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THE LATEST IN DRUG DELIVERY

COVID-19 & CLINICAL TRIALS

THE NEED FOR A UNIFIED SUPPLY CHAIN

June/July/August 2020

Natoli Engineering explains how to help organisations reduce the stress and loss of product development and delivery with Quality by Design.


QUALITY

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Our biosafety testing laboratory provides testing support for the biosafety and characterization of raw materials, cell bank and virus seeds for vaccines, cell and gene therapies, monoclonal antibodies and other recombinant protein based biological medicines, including a vaccine testing solution for coronavirus.

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Contents

Jun/Jul/Aug 2020 | Volume 20 Issue 4 REGULARS 5: EDITOR’S DESK

Why diversity in clinical trials continues to be a problem.

6: A SMALL DOSE

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

10: OPINION

How a shift towards unified supply chain management can accelerate timelines and help mitigate risk for clinical trials.

14: IN THE NEWS

A short selection of stories from the world of science.

16: COVER STORY

Natoli Engineering explains how to help organisations reduce the stress and loss of product development and delivery with Quality by Design.

50: TALKING POINTS

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

FEATURES 8: PERSPECTIVE ON PHARMA

The unexpected changes of moving from academia to the pharma industry.

28: COVID-19

EPM speaks to World Courier about the logistical challenges faced in the wake of Covid-19.

30: DRUG DELIVERY SUPPLEMENT

Expert opinions on the latest advancements in drug delivery.

42: WHAT’S TRENDING

Why Covid-19 is making the argument for remote clinical trials.

49: CONTRACT MANUFACTURING

EPM speaks to West Pharmaceutical Services about the essentials of contract manufacturing and the latest trends affecting manufacturers.


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THE STEPS TAKEN

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

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That the pharma industry isn’t immune to these problems should come as no surprise.

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t a time of global upheaval, when marginalised voices are sounding out across the world, it’s important that we listen to what’s being said. It’s also important that we look to the industries we work in and understand how we can be better, how we can support those calling out for it, and how we can affect real change in both small ways and large.

That this issue of EPM has been produced during the months of Black Lives Matter protests, Pride month in June, not to mention International Women in Engineering Day, shouldn’t matter. It needn’t take a movement or awareness raising events for us to consider how skewed our own perspectives can be of the goings on within our industries. That the pharma industry

EDITOR’S DESK isn’t immune to these problems should come as no surprise. Take clinical trials for instance and the lack of diversity that continues to be detrimental to marginalised groups. Consider that in the US, it’s thought that less than 5% of African Americans are represented in clinical trials. Now consider the health risks people in those communities are at higher risks of – cardiovascular

diseases, diabetes and even cancer. Finally, consider that the medicines designed to treat these conditions, might not have been created with representatives of these patients in mind. We expect the medicines we take to work because they’ve been developed by extremely intelligent people who understand the complexities of biology and things like dissolution rates and excipients. But medicine, with all of its complexities, affects each of us in different, sometimes substantial ways. Unfortunately, the pharma market is geared towards a system that prioritises costs and can be obsessive with driving a product to market as quickly as possible. However, this is often at the sacrifice of diverse patient groups. The reason for this is that a more limited patient group presents less risk of adverse events, increasing the likelihood of success for that particular drug. Progress is being made – though that doesn’t mean the issue should be pushed aside. In the wake of Covid-19, the UK has set up the NHS Race and Health Observatory to identify and tackle the challenges facing people in BAME communities. In the US, the FDA has taken a number of steps to both educate and make more transparent the issue of diversity in clinical trials. These steps are definitely welcome – and long overdue – but it’s still only one area of life sciences that is seeing improvement. We need to continue to ask questions about how our industry operates and recognise and challenge when not enough is being done.


6

A small dose

Lonza to help Anthos Therapeutics develop and manufacture lead antibody

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harmaceutical company Lonza has partnered with biotech Anthos Therapeutics to support the development and manufacture of an antibody which could treat a range of thrombotic disorders. Lonza will support Anthos Therapeutics in the development of its Abelacimab antibody, which has shown potential in early clinical trials to treat a variety of cardiovascular problems. Lonza will use its global network of process development and manufacturing suites to support Anthos Therapeutics in the development of Abelacimab. In particular, Lonza’s integrated end-to-end offering will bring drug substance and drug product capabilities for Abelacimab under one

Siemens and Exyte collaboration targets smart manufacturing

quality system. More so, it brings with it a dedicated team working on the antibody to help potentially bring the product to market faster and reduce investment risk. Jonathan Freeman, co-founder and COO of Anthos Therapeutics said: “Our partnership with Lonza provides Anthos Therapeutics access to its worldclass development and manufacturing expertise. The integrated drug substance, drug product and labelling/packaging offering enables efficiency and speed to accelerate patient access to this potentially life-preserving therapy. Importantly, Lonza’s value-based milestonedriven business model addresses the product, timeline and financial needs of our company and our investors.”

most inno Switzerla

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rocess automation provider Siemens has teamed up with Exyte to deliver end-to-end solutions for the construction of smart biotech facilities. The move comes against the background of Covid-19 - with pharmaceutical companies facing challenges in developing new vaccines and medicines at scale at their existing production facilities. The collaboration will offer standardised, turnkey solutions that are compliant with current Good Manufacturing Practice and Good Automated Manufacturing Practice to biotechnology manufacturers, as well as cell and gene therapy manufacturers.

In particular, Exyte will integrate its configurable biomanufacturing ExyCell modules with Siemens’ technology. The first buildings being designed with these technologies in mind are cell and gene therapy manufacturing and biological production sites in China and Europe. “We are excited to collaborate with Exyte to provide prefabricated, modular biotechnology solutions with our technology already embedded. As a market leader for the pharmaceutical industry, we offer know-how for process automation with our Simatic PCS 7 and WinCC automation platforms, as well as power supply and fire protection for modular cleanrooms,” said Eckard Eberle, CEO Siemens

Process Automation. Luca Mussati, vice president Pharmaceuticals & Biotechnology at Exyte states: “Our partnership with Siemens enables us to pre-integrate Siemens’ technology into ExyCell modules, thus offering clients end-to-end solutions for their facilities. Our collaboration allows our clients to reap the benefits of industry 4.0 without the necessity of engineering them from scratch each time, thus saving them time and money. ExyCell modules are suitable for new buildings as well as for the retrofit of existing buildings, and can be provided either in standard, off-the-shelf plant configurations, or modules that can be combined to meet specific customer requirements.”


