small molecule drug development is challenging the industry narrative surrounding the long-term viability of investing in research and development (R&D) of small molecule drugs.

Key Challenges Before weighing up the benefits of outsourcing clinical packaging strategy to a CDMO, awareness of the common packaging challenges sponsors of small molecule studies encounter is key. The first relates to the profile of clinical packaging.

Packaging requirements and processes are typically unseen or overlooked and as such are not given the attention needed during a program’s planning phase. The second relates to a lack of standardisation.

Products, protocols, and patients differ with each study so unique packaging strategies must be crafted. Dosing formats for small molecule drugs are incredibly varied (covering tablets, capsules, inhalers, IV and injectors) and there is no one size fits all solution.

In fact, the pipeline for new drug manufacture continues to be dominated by solid oral dose formulations, with almost half (46%) of drugs in the development pipeline administered orally.2 Furthermore, small molecules are recording the highest number of FDA approvals for decades and accounted for around 70% of New Molecule Entities (NME) approved for use by the FDA over the last five years.3 There are also more small molecule phase I trials taking place than ever before, with in excess of 7,500 launched or entering development over the past five years.4 Growth in small molecule drug development is great news for patients, especially across oncology and orphan disease areas where investment is currently most concentrated.5 However, it does raise 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

The third is change, or rather the impact of change – in study size, scope and clinical direction, as well as variable patient demand on packaging requirements. As such, to reduce risk of stockouts, sponsors must continuously monitor the broader supply chain to inform a responsive packaging operation.

The fourth and final problem relates to institutional learning. For sponsors who manage clinical packaging activity in-house, vital product and/or program learning can easily become lost with personnel moves or changes in company strategy, which can jeopardise broader supply chain performance.

Early Engagement Through early engagement with a CDMO partner, these challenges can be effectively

managed, and programs kept on track.

However, in order to weed out risk, it’s imperative that sponsors engage CDMO partners at the earliest opportunity so that packaging strategy can be developed with the bigger picture in mind and processes streamlined. Engaging with a CDMO for clinical packaging support once the study and kit is already designed, planned, and submitted often necessitates expensive rework activity when initial plans fail to take into consideration factors such as use of shippers or blinding criteria.

Ensuring full kit design during the initial phase of planning is critical as this influences the materials, quantities, and tooling requirements. Lead times associated with the individual kit designs will impact duration and deliverables. The stability and dose form are also critical element as this can restrict the choice of packaging for the kit. Blinding should be explored at the earliest opportunity as it can impact packaging. Sponsors must be aware that timelines and study design can be impacted negatively if they do not know if the IMP and comparator drug are available and if blinding is even possible.

From quoting to deciding on how many kits and if a comparator drug needs sourced; through to kit design; production and labelling; your CDMO should deliver right, first time bringing all elements together for distribution of final kits.

Selecting The Right Fit The value of engaging early in a study’s planning phase will be lost if the CDMO fails to offer the breadth and depth of expert services, technology and support sponsors need to develop cost-effective, patient-centric packaging operations that keep pace with the demands of modern small molecule trials. When choosing a CDMO partner, sponsors should look for a vendor that can provide an end-to-end packaging solution that includes design, sourcing materials, packaging, labelling and associated services – such as comparator sourcing, QP release, logistics and distribution. To deliver further value, these components should be project managed by supply chain experts and underpinned by integrated IRT technology.

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Packaging Opting for an established CDMO partner with global infrastructure and expertise across sciences, pharma and clinical services will also ensure continuity as programs progress through the phases to commercialisation. A final consideration when selecting a CDMO partner should focus on the vendor’s environmental management and sustainability credentials.

CDMOs are working around the clock with significant numbers of clients supporting domestic and global clinical trials 24/7. Unlike most sponsor businesses, CDMOs have the infrastructure in place to meet sponsor needs and study timelines and an understanding of the imperative to be able to react, adapt, move fast and to get drug from receipt to final packaging and onwards safely to patients. When you consider the regulatory requirements from the FDA, MHRA, EMA, it is vital that the right bottling lines, blistering lines and overall supply chain capabilities are in place to deliver for your clinical supplies. There is no packaging request that cannot be managed for small molecule, with a CDMO that has established manufacturing capabilities and decades of experience to help you get it right, first time.