7

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THERMO FISHER SCIENTIFIC PARTNERS WITH CSL TO MEET BIOLOGICS DEMAND

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hermo Fisher Scientific has entered into a strategic partnership with global biotech company CSL to help meet the growing demand for biologic therapies.

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

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

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

ovative drug delivery market and overtakes Germany as

The partnership will also see Thermo Fisher leverage its pharma services network to support CSL’s product portfolio. More so, through a long-term lease with CSL, Thermo Fisher will operate a new biologics manufacturing facility in Lengnau, Switzerland, when construction is completed in 2021. The facility in Lengnau will support the manufacturing of CSL’s product for

haemophilia patients through a suite of highly flexible bioproduction technologies that provide a pathway from development to largescale production. “We continue to invest to meet the growing need for flexible biologics capacity, and Lengnau will significantly expand our pharma services capacity and capabilities,” said Michel Lagarde, executive vice president of Thermo Fisher Scientific.” “This partnership clearly strengthens our unique customer value proposition, which leverages our scale and depth of capabilities for pharma and biotech customers. In addition to adding a high-volume

Lonza launches enhanced product line for clinical trials

production site, we can also address a broadening range of manufacturing needs for our customers, including CSL. This approach creates a win/win by making it simple for customers to start with us and stay with us as their requirements grow.”

C

Paul McKenzie, chief operating officer, CSL, said: “Through this strategic partnership with Thermo Fisher, CSL will now be able to access a wide range of capabilities provided by a leading pharma services provider, and we are confident that the management of the Lengnau facility and team will be in the very best of hands.”

The company’s Capsugel DBcaps double-blinded capsules have been designed as an over-encapsulation tool to be used during clinical phases. The capsules can be used with medical devices, as well as for overencapsulation of uniquely shaped dosage forms and comparator products.

apsule manufacturer Lonza has introduced an enhanced product line aimed at tackling concerns around bias during blinded clinical trials.

The capsules are particularly ideal as a cost-efficient solution for companies who would otherwise have to produce placebo forms that are identical in shape and size to the candidate product. Julien Lamps, product manager at Lonza said: “Capsugel DBcaps capsules have been specifically created to combat the main hurdles during double-blinded clinical trials. This opaque product has an extended capsule length and dual locking rings which mean that they

are not only allowing a high visual coverage of the form that is placed inside, but also extremely hard to open without damaging the capsules and breaking the blind.” “We have broadened our portfolio by adding an HPMC version to the standard gelatin one. This makes them suitable for use with multiple formulation properties, like for example hygroscopicity or prone to promote crosslinking phenomena. The capsules are available also in a range of sizes and colours, making them suitable for a variety of products in all shapes and sizes. In addition, their shorter length makes them easier for patients to swallow, helping to improve patient compliance.”


8

PERSPECTIVE ON PHARMA

Moving from academia to industry

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s an early career scientist with a good number of years of graduate and post-doctoral training (two post-docs, actually), I made an unexpected leap: from academia—where I thought I would spend my entire professional life—to industry. And though it wasn’t a move I’d initially planned, I’m the first to say that I’m incredibly happy to have ended up here, since it’s afforded me research and personal growth opportunities I didn’t even know I wanted. After I received my doctorate in biology, I completed a postdoc in HIV research and a second, NASA-funded post-doc in the effects of microgravity on genomes. My dream— and a very concrete goal for many years—was to become a professor at a research university, running my own lab in an area I was passionate about. But then life intervened: my wife was offered a teaching position in Indianapolis that she couldn’t pass up, so we relocated. After a few months of fruitless application to teaching and research positions at local universities, I started looking JUNG DOH, market development scientist at Beckman Coulter Life Sciences, explains how they entered the pharmaceutical industry after an unexpected opportunity arose.


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Finally, I’ve been surprised and heartened by the strong sense of “family” that exists within a company.

elsewhere. There are a lot of pharma and biotech companies in Indianapolis, so I started exploring some of them. In the interview process, (and much to my surprise), I discovered that they shared many of the same passions and goals I did: to benefit human health and life in fundamental and lasting ways. The company where I ended up and still work, Beckman Coulter Life Sciences, was particularly interesting to me, since one of their key focuses was on next generation sequencing (NGS). Toward the end of my Ph.D. and in my post-doc training, NGS was becoming more routine, and I was fortunate to be able to learn and apply the techniques in my own research. So I joined Beckman Coulter Life Sciences, which offers a range of scientific research instruments used to study complex biological problems and to advance scientific breakthroughs, first as a marketing application scientist, and then expanding into a dual role as application scientist and proof of principle scientist. In the latter, I worked with customers to develop modified protocols and tools to help research be done more efficiently. I then became product manager for our genomics product line, and as of this year, I have yet another new role, as market development scientist. In this role, I engage with the scientific community to learn from them, as well as support them to perform

research better, faster, and with superior results and outcomes. I also bring the learnings and techniques gained from these collaborations to create collateral to offer other labs, or help our internal team develop product offerings for a specific need. After making the leap into industry, I never looked back. There are, of course, benefits to both sectors. In academia, there’s a certain degree of freedom and job security—once you’re tenured, that is. But it takes a lot to get tenured these days—the funding and grants and a constant stream of publications—particularly in biology and related disciplines. Though industry may seem more constrained at first glance, in many ways, there’s as much or more opportunity, since there are a plethora of techniques to learn and apply in novel ways. And since technology evolves so rapidly, especially in genetic engineering and diagnostics, it seems like there are always new methods to master. Related to this aspect, and alluded to earlier, is the strong sense that mine and my colleagues’ work is genuinely helping people across the globe. I got an inkling of that in the interview, but it’s also been a palpable part of my work here. With the current pandemic, for instance, the company came together, and, within a matter of weeks, we were able to offer labs RNA extraction solutions for the virus, which are so critical right now. I felt honoured to be part of a company doing such great work, with flexibility and speed. It definitely speaks to the versatility of the industry. Beyond the scientific, I’ve learned about areas seemingly outside of science, but that are actually integral parts of the business. When I was

9 product manager, for instance, I learned how to manage people, run meetings, build financial models, approach marketing and sales, and many other facets of the business. I had no formal business training going in, but you learn by doing, from your manager and peers. I ended up really loving all these other parts of the business of science—they’re challenging, but incredibly rewarding, because they push you beyond your comfort zone. For that, industry has opened up areas that I didn’t even know would be important, let alone fun and rewarding. Finally, I’ve been surprised and heartened by the strong sense of “family” that exists within a company. Part of this is felt through the opportunities for development, which is evident in all the stages I went through and all the roles I’ve had. There’s a sense that staff are supported to grow as scientists and as people, which has made my accidental leap into industry all the more fulfilling. For young scientists, there’s a lot to think about when making decisions about what to study and what track to follow. I would encourage people to not get too hung up on tracks, but to stay open to the possibilities—in other words, don’t get too stuck on academia as the only option just because it’s where you’ve done your training. What really matters is having a passion for what you do, and following your interests. Genetic engineering is an area that’s exploded in recent years, and will likely grow in the coming years. I’ve been lucky that my own work has translated so tangibly into helping people, and at a large scale—but the same is true for many other areas in medical science. So carry on—you may end up in a totally different place from where you started, and that’s not a bad thing at all.


Opinion With Covid-19 forcing many sponsors to proactively reevaluate R&D pipelines and existing supply chains, there is renewed emphasis on the importance of appropriate time and resource allocation.

OPERATING CLINICAL TRIALS IN THE COVID-19 CLIMATE Author: Abi Pesun - director at Almac ONE How a shift towards unified supply chain management can accelerate timelines and help mitigate risk for clinical trials.

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n light of the global pandemic, sponsors are having to strategically reevaluate their R&D pipelines and decide whether or not planned clinical trials can go ahead in existing timeframes and if existing trials can continue in their current scope of work, due to in-country restrictions globally. For sponsors conducting Covid-19 studies, they need to decide whether to re-prioritise over existing studies and if so, they have to set up with accelerated timelines, due to the urgent need to establish drug eďŹƒcacy in prevention or treatment of the virus. With so much disruption, designing and maintaining streamlined clinical supply chains that safeguard timely, compliant and cost-effective drug production and distribution to patients matters more than ever.


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OPINION

IDENTIFYING THE BLACKHOLE If supply chains are fragmented, the risk Covid-19 presents can escalate further. If the physical supply chain fails to align with the digital supply chain the opportunity for error, delay and negative patient impact multiplies. Typically, sponsors outsource the management of the physical and digital supply chain to separate vendors. This can create an unintentional yet inevitable void between the two disciplines; a blackhole where vital study data can be lost, errors breed and the opportunity for process automation and continuous improvement missed. The outcome of all of this is fragmented, at times unresponsive, cumbersome and error-prone supply chains that cause delay and disruption to a sponsor’s ability to safely and cost-effectively deliver the right drugs to patients at the right time, place and temperature. For sponsors needing to amend protocols to accommodate evolving requirements caused by the pandemic, the lack of speed and agility offered by such disparate systems, processes and suppliers can make change slow and difficult to achieve. PRIORITISING TIME AND RESOURCE This fragmented way of working also demands excessive time and resources from sponsor teams, who need to piece disparate data together, liaise between multiple vendors to set expectations, troubleshoot issues and negotiate resolutions. With Covid-19 forcing many sponsors to proactively re-evaluate R&D pipelines and existing supply chains, there is renewed emphasis on the importance of appropriate time and resource allocation. The ability to prioritise core, strategic activity that champions business continuity will be afforded to sponsors that aren’t restricted by traditional vendor management models but can instead reliably handover clinical supply set up and maintenance tasks to a single vendor with dual expertise. BRIDGING THE PHYSICAL AND DIGITAL DIVIDE To create agile and effective operations, the gap between the physical and digital supply chain must be bridged. The primary way to achieve this is by utilising a single vendor with the dual expertise and capability to create one harmonised operation that unifies the physical supply chain with the technology that underpins it. Through a strategically developed single set of processes, combined with closed loop technology (mutual recognition procedure (MRP), interactive response technology (IRT), event related potential (ERP), forecasting and temperature management systems), data can be managed to provide greater visibility and control from production line to patient.

Access to dual expertise in clinical supplies and technology all under the same vendor roof, results in a typical five-fold reduction in errors when releasing inventory and raising shipment orders; requires less time and resource from sponsors; delivers process automation to drive efficiency and offers a unified view of data, which facilitates smart decision-making and continuous improvement. ACHIEVING SEAMLESS AND STREAMLINED SUPPLY CHAINS Utilising a single vendor model with dual expertise across clinical supplies and technology, better supports sponsors to effectively respond to the supply chain challenges and constraints caused by the shifting clinical trials’ landscape. Established, pre-validated processes and procedures translate into faster yet highly controlled, physical and digital supply chain set up. This removes delays that manifest when multiple vendors are involved. For all sponsors, especially those initiating Covid-19 studies, the ability to set-up core functions at rapid pace to align with ambitious study start dates is imperative. Utilising a unified supply chain strategy has supported reduced study set up time for several sponsors, with one Covid-19 trial sponsor up and running in two and a half weeks. Timelines that are inconceivable with a fragmented approach, yet have the potential to facilitate urgent scientific breakthroughs. By unifying the supply chain, sponsors can effectively manage changing study supply strategies, reprioritise deliverables and manage the wider business impact of the pandemic. Equally, by removing the data blackhole that exists in a multi-vendor model, a ‘right first time’ ethos can be established that mitigates error. Instead, key experts across supply chain management, manufacturing and logistics can work in partnership, uninhibited by the constrictions of a multi-vendor model and with a common goal, to ensure alignment between physical processes and the supporting technology. A NEW BENCHMARK FOR FUTURE PREPAREDNESS During the current climate, this means packaging and distribution strategies can be aligned with any changes required in the IRT and protocol amendments, required to assure resupply to active patients despite quarantines and site closures, can be integrated within the physical and digital supply chains. The shift in how clinical trials have been conducted in the past few decades has been significant - meaning sponsors must continue to evolve their operations to keep pace with new demand. Covid-19 represents an extension of this evolution, as sponsors recognise the restrictions siloed supply chains have on their ability to respond with speed to urgent demand and effectively manage risk.