Outsource to Optimise Operations When it comes to primary packaging of solid dose, small molecule products, such as tablets and capsules, processes across trial phases must be as efficient and compliant as possible. A key benefit of partnering with an established CDMO is access to automation that can reduce primary packaging lead times and minimise waste. Access to engineering expertise for tailored tooling and packaging design capabilities is another prime advantage.

By working with a CDMO with holistic visibility over the entire clinical supply chain, primary packaging can play an active role in helping sponsors to reduce overages, plan for variable recruitment scenarios and create robust forecasting strategies that enable sponsors to contingency plan and de-risk clinical supplies. Optimised primary packaging processes and access to expert design and guidance will also minimise waste and negative impact on future stages of a study drug’s lifecycle, including secondary packaging and distribution.

Where secondary packaging is concerned, access to expert kit and patient pack design, enhanced label generation, fully automated labelling and production processes that reduce cycle time and promote compliance wwww.international-pharma.com

are key benefits of outsourcing to a CDMO with global resources at its disposal.

Flexible Study Design and Increasing RoI Potential The small molecule market is anticipated to grow with a CAGR of 9.0% over the next seven years,6 with small molecule drugs becoming increasingly complex and targeted; presenting both new challenges for sponsors to tackle and opportunities to exploit.

From entrepreneurial companies to big pharma, outsourcing clinical packaging strategy to capable CDMOs will help keep ambitious trial timelines on track, minimise waste and inefficiency and ensure continuous resupply to patients. It will also release sponsor personnel to focus their attention on core business activity, reduce operational costs, increase regulatory compliance and optimise processes to support expedited trial completion and return on investment.

In clinical packaging, elements which can change include study size, visit schedules, clinical site, patient demand and regulatory compliance. Scrutinising plans early in the process means that packaging alternatives can be modified as required.

In one sponsor’s case, early planning of the packaging design resulted in the switch from a visit kit to multiple weekly dosing in a compact wallet design. This not only made patients’ lives easier but resulted in a reduction of overall clinical supply units from £300k to £108k, a time saving of an estimated six weeks and a cost savings of approximately £600k. To understand clinical packaging and ensure efficiency and compliance, it must be viewed as part of the bigger picture and undoubtedly, the benefit of outsourcing to a CDMO is a strategic business decision in order to mitigate risk and ensure supply to patients.

The Future of Small Molecules Compounds over the coming years are possibly going to take a similar pattern to what we experienced in the past 10-15 years with antibiotics, where we saw changing trends on their perceived relevancy. What we are witnessing now is a renewed interest in antibiotics. Similarly, we are now seeing that small molecules have not gone and like antibiotics, they have just changed. As we look to the future, small molecules are being paired with biologics and gene therapies. Only time will tell, but these pairings are where we are likely to see small molecules thrive.

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https://www.globenewswire.com/newsrelease/2019/10/10/1928253/0/en/BiologicsMarket-To-Reach-USD-625-6-Million-By-2026Reports-And-Data.html#:~:text=Biologics%20 market%20is%20growing%20at,and%2011.

6%25%20CAGR%2C%20respectively.&text= On%20the%20basis%20of%20product,by%20 vaccines%20and%20cellular%20biologics.

GlobalData: Drugs in preclinical, phase 0, phase I, phase II, phase III, pre-registration or IND/CTA filed as of 16 Apr 2020 (includes drugs exploring multiple routes of administration) https://www.europeanpharmaceuticalreview. com/article/113231/trends-in-the-cdmoindustry-for-2020/ https://themedicinemaker.com/manufacture/ small-molecules-sizable-market-opportunities https://themedicinemaker.com/manufacture/ small-molecules-sizable-market-opportunities Europe Small Molecule Drug Delivery Market Forecast to 2027

Adrian Collins Adrian Collins graduated from Queens University Belfast with a BSc in Chemistry in 1991. He joined Almac in 1992 and has since worked in a manufacturing capacity with responsibilities for timeline provision, production planning, pack design approval and manufacturing. He has over 25 years of pharmaceutical experience in the clinical trial packaging area for a wide range of Pharma and Biotech companies, from small specialist providers to multinationals.