A CLEARER VIEW OF ANNEX 1

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

*Annex 1 of EudraLex Volume 4 Good Manufacturing Practice (GMP) guidelines, draft 12 - February 2020 Š 2020 Ecolab USA Inc. All rights reserved. 28APR20/EU

TM

10316.4_EPM

ecolablifesciences.com/annex1


14 ALMAC GROUP WELCOMES REGULATORY DECISION REGARDING NORTHERN IRELAND POST-BREXIT

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lmac Group has welcomed the European Medicines Agency’s (EMA) confirmation that post-Brexit, Northern Ireland will remain in regulatory alignment with the EU. The decision, confirmed by the EMA and the UK government, means that EU laws in respect of medicinal products will continue to apply in Northern Ireland following the UK’s withdrawal. In response to the decision, Alan Armstrong, CEO, Almac Group, commented: “This latest confirmation, coming from both the EU and the UK, is a welcome step and ensures our current and future clients can continue to receive an unfettered solution with exclusive access to both the EU and UK marketplace. Crucially, our unique location in Northern Ireland ensures we can provide uninterrupted service provision now, and into the future, maintaining our position as a global leader in the life sciences sector.”

IN THE NEWS

Government must act to protect older people from Covid-19

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he British Geriatrics Society (BGS) has called out the UK government on its response to the Covid-19 pandemic and how it has disproportionately affected older people. In a press statement, the BGS stated how “too little was done too late to minimise harm to vulnerable older people” from Covid-19. In particular, the BGS criticised how the social care sector has been neglected by successive governments – which has impacted the ability of the health and care system to respond to Covid-19. A properly funded and integrated care system would have helped the country cope better with the crisis, but some actions could have

been implemented by the current government to mitigate the impact on older people, the BGS argues. This includes the Ageing Well Programme, which outlines a model for enhanced health support to people living in care homes, and for safe, effective community alternatives to emergency hospital admission, or rapid support to those discharged from hospital. The BGS said that this programme

was Covid-ready with funding allocated, and could have helped mobilise better support for older people during the pandemic. Instead, there was a decision to prioritise hospital-based services over additional support for care homes and community services. The BGS states this decision left those within those services feeling undervalued, unsupported and exposed to greater risk. The BGS is now calling on

the government to fast-track the implementation of the Ageing Well Programme so the country is prepared for potential future waves of the virus. Professor Tahir Masud, president of the British Geriatrics Society, said: “The impact of this pandemic on older people has been devastating and the government must act now to protect older people from a second wave of the virus.”

The median age of Covid-19 cases is 51.

Covid-19 has resulted in 12,526 deaths in UK care homes.

Did you know?

89% of Covid-19 deaths have been in people aged over 65 and over.

People aged over 80 are five times at risk of dying from Covid-19.


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significant concern in tablet manufacturing is speed to market. Moving too quickly, however, may cause delayed production, lost product, and missed deadlines. Even under ideal circumstances, tablet development will encounter unknown variables before a final product is realised. To reduce problems, performing several simple experiments and creating characteristic profiles enables R&D and production to accurately evaluate new drugs as oral solid dosages. Experimental data is used to characterise formulation performance with both patients and manufacturing organisations as ultimate customers. Understanding these compaction and compression characteristics is fundamental because they often drive changes in production requirements. These anticipatory experiments result in less formulation changes prior to full-scale production. Changes to production-ready formulations are the costliest and most timeconsuming because they must meet FDA, scale-up and postapproval changes (SUPAC), compliance, or other regulatory guidelines. The pharmaceutical industry benefits from utilising vendor partnerships for troubleshooting techniques and solutions. A quality tooling vendor can provide help to prevent tableting issues with information provided in compactability, tabletability and compressibility profiles. The study completion and analysis outlined below also provides smoother transitions from R&D to full-scale production. GATHERING POWDER PERFORMANCE DATA WITH SINGLE-STATION PRESSES Single-station tablet presses offer crucial advantages during

COVER STORY

It’s all

experimental

Natoli Engineering explains how to help organisations reduce the stress and loss of product development and delivery with Quality by Design. new tablet early formulation and pre-clinical development. When utilising a single-station press, operations that would otherwise occur automatically are performed manually, such as blending and the die filling process. The advantage of a singlestation press is it allows R&D scientists to perform tableting studies on the active pharmaceutical ingredient (API). Having these data can assist in excipient selection. Use of single-station tablet presses also makes performing formulation studies easier. Each study works harmoniously to provide data about a tablet’s planned components and how well they consolidate and compress.

COMPACTABILITY PROFILE This profile illustrates how readily a material undergoes changes in volume when compressed. It is a measure of how a powder can be changed into a tablet and the resulting strength of the tablet. A simple plot of compression force against the resulting tablet’s breaking strength is often referred to as a manufacturability plot. To compare various sized tablets, the compaction pressure is calculated by using applied force and punch cup area. A tablet’s solid fraction is an important parameter because small changes in solid fraction can affect tablet properties. Figure 1 illustrates a compactability profile for two excipients and a blend of the

two generated on a singlestation tablet press. The three samples have a magnesium stearate level of 0.5% for lubrication. TABLETABILITY PROFILE To better understand tablet tensile strength’s relationship to force used in tablet compression, it is vital to plot the tablet tensile strength against compaction pressure. Both variables are normalised to the tablet area to facilitate comparison of tablets of different size or tablets compressed on other tablet presses. In the tabletability profile in Figure 2, we see a typical formulation profile compressed on a singlestation press. Each formulation contains a high drug load; one is a direct blend recipe and the other a wet granulated drug product. Tablets with a tensile strength of greater than 2 MPa are desired, and as neither formulation is found to form a suitable compact at any pressure between 50 MPa and 300 MPa, further study should occur before expending efforts on a rotary tablet press. Figure 3 illustrates the tabletability of the three samples measured for Figure 1. It is clear that microcrystalline cellulose (MCC), with 0.5% magnesium stearate, provides the strongest compact. This is due to the MCC plastic deformation characteristics. The lactose monohydrate, with 0.5% magnesium stearate, also provides a robust tablet at reasonable compaction pressures. By blending the two excipients, it’s possible to add functions to the formulation’s performance, including plastic and brittle deformation characteristics. A 3-to-1 ratio of lactose-to-MCC provides a slightly stronger tablet than


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LEFT: Figure 1. The compactability profile for two excipients and a bland of the two generated on a single-station tablet press. RIGHT: Figure 2. Typical formulation profile compressed on a single-station press.

LEFT: Figure 3. The tabletability of the three samples measured for Figure 1. RIGHT: Figure 4 shows the compressibility profile of the same excipients as Figures 1 and 3.

LEFT: Figure 5 RIGHT: Figure 6.

one made from pure lactose. COMPRESSIBILITY PROFILE The compressibility profile illustrates how readily a material undergoes volume changes when compressed, and affects tablet properties like dissolution, hardness, and friability. Analysing tablet compressibility data will ensure the tablet quality throughout the R&D and manufacturing processes. IMPORTANCE OF THE ROTARY TABLET PRESS IN R&D The use of a rotary R&D press is the next step in planning tablet compression scale-up to meet client needs. Integrating this step into tableted product

development allows additional study completion and provides data at larger-scale production that can be used for further scale-up and production considerations.

can occur due to the pitch circle diameter of the tablet press turret, increases in the tangential punch velocity, and decreases in compression dwell time.

As previously shown in Figure 2, there is a stark contrast between compaction profiles of the direct compression blend compared to the wet granulation when completed on a single-station press versus a rotary press (as presented in Figure 5). The differences in moving to a large press with 30+ tooling stations will significantly change the compaction process even further. These changes

A simple strain rate study helps determine whether a blend produces an acceptable tablet at various turret speeds and dwell times. Figure 6 reveals that the strain rate-sensitive formulation will need almost twice the dwell time to produce a quality tablet compared with the wet granulation. With respect to API, completing these tests can be costly, so what can be done to

reduce costs? Discuss tablet compression tooling options with reputable vendors. Tooling manufacturers offer modifications that may reduce or solve the problem of reduced strain rate.

These anticipatory experiments result in less formulation changes prior to full-scale production.


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PACKAGING

Why weighing is an essential part of quality control for pharmaceutical packages.

If a box contains an incorrect amount of product, it could affect a patient’s outcome.

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WE GH IT UP

harmaceutical manufacturers are governed by strict standards for quality assurance and quality control (QA/ QC) across the entire production process. The required rigour extends into the packaging of those pharmaceuticals as well, including how manufacturers verify package contents by weight. THE ROLE OF THE CHECKWEIGHER Pharmaceutical checkweighers are used to weigh individual pharmaceutical packages inline, ensuring each package falls within a specified weight range. If a package is too light, perhaps missing a single blister pack, it will fail the checkweigher test. Likewise, boxes with too many blister packs would also be rejected. Letting a product leave the facility with too many or too few blister packs, or missing other components, is not trivial. Most important is patient safety. If a box contains an incorrect amount of product, it could affect a patient’s outcome. An error in packaging also tarnishes a brand’s reputation and leads to potentially costly and disruptive recalls. A mishap resulting in a recalled pharmaceutical product can, depending on the product type

and number of batches affected, have a significant financial impact on the manufacturer. Equally damaging are customer complaints over poor quality products, especially when they go viral on social media, as loss of brand reputation can have a dramatic impact on sales. Inline checkweighers are now common across many manufacturing applications, but not all checkweighers are built for the rigours of pharmaceutical production. Pharmaceutical manufacturers must consider production factors such as line speed, package size and type, package transfer and vibrations from plant equipment when implementing a checkweigher solution. They must also comply with extensive regulatory and quality standards that can add cost and complexity to production if not properly implemented. PRODUCTION CHALLENGES Pharmaceutical packages in the form of cartons, blister packs, glass vials, plastic bottles, aerosols and pouches are typically lightweight, creating a special challenge for checkweighing. The variance in weight between a correctly packaged product and an over -or - underfilled one can be 100 milligrams or less. Consider

an informational leaflet legally required to be included in the package: it weighs so little that a checkweigher not set up properly or not sensitive enough could pass a package without it. This could lead to customer complaints or require a product recall. The margin for error for checkweighers in pharmaceutical production is small. Another challenge, common in many production environments, is the effect of vibrations from other plant machinery on checkweigher accuracy. Even seemingly minor vibrations can affect a reading and lead to a false-rejection or passing of an out-of-spec package. A checkweigher fit for this specific purpose must incorporate a design that shields against vibration and other seemingly minor environmental influences such as airflow. Line speed can also impact the performance of a checkweigher. Packages on a fast-moving production line are harder to weigh accurately. As they are transferred from belt to belt at high speed, the settling time during weighing is increased. The light weight of typical pharmaceutical products means that they are also at risk of rotating or falling during transfer which can impact downstream operations.