Adrian has first-hand experience in the processes involved in differing types of Pharmaceutical Primary Packaging Strategies, involving many types of Equipment & Packaging components for small phase I trials to large scale phase III trials. In these 25 years he has assisted Almac to provide tailored solutions to many clients.

INTERNATIONAL PHARMACEUTICAL INDUSTRY 79

Packaging

Balancing The Complexity-efficiency Equation in a Fast-changing Prefilled Syringe Packaging Market Marcelo Cruz, Director of Business Development and Marketing at Tjoapack, discusses the fast-changing pharmaceutical market landscape and explores the latest trends in prefilled syringes. He explains how companies can balance the complexity-efficiency equation to deliver patient-centric drug products while optimising productivity.

The global prefilled syringes market is forecast to grow from $5.85 billion in 2021 to $11.94 billion in 2028 at a CAGR of 10.7%.1 Some of this growth is being driven by the positive demand shock caused by the COVID-19 pandemic, and the on-going global mass vaccination campaign.

Nevertheless, there are other longerterm trends shaping the industry and spurring on demand for prefilled syringe packaging.

The rapidly rising demand for biopharma therapies to treat chronic conditions, such as cancer and autoimmune diseases, has driven growth in the parenteral segment overall. This is because the nature of biologics means that most treatments must be delivered by injection.

At the same time, many in the pharmaceutical industry are turning their attention to enhancing the patient centricity of these treatments to improve patient experience and compliance.

The convenience they offer for selfadministration makes prefilled syringes a highly attractive means of achieving this goal, for both biopharma treatments and other therapies.

All of this, however, is introducing technical complexity into the packaging space, particularly when it comes to the packaging of prefilled syringes. How can pharma companies take advantage of rising prefilled syringe demand while ensuring optimum manufacturing efficiency?

The Search for Patient Centricity Useability – and particularly self-admini80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

stration – is a key challenge for many drug developers, across all dosage forms.

Providing patients with the ability to administer their treatment themselves, without the need for a healthcare provider (HCP) or carer, can free up professionals’ limited time and resources, while also enhancing convenience for the patient.

By encouraging patient adherence, this enhanced convenience can have a positive impact on the effectiveness of a treatment too. In doing so, it can relieve pressure on healthcare systems by minimising the need for patients with chronic conditions to be seen by doctors.

However, the complexity of preparing traditional injectable dosage forms for use means they have a key disadvantage when it comes to useability and self-administration.

The issue is particularly pressing for older patients. Dexterity issues, poor eyesight, and other age-related factors, can all exacerbate existing useability challenges associated with injectables.

process – something that pharmaceutical companies need to be aware of when preparing for the commercialisation of their drug product. Key considerations include: •

Sterility – As with other parenteral dosage forms, prefilled injectables must be processed and packaged in a clean and sterile environment to ensure optimum hygiene and safeguard patients’ health. It is vital to have access to equipment and standard operating procedures (SOPs) capable of maintaining compliance with stringent requirements.

•

Safety – Due to the inherent risk in handling pathogenic and transmissible microorganisms during the manufacture and packaging of biological materials, GMP must not only prioritise the safety of patients, but of operators and the environment as well. Quality Risk Management (QRM) principles are particularly important and should be used to develop control strategies across all stages of manufacture to achieve consistency, minimise variability and prevent contamination and cross-contamination. Having good spill responses in force is essential and can protect line operatives should a breakage occur, while also minimising the impact of the spillage on neighbouring products.

•

Packaging materials – sourcing the packaging materials and components needed for prefilled syringes is often challenging. Since the process of assembling and packaging prefilled syringes is relatively novel to the contract packaging industry, the lead times for packaging materials are increased. This creates a need to plan meticulously when deciding to start packaging prefilled syringes.

•

Sourcing high-quality branded equipment – Contract packaging organisations (CPOs) should have a clear vision of the activities they want to perform when packaging prefilled syringes and use this to source the relevant equipment. Where equipment

Taking this into account, drug companies have been searching for options to make injectable drug products easier for patients to use themselves in a non-clinical setting, such as their home, or school or workspace.

Prefilled syringes are seen as key to achieving this goal for patients and HCPs. By coming already filled with the precise amount of drug formulation for a single dose, they allow patients to administer their medication, without the need to accurately measure anything out. This eliminates complex preparation requirements, saving patients a considerable amount of time and stress, while minimising the risk of under- or over-dosing.