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Checkweighers designed specifically for pharmaceutical applications are built to overcome the challenges outlined above. These more advanced checkweighers can accurately weigh light packages at speeds as high as 650 packages per minute. They are also often equipped with features to maximise weighing accuracy. For example, a closed cabinet design shields packages from environmental factors at the point of weighing and a slack belt conveyor design reduces vibrations introduced by the operation of the checkweigher itself. Finally, a knife edge design minimises dead zones on product transfer, reducing the chance that packages will be knocked around and disoriented. REGULATORY CHALLENGES Process control equipment can help alleviate the many production challenges that manufacturers need to solve, but strict regulatory requirements and quality control standards increase the complexity and cost of pharmaceutical production. For example, manufacturers must comply with the US Food and Drug Administration’s (FDA) Title 21 CFR Part 11 which mandates that the software used on systems like checkweighers produces auditable electronic records with high levels of data integrity. There are also prescriptive standards such as Good Manufacturing Practice (GMP) that manufacturers must adhere to in order to remain competitive in the market. A pharmaceutical checkweigher may come with the requisite features to make it compliant, but it isn’t a plug-and-play solution. It’s critical to partner with a knowledgeable and trusted equipment provider who can work closely with the manufacturer to implement an effective checkweighing solution that adheres to all regulatory guidelines.

Installation qualification (IQ) is conducted with the support of the equipment provider to ensure the system is set up properly and optimised to suit the production environment, determining the specifications the checkweigher needs to meet for it to function as an effective QA/QC tool. The qualification team documents this set up, which serves as an important tool for the operator should the system be audited in the future. Manufacturers should also rely on the provider to support operational and performance qualification (OQ and PQ), the detailed set of instructions for the operators in the operation and ongoing verification of the checkweigher system performance. The qualification team can consult with the manufacturer and help them develop standard operating procedures (SOPs) to standardise operation of the checkweigher, reducing the risk of any errors. MAKING THE RIGHT CHOICE To mitigate the risk of product recalls due to improperly

packaged pharmaceuticals, manufacturers should implement a checkweighing solution that is built specifically for the application. The right checkweigher is equipped with the features necessary to ease regulatory compliance, overcome production challenges and ensure it meets the high standards set by industry leaders. But even the perfect checkweigher takes work to implement, which is why selecting a trusted and knowledgeable equipment provider can ease much of the burden that is involved with installing a checkweigher. This is why it is critical to partner with a provider who can help every step of the way, offering guidance on everything from the placement of the checkweigher online to what instructions should be included in an SOP.

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Author: MIKE MUNNELLY marketing manager, product inspection, Life Sciences Manufacturing, Thermo Fisher Scientific


Leading the Way in Medical Devices and Connected Health Phillips-Medisize, a Molex company, is committed to serving pharmaceutical, diagnostics and medical device customers by creating technology and products to improve people’s lives. We operate innovation centers in North America, Europe and Asia, and manufacturing sites at 26 locations in 10 countries. With over 5,500 employees working in a quality-conscious culture, we take you safely and quickly through the process of bringing your medical product to market.

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PACKAGING — SPONSORED CONTENT

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he road to the ideal packaging or medical device is long. It starts with an appropriate design for manufacturing and leads all the way to large-scale production. How can all the requirements be combined? The Sanner IDP-Process shows how a modern and efficient packaging concept can be developed. IDP stands for ‘Idea. Design. Product.’ The holistic development process comprises six phases. 1. CONCEPT PHASE First, Sanner specialists develop different approaches based on customer demands, considering the criteria for serial production. The concept phase also includes a first, rough cost estimate, as well as a detailed examination of regulatory requirements and the patent situation. First sketches are created in CAD and explained in detail. Customers can choose between several possibilities, all of which fulfill the given requirements. 2. DESIGN PHASE While the selected product concept is developed further, the experts prepare the manufacture of close-to-production product samples. Customers receive detailed CAD data, as well as a physical 3D model. The selected material is checked for suitability with regulatory requirements and longterm availability. Thanks to comprehensive usability engineering, for instance sensorbased respiratory add-ons are made more ergonomic and finger rest enlargements of syringes ensure a better grip during injection. Risk assessment also has a key function: an FMEA analysis checks whether the design meets all requirements. 3. PROTOTYPE PHASE The prototype phase is the most critical and complex phase of the entire process: all requirements must be finalised and tested for near-serial product samples and subsequent large-scale production. Good project management on the part of the packaging solutions manufacturer is just as important as the close cooperation with the customer during finalisation. Stability tests can only be performed if all quality requirements and deadlines are adhered to. This results in a tested and approved product design for the successful transfer into serial production.

4. INDUSTRIALISATION PHASE The industrialisation phase mainly consists of the production, installation and qualification of serial production equipment, as well as the definition of parameters for a smooth and efficient production process with consistently high product quality. The manufacturing tool is subjected to a comprehensive qualification process in accordance with cGMP guidelines, including design qualification and FAT of the tools, followed by installation and operational qualification. 5. IMPLEMENTATION PHASE The production processes are validated and all documents for packaging approval and registration are finalised. According to a testing plan especially developed by quality management, Sanner experts inspect all relevant functionality parameters, such as test dimensions or desiccant weight. If the final inspection is successful, constant product quality, and consequently a timely market entry of the pharmaceutical product, is ensured.

Why an appropriate packaging concept and a good design for manufacturing are crucial to ensure a fast and reliable market introduction of new products. Author: URSULA HAHN - head of product management, Sanner GmbH

6. ROLLOUT PHASE AND BEYOND A continuous control of serial production is indispensable during roll-out and production. Sanner monitors the functions of all production equipment through preventive maintenance. All test results and the operating data are integrated into Sanner’s own MES, ensuring continuous traceability. For the customer, it is also important to be closely involved in the development process. High transparency and open communication in all project phases are crucial for everyone to be informed about the current status at any time. Thanks to professional project management and profound expertise, the six-stage Sanner IDP-Process creates a successful tailormade medical device or packaging solution with a focus on quality, time and costeffectiveness.

l a e d i e h T ng packagi n i solution six steps


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CASE STUDY

Who: Marianna D’Onghia, marketing co-ordinator at I Holland. What: Explains how a tool management system can help fulfil pharmaceutical expectations.

Case study

How: By helping Eli Lilly and Company implement a new system.