With this in mind, prefilled syringes offer considerable potential when it comes to developing more patient-centric therapies.

However, there are challenges to overcome to achieve optimum manufacturing efficiency and productivity.

Complex Production Requirements Manufacturing and packaging prefilled syringe products is a particularly complex

Winter 2021 Volume 13 Issue 4

Packaging for packaging prefilled syringes is new, lead times for qualification and subsequent validation of the respective equipment are much longer and this needs to be taken into account. In addition, some CPOs end up purchasing the prefilled packaging lines without a 100% understanding of all their nuances which can lead to delays and unnecessary expense.

•

•

Number of components – prefilled syringes present unique problems when it comes to packaging, often because of the number of components that are included in syringe kits. A syringe may be accompanied by a loose or staked needle, and a safety device, which may feature a finger flange or a backstop. Other inserts may be included, such as alcohol pads for sterilising the skin prior to injection, or information leaflets in the secondary packaging to offer guidance on using the syringe.

Temperature control – biologics must be kept at an appropriate – often cold – temperature throughout manu-

wwww.international-pharma.com

facturing, packaging, transport, and storage to maintain their efficacy.

Without this, the batch could become unsafe for patients.

•

Quality – syringes are much more sensitive than other formats, which is reflected in heightened quality standards. Preparation for packaging of prefilled syringes and active operation of packaging lines requires a significant level of attention from the quality department. Every step from acceptance criteria, handling of the individual products, and up to cleaning protocols of the packaging lines must be carefully controlled.

There are many ways manufacturers can overcome these challenges and meet growing demand for prefilled injectables.

One approach that is proving effective is to outsource the packaging part of the production process to packaging specialists.

For many years, packaging was considered a small, unimportant part of the manufacturing process for pharmaceutical products. This led companies to outsource it as part of a broader, end-to-end service to contract development and manufacturing organisations (CDMOs).

Meeting these needs can be difficult for manufacturers to achieve, especially when producing prefilled syringe products for the first time.

However, there is a significant drawback to this approach. CDMOs do not always have dedicated expertise or line capacity to meet the increasingly complex packaging needs of prefilled injectables. To overcome this issue, a growing number of companies are turning to specialist CPOs instead.

Tackling Production Challenges However, the complexities of producing and packaging prefilled syringes shouldn’t dissuade pharmaceutical companies from harnessing the benefits of this dosage form.

CPOs are uniquely well equipped to support the industry with the packaging of new more patient-centric, yet complex, dosage forms, such as prefilled syringes.

They have comprehensive knowledge about the injectables market, the regulatory

INTERNATIONAL PHARMACEUTICAL INDUSTRY 81

Packaging environment and the unique processing needs of injectables. Due to the nature of their role in the supply chain, they can offer the flexibility and the capacity to develop customised packaging services that can add real value to customers, benefiting their business over the long term.

CPOs are becoming an integral component in the pharmaceutical ecosystem, supporting drug companies in meeting the needs of their customers while reducing cost and enhancing production efficiency. They offer much more than a simple transactional service; they are an integral strategic partner that can help pharma companies deliver an improved experience for patients.

Automation is Imperative A CPO’s approach must be tailored to the volume of the products to be packed, their sensitivity, acceptability criteria and handling requirements with automated, semi-automated or manual packing often all being an option.

It is important to automate PFS packaging processes wherever possible in order to improve efficiency. This is only achievable through investment in and utilisation of appropriate equipment.

The following technical capabilities are all hallmarks of a CPO that can deliver more efficient services: • Automated in-process controls including camera and inspection systems, mechanical controls and complete coding and vision control • Electronic batch release (e.g. manufacturing execution systems (MES)) • Modular approaches that accommodate different components and processes • Automation of insertion of plunger rods and back-stops • Inline labelling.

However, once these are in place, a constant focus on innovation and improvement is essential to creating efficiency in future operations.

Further Enhancing Patient-centricity with CPO Partnerships By efficiently packaging the additional components that are necessary with prefilled injectables, CPOs can help optimise the patient-centricity of products.

CPOs can offer efficient and effective kitting services, for instance. This means 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that they can provide each pack with added features, from swabs and bandages to disposable needles, that might be needed by a patient to administer their medication safely and comfortably.

Thanks to their expertise and their ready-made specialist infrastructure, CPOs can deliver this service at scale, and for multiple markets around the world. They can supply packaging, leaflets, and other items to meet local regulatory and language requirements.

As a result, working with a CPO can deliver benefits not just for pharmaceutical companies searching for ways to streamline manufacturing operations, but for patients as well. By helping to deliver medication that is easier to use, they can play a significant role in patient adherence.

Time to Address Prefilled Syringe Packaging Challenges Given their unique benefits when it comes to enhancing the useability and convenience of self-administered treatments, it is no surprise that prefilled syringes are predicted to experience significant growth over the next ten years.

As more new biopharma treatments for chronic conditions enter the market, we can expect even more of them to be administered via prefilled syringes, rather than traditional parenteral formats. Thus, we will see an expansion of the self-administration trend across more treatments for a wider range of conditions, allowing patients the convenience of taking their treatments

themselves, while further freeing up HCPs’ time.

However, meeting this accelerating demand for prefilled syringes costeffectively while also ensuring safety and regulatory compliance can be a challenge.

To overcome this issue and balance the complexity-efficiency equation, optimising the packaging process is crucial.

REFERENCES 1.

https://www.fortunebusinessinsights.com/ industry-reports/prefilled-syringes-market101946#:~:text=KEY%20MARKET%20INSIGHTS%20 Listen%20to%20Audio%20Version%20The,a%20 CAGR%20of%2010.5%25%20during%20the%20forecast%20period.

Marcelo Cruz Marcelo Cruz is Director Business Development and Marketing at Tjoapack. With over a decade of experience in the pharmaceutical industry, and over 15 years of driving global strategic marketing and sales, Marcelo is responsible for the overall Business Development strategy and organic growth activities at Tjoapack. In his role he also leads the development and implementation of inbound and outbound marketing strategies to accelerate lead generation and drive the wider commercial strategy for the business.

Winter 2021 Volume 13 Issue 4

INSIGHT / KNOWLEDGE / FORESIGHT

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INTERNATIONAL PHARMACEUTICAL INDUSTRY 83

Logistics & Supply Chain Management

Digital Transformation: The Modern Pharmaceutical Control Tower The COVID-19 pandemic demonstrated that pharma supply chains need to realign their processes, people, and data to identify digitalisation opportunities to integrate resiliency moving ahead. During the pandemic, we witnessed supplier bottlenecks, delays at airports, harbors, and border crossings, and an increased risk of damage and theft. However, many organisations lacked the visibility to know when issues were happening and did not have the ability to make rapid decisions to respond to them.

Additionally, the global nature of today’s supply chain has resulted in longer and more variable lead times. The industry has a greater number of suppliers, partners, carriers, countries, customers, languages, and logistics channels to work with than ever before, as well as increasing costs from APIs, carriers, and labour. Legacy systems are unable to deliver crucial realtime information that allows organisations to respond quickly to changing patient needs, potentially delayed deliveries, or quality issue prevention. This is where a comprehensive control tower can helpby integrating multiple systems that give pharmaceutical leaders descriptive, preventive, and prescriptive analytics to improve decision making.

Visibility is Necessary, but it is not Sufficient Pharma manufacturers utilise ERP systems, quality management systems, and other digital tools to connect their customers and supply chain. Yet, while businesses often feel that they are drowning in data, they are at the same time having trouble finding insights. Poor data control is responsible for significant supply chain issues, given the silos that often exist, the many points along the supply chain, and the potential for error. These issues prevent companies from making their data work for them to create efficiency and reduce costs.

Often, companies find themselves responding to today’s crisis at the risk of making longer-term decisions, as they lack data that works for them. The value of data 84 INTERNATIONAL PHARMACEUTICAL INDUSTRY

does not lie in its quantity but in what can be done with it. Utilising the right tools and technology to gain understanding will enable control. Control facilitates improvement, and a focus on continual improvement will identify new opportunities.

While collecting visibility data is critically important, it is insufficient on its own. Supply chain leaders need to analyse data, determine root causes, investigate alternatives, and understand their impact and opportunity costs – all to derive insights that drive action.