GREAT EXPECTATIONS THE USER & CHALLENGE In 2018, a leading pharmaceutical manufacturer, Eli Lilly and Company, contacted I Holland to help their Spanish manufacturing plant implement a new tool management system. The site was already using basic software to monitor tooling; however, it operated an old US-based system which was no longer supported and maintained. Lilly’s main aim for implementing a new system was to proactively monitor tooling and maintain a full audit footprint, a key feature required by pharmaceutical companies to ensure that they are following good manufacturing practices. It was important for the new system to contain features that aided with traceability for individual punches, as well as the ability to record complete audit trails of all tooling, maintenance and measurement methods used.

Overall, Lilly Spain had four main goals they wished to achieve with a new tool management system: 1. The ability to monitor tooling life, commencing from when a tooling set is received from the manufacturer, until the tooling is disposed of and no longer in use. 2. To easily trace individual punches and dies within a set. This included where the tooling is stored, maintenance actions that have been carried out during its lifetime, and what machines the tools have been used in. 3. For the system to understand and identify areas of potential improvement in the company’s tablet production system. This needed to include audit reports, maintenance action reports and inventory and product reporting. 4. To have access to assistance and technical support when necessary.


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CASE STUDY

MARIANNA D’ONGHIA Marketing co-ordinator at I Holland

THE SOLUTION AND ITS IMPLEMENTATION With over 70 years of tablet compression knowledge, I Holland developed the innovative Tool Management System (IHTMS). The software has been specifically developed to maintain efficient, well organised and in-depth monitoring tooling life, and tablet production, giving manufactures a complete transcript of tooling usage and maintenance. The system allows tablet manufacturers to keep a record of tablet quantities by number of tablets, work order or batch information to ensure that production is running efficiently. It also incorporates an in-depth guide to tooling specification and troubleshooting so that any problems flagged up by the IH-TMS can be rectified or further investigated. In addition, it has the capability to archive tablet and tool images/drawings. The system also has alarms to alert the users of any problems including over compression, tooling replacements or when maintenance is required. After a thorough assessment of the all the key goals required by Lilly, they were clearly achievable using IH-TMS. The software was installed onsite at Lilly’s plant in Madrid during a four-day visit. I Holland used the time to train Lilly’s key stakeholders, explain the benefits of the software and how to get the most from the system toward their stated goals. All training was provided before validation commenced, entering real data in parallel with the old system. This meant that after validation had finished, Lilly could enter the data in an “easy and quick way” making the training “really useful”. Working with Lilly’s skilled engineers, I Holland fully customised the system so it would integrate seamlessly into current manufacturing processes. Users were taught how to adapt the system for future change, making it a sustainable monitoring system capable of evolving to meet any eventuality. This included translation and changing the system language to Spanish once the initial set-up had taken place. HOW DID IH-TMS HELP WITH LILLY SPAIN’S GOALS? As soon as the I Holland Tool Management System was validated, Eli Lilly saw advantages when comparing it to their former system. Pablo Poza, Lilly’s maintenance coordinator said: “The system is working as we

expected, and it has fulfilled the expectations we had with our requirements.” MONITOR TOOLING LIFE A core feature of IH-TMS is the ability to keep track of maintenance features that tooling has undergone, thus being able to monitor tooling life from when the set is first received, to when they are disposed of. The correct maintenance is critical in obtaining the maximum life from punches and dies as problems can be detected before they impact on production. If followed correctly, a maintenance procedure allows the person in charge of managing the tool room to prioritise maintenance activity by creating a work-to list. For a highly efficient company like Lilly Spain, the ability to accurately predict when tooling will need to be replaced, so as not to lose any time and/or money on tablet press downtime, was essential. The control provided by the management capabilities of IH-TMS allows Lilly to “get the maximum yield of tools and establish replacement planning for buying new tools before problems start to appear.” Additionally, one of the most important features of IH-TMS that Eli Lilly uses for monitoring tooling life, is the ability to measure tooling and for data to be easily transferred into the system. As a good general rule, tooling measurement should be carried out at regular intervals, even if repair has not been necessary, to check for natural wear occurring during the compaction process. It is important to ensure that critical tooling dimensions have remained within tolerance. Lilly reported that their metrology activities were much faster following the application of IH-TMS. The software has enhanced the department’s productivity by enabling staff to keep an overview of several jobs as the system easily records and displays the information required. TRACEABILITY Within tablet manufacture, the importance of knowing where tools are and what condition they are in, should be a priority. Without this information, either unnecessary tooling replacements are made, or punches are deployed when they should be in maintenance or replaced. Unnecessary replacement of punches or scheduling the


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CASE STUDY

use of unfit tools for production reduces productivity in the long run and can make a difference to the bottom line – a concept which Lilly fully understands. Traceability of tooling is, therefore, a necessity in tablet manufacture and a key requirement for a driven company like Lilly Spain. When tooling arrives on site and a batch campaign is started, Lilly first record and issue the tooling onto the system. From there, they are now able to store all the relevant data they need from the beginning, when tools have been ordered from their trusted suppliers, to the end of the tooling life. Within the tool management system, they can see what activity each individual tool has gone through, what tablet batches the tooling has provided, any images/drawings associated with the set or individual tool, and all measurements. In fact, Lilly’s most used feature of IH-TMS is the ability to issue and return tooling to and from production. This enables them to know exactly where all tools are during any one given time and is especially useful during shift change. REGULATORY COMPLIANCE Examining and reporting on location, maintenance procedures and tolerances, in-keeping with accepted standard operating procedures (SOPs) for regulatory requirements, was also an important objective for Lilly Spain. IH-TMS has been

developed to allow proactive monitoring of tool rotations, tooling inventory and tooling maintenance. The system, which is compliant with protocols like the FDA’s Code of Federal Regulations – 21 CFR Part 11, can generate nine different types of reports, including audits, maintenance actions, inventory and product reports. These all support Lilly’s regulatory compliance goals and are used for regular updates to all key staff. Because the system can easily produce these reports, reporting has not only been more manageable, but also allows Lilly to check and monitor tooling effectively and on a regular basis. This in turn can be “translated into more actions, easily and quickly”, helping to increase productivity to their current processes. ONGOING TECHNICAL SUPPORT The last requirement for Lilly was assistance and technical support that the previous system’s manufacturer could no longer provide. From implementation of the system through to the current day, I Holland has been on hand to assist with any challenges Lilly may have faced. Mr. Poza highlighted: “The I Holland technical support for any questions/doubts is much better than the one we had with our previous supplier.” This increase in technical support is accentuated by a good working relationship with the highly motivated staff at Eli Lilly.