The Changing Supply Chain In response to these challenges, the pharma supply chain control tower has arisen. A control tower acts as a centralised hub, using real-time data from existing systems, integrating with other systems, processes, and tools across the end-to-end supply chain, and driving tangible business outcomes.

Control towers are designed not only to provide the required visibility to survive and thrive, but they should also be able to discern real-time key performance indicators (KPIs) populated by data from across the extended supply chain.

A pharma supply chain control tower should provide four key benefits to the modern supply chain team, including internal stakeholders, box manufacturers, carriers, and logistics providers: •

Visibility – provides real-time access to information across the end-to-end supply chain. Data loggers travel with the products delivering product quality conditions along the supply chain so that stakeholders can be proactive and prevent lost loads.

•

Analytics – contains powerful analytics tools that enable supply chain managers to make sense of visibility data, performing “what if” analysis to facilitate effective, rapid response and root-cause analysis to drive operational and process improvements. This data helps supply chain leaders and quality teams automate workflows, save time,

cope with disruption, manage risks, and target opportunities.

•

Responsiveness – helps ensure that each part of the supply chain knows when and how another segment will impact it, and the monitoring helps enable continuous improvement. It also includes the ability to identify issues and respond to problems before they escalate.

•

Collaboration – data is the currency of the future, not only because it enables enterprises to make decisions but because it automatically connects previously siloed people and processes to work towards a common goal. The need for collaboration was evident during the COVID-19 vaccine distribution, where manufacturers, packaging providers, carriers, hospitals, clinics, and governments worked together to keep the vaccines safe.

Real-time technology and the pharma control tower were the common thread connecting these stakeholders together.

The Benefits of the Pharma Supply Chain Control Understanding enables control. To describe the difference between a control tower and what most companies have through reports and data visualisation tools, consider an airport control tower’s role. If air traffic controllers only had visibility into landed planes, the results would be disastrous.

Pharma supply chains should be no different. Yet, many businesses only have visibility into landed products. Many have made substantial investments in business intelligence (BI) tools designed to increase the level of visibility in their supply chain activities. Post-shipment data may be fragmented yet converted into graphs and analysis – but does it add value, or is it simply more numbers to review?

To be truly empowering, the pharma control tower not only needs to report on the data in the supply chain, making it practical, but it needs to understand the relationships between people, processes, and products. It must be able to convert Winter 2021 Volume 13 Issue 4

Logistics & Supply Chain Management increasing their responsiveness, knowing that a supply chain disruption has occurred.

Having the ability to respond quickly and intelligently is what differentiates best-inclass solutions from their counterparts.

A control tower should enable crossfunctional team members to work proactively to resolve the most pressing issues. The most sophisticated control towers provide realtime dashboard visibility, actionable insights to assess the operational and fiscal impact of issues, greater workflow automation throughout, and proactive services to help pharmaceutical manufacturers respond to problems before they escalate.

data into information and insights and supply the level of responsiveness needed to respond to risk. To do this, the pharma control tower needs to highlight exceptions, shortages, critical orders, bottlenecks, excess inventory, and potential delays. It can only do this if it has much more than visualisation capabilities. Instead, it needs to have built-in intelligence.

Replacing descriptive and diagnostic data, which show what happened and why, with predictive and prescriptive analytics illustrating what will happen—or how issues can be prevented from happening—will be crucial to moving forward. Today, most data is descriptive, using historical data to provide users with insight into past events, merely illustrating what happened. Diagnostic data uses descriptive information to supply insights into why it happened. Predictive analytics goes one step further and is used to find problems and offer recommendations on the measures needed for the best results, allowing for insights into the issues, as well as the solution to the problems.

Prescriptive analytics should be included in the supply chain control tower to provide insights that enable businesses to act before delays or deviations affect the end patient or customer. This data controls performance and ensures that the crossprocess team understands exactly why wwww.international-pharma.com

issues occur to work together to prevent them from happening again. They supply stakeholders with the ability to shape the future and support business strategies while minimising losses. This is how true value is generated.

Looking Ahead The visibility, understanding, and control that a supply chain control tower provides should allow pharmaceutical manufacturers to identify whether they are obtaining a required level of business performance.

These benefits include increased responsiveness, less waste, improved compliance efforts, reduced cost-to-serve, and better controlled risks.

They should identify shortage issues before they affect the end patient.

Control towers that leverage on-demand technologies supply real-time alerts to stakeholders and suppliers to excursions or deviations requiring immediate resolution – during shipment and after. Any issues should be easily found via alerts triggering predefined quality and business metrics that exceed their tolerances and thresholds, ensuring that the most critical issues are highlighted and resolved quickly.

Finally, today’s control tower should enable supply chain leaders to collaborate and address issues as they surface, thereby

Conclusion The next generation of analytical tools provide transparency and visibility into the complex nature of the modern pharma supply chain and services that facilitate proactive responsiveness. Pharma manufacturers and logistics providers today live in an ondemand world. As a result, they need to be able to understand and use tools easily.

The insights available today allow business professionals to detect problems before they occur and to respond appropriately.

By identifying all variables in the chain through a control tower, understanding their impact, and turning knowledge into action, supply chain leads can build responsive, collaborative supply chains that are safer and more efficient for everyone.

Ada Palmadottir Ada Palmadottir is Business Development Director at Controlant. With more than 20 years of experience in pharmacy, management, and technology, Ada has extensive international experience in sales, operations, and marketing, specifically in the areas of product, vertical alliance sales, and partnerships related to pharmaceutical products. She is a licensed and experienced pharmacist and earned a Master of Pharmacy from the University of Iceland and a Master of Business Administration from the Norwegian School of Management in Oslo.

Ada has been working with Controlant for more than ten years.

Email: ada@controlant.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 85

Health Outcomes

Behavioural Science: An Untapped Opportunity for Medical Affairs Just proving that an intervention has benefits is not always enough for it to be adopted into clinical practice. Yet in the past, pharma Medical Affairs teams have leaned heavily on empirical evidence to influence the uptake of new drugs and therapies.

Here, Ben Routley of Bioscript/Mark Pringle of NeoHealthHub examine how the use of behavioural science techniques (BST) can improve the impact of client communications.

BST has been a pivotal part of the guidance issued by Scientific Advisory Group for Emergencies (SAGE) and of the strategy of the UK Government during the Covid-19 pandemic, and because of this, the practice has come into sharper focus. The more forwardthinking pharma organisations are now starting to embrace this form of customer engagement.

Across many industry sectors, behavioural science is an accepted part of marketing and sales. If customers are to be convinced of the benefits of one brand over another, or the latest version of a product over a previous generation you can’t just cite statistics about the item’s efficacy: you also need to engage people’s emotions to make them ‘buy into’ the new offering by using the rational and emotional sides of their brain.

home, maintaining social distance, wearing masks and getting vaccinated. Therefore officials had to supplement the hard science with more emotive and ‘human’ messaging that talked about protecting loved ones, and everyone ‘doing their bit’ to accelerate the end of the pandemic and the return to normality.

Behavioural science should not be regarded as a black art; it is not magical, nor is it difficult to understand and apply.

In its simplest form it offers a practical and pragmatic solution to modern medical communications challenges, particularly where the proposition is very different from its predecessors.

This high-profile application of ‘behavioural science’ has proved thoughtprovoking right across the healthcare ecosystem, and the discipline’s potential is now subject to fresh investigation by certain sections of the pharma industry – particularly in Medical Affairs.

For many years, Medical Affairs in forward-thinking life science companies has been evolving towards something much more strategic than a once-simple drug launch process, with a greater emphasis on tailored messaging to different stakeholders and segments. However, messaging alone does not necessarily lead to a change in behaviour, particularly in more cautious prescribers or those treating patients with more complex needs.

Tailoring Messaging to Different Stakeholders Over the past five years, Medical Affairs – which provides the bridge between the pharma industry and the wider medical community – has seen its role in the development and commercialisation of products expand. This is especially the case as treatments become more complex and their paths to market become more complicated.

The shift to more advanced treatments such as gene or stem cell therapies means that there is now a lot more to communicate if we are to build understanding and realise their potential. And it is here that behavioural science techniques (BST) offer the life sciences something powerful and different.

Beyond Targeted Messaging So Where Does BST Come into this Picture?

As treatments become more specialised and targeted, the ability to communicate their benefits in the most effective way possible is more critical than ever.

Integrating behavioural science into medical communications is about going beyond targeted messaging to address the motivations and inherent biases that shape clinical decision-making.

Typically, scientific (rational) information around efficacy and safety have been communicated at length in a bid to convince physicians that rationally, product A is better

‘Confirmation bias’ – where people read into something what they expect to see or hear – or ‘status quo bias’ (inertia) can play an important part in determining outcomes.

Behavioural science can help to challenge these subliminal decision influencers.

Getting people to cement a decision and make a change requires lateral thinking – just as it has during the pandemic. In the UK, government bodies and public services have sought personal commitment from citizens to engage in considerate, riskreducing behaviours. Simply citing the science, however powerful, proved to be only moderately effective in securing public buy-in to safe practices such as staying at 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Winter 2021 Volume 13 Issue 4

Health Outcomes is an opportunity for early movers to gain an advantage while the practice is still relatively under-utilised.

Up to now, the uptake of BST in life sciences has been relatively muted, linked to perceptions of the discipline being a soft science lacking evidence-based studies.

That’s despite growing acceptance that applied behavioural science can bridge the gap between knowledge and implementation, i.e. between accepting that something is the case and doing something about it.

But as companies increasingly realise the potential of BST, the harnessing of these techniques and the application of them to Medical Affairs communications is beginning to make strong inroads in such areas of life sciences as strategy development, clinical education, medical engagement, and diagnosis and treatment decisions.

Failing to make the most of this potential could represent a loss of market opportunity – a position that most pharma companies would prefer to avoid.

Ben Routley

than product B. However, we know that people don’t always interpret information rationally and therefore don’t make optimal decisions. Psychological, cognitive, emotional and cultural factors also all influence decision-making. In the context of prescribing, HCPs’ behavioural influencers may include issues such as: positive experiences with existing treatment options, lack of clarity regarding how to best manage adverse events, and accepted expectations toward patient outcomes. So communication around these issues can be key.

Moreover, due to the pandemic, the absence of face-to-face congresses, where data would be interpreted among peers, means that Medical Affairs teams need to go further to help translate the science by leveraging alternative means of communicating. For clinicians then, the wwww.international-pharma.com

opportunity for Medical Affairs teams may be to recreate peer networking opportunities on a smaller scale, delving into the science beneath the headline data and giving physicians a chance to think through a new therapy’s relevance to their own patients.

Our experience has shown that combining simple data communication with practical support allows reflective and considered analysis, enabling audiences to make more-informed decisions on the balance of risk and benefit. This approach not only provides a platform for authentic scientific exchange but also brings rich insights into further behavioural drivers and gaps in the evidence package.

Bridging the Knowledge Gap As the pharma industry wakes up to the potential – and clear need – for a BST approach to medical communications, there

Ben Routley​, MSc is Head of Commercial Services at Bioscript, the leading international provider of consistent, high-quality, scientifically-robust value communications and strategy support across the pharmaceutical product lifecycle.

Email: ben.routely@bioscriptgroup.com Web: www.bioscriptgroup.com

Mark Pringle Mark Pringle is a Clinical Psychologist and Behavioural Science Specialist and Chief Solutions Officer at NeoHealthHub, a partner of Bioscript that works with life science organisations to maximise their impact across the pharmaceutical and healthcare brand lifecycle.

Email: markpringle@neohealthhub.com

INTERNATIONAL PHARMACEUTICAL INDUSTRY 87

Advertisers Index

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ASTELL SCIENTIFIC

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Aurena Laboratories

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BSP Pharmaceuticals S.p.A

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Cerba Research

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Denny Bros Ltd

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FUJIFILM Wako Chemicals U.S.A. Corporation

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Gerresheimer AG

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Kahle Automation

IFC Krautz Temax Page 23

LTS Lohmann Therapie-Systeme AG

BC

Natoli Engineering Company

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Nemera

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Nolato AB

Page 47

Peak Scientific Instruments

Page 3 R.G.C.C Page 83

Senglobal Ltd.

IBC SGS Page 21

SPL Scientific Protein Laboratories

Page 37

Trilogy Writing & Consulting GmbH

Page 17 & 41

Valsteam ADCA

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Winter 2021 Volume 13 Issue 4