CONCLUSION Software like I Holland’s Tool Management System can identify maintenance issues or poor handling problems by auditing all tooling and its respective processes. A professional tooling procedure audit is a simple way to directly detect and rectify this, ultimately saving many hours of reduced production through unplanned tooling maintenance and replacement. Overall, the system has met or exceeded Lilly’s four main objectives; monitoring tooling life, traceability, regulatory compliance and technical support and they are already seeing a difference in production following the implementation of IH-TMS. Furthermore, the simplicity, ease of use and features of the system mean that the team at Lilly have been able to unify different activities onto one system, a feature which they could not do before. This includes measuring tooling, taking/ storing photographs and creating/analysing reports. Final words from Pablo Poza: “Without any doubt, it is a great management system, easy to use, really useful and very visual. The comments have been positive, especially for the easy management and for being very intuitive, managing all the information easily.” Liam Preston, sales and service engineer for I Holland added: “I am excited to see how IH-TMS helps Lilly’s tooling maintenance productivity. The more they use the system, the more they will appreciate the different features that will help with their existing processes. Overall, it has been a very enjoyable and fulfilling experience working with Lilly to help meet their goals with IH-TMS.”


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COVID-19

EPM speaks to World Courier about the impact Covid-19 has had on the clinical trials sector and how a direct-to-patient approach can help trials continue.

Quick questions with Alex Guite, vice president of Services and Alliances, World Courier EPM: What’s the impact been on clinical trials due to Covid-19? GUITE: Clinical trials have been disrupted worldwide with significant impact to the patients who rely on them, as a result of Covid-19. Manufacturers face patient safety risks, regulatory restrictions, funding issues, and logistical challenges associated with getting treatment to patients in this new context. In fact, a

recent Association of Clinical Research Professionals study found that nearly 80% of clinical research study sites indicated at least one of their current trials had been put on hold or cancelled in recent weeks, which is something we are observing first-hand. These delays are a concern for trial participants, and the impact will be felt across entire rare or orphan disease populations. As a result, World Courier has been working to transition applicable clinical trials to a Direct-to-Patient model that allows the studies to continue while still protecting product integrity, minimising disruption to the treatment regime and, most importantly, assuring patient safety. EPM: Following that, do you expect a fall in drug approvals due to potential delays within the clinical trials space? GUITE: While the long-term impact of drug approvals remains to be seen, a study of World Courier’s manufacturer customers found that 78% believe most delayed clinical trials will be re-initiated post Covid-19. The study also revealed manufacturer’s belief that rapid approvals for new medical devices (e.g. ventilators) during Covid-19 could lead to faster approval pathways for drugs in the future, post-Covid-19. However, we have seen that collaboration and flexibility remain key for manufacturers as they continue to gather data and for patients as they continue to receive necessary treatments – and ultimately for products to be launched to the market. EPM: What’s World Courier doing to help clinical trials continue to operate? GUITE: Traditionally, clinical trials are conducted at a clinical site – within a hospital

or healthcare setting – but Covid-19 has made it difficult for patients, particularly those who are immunocompromised or vulnerable, to leave their homes. As a result, many of our customers are seeking innovative strategies for bringing the clinical trial to patients, rather than asking patients to come to the trial. We have extended our established Direct-to-Patient logistics model to support trials shifting from the traditional setting to the patients’ home, as well as managing the set-up of new trials with a Directto-Patient model. In fact, during the month of May we expanded availability to 56 countries, as some countries lifted restrictions on these types of services to care for patients and continue trials during this time. EPM: How can a Direct-to-Patient approach help continue clinical trials during the pandemic? GUITE: A Direct-to-Patient approach allows for drugs to be delivered and administered in the patient’s home and/or biological samples to be uplifted from the patient’s home. This enables patients to follow the current guidance of public health officials (i.e., social distancing and self-isolating), accommodates the re-direction of healthcare capacity towards Covid-19 treatment, as well as accounting for patients who may be reluctant to enter healthcare settings in the current environment. We’ve seen a five-fold increase in our daily Direct-to-Patient shipments, compared to the pre-Covid-19 average. Delivering treatments directly to the patient’s home protects product integrity, minimises disruption, and – most importantly – assures that patients can continue to access medicine.


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One lesson learned is the need to be prepared, flexible and collaborative.

EPM: What are the logistical requirements needed to make this a possibility? GUITE: World Courier has a 50year history of maintaining supply channels in times of public health crisis or transport disruption. And, while we’ve supported Directto-Patient clinical trials for many years and have established best practices for logistics management, the Covid-19 pandemic requires our logistics programmes to be even more flexible, ensuring our customers can operate as close to business-as-usual as possible during this time. When implementing World Courier’s Direct-to-Patient approach, before a product can even reach a patient’s home for administration, we must address the logistical barriers associated with shipping products – particularly in countries that have limited passage to prevent further spread of the virus. In some cases, these challenges have tripled the time it takes to manage a shipment. In turn, World Courier identified alternative routes that

could expedite product movement but still ensure we’re meeting country-specific regulations. Even as commercial flight availability has reduced, we maintained air connectivity by booking space on airlines across a range of carriers. Having this diversity of options allows us to pivot based on the latest conditions and product needs. Because of our carrieragnostic approach and contingency planning, we haven’t declined a single shipment since the start of the pandemic. Another requirement to make Direct-to-Patient clinical trials a reality is protecting patients, our associates and all supply chain participants. To this end, we have supplied our drivers with personal protective equipment (PPE) and implemented a contact-free pick-up and delivery process. These process modifications are temporary and in line with World Health Organisation guidance on social distancing, use of personal protective equipment and infection control.

EPM: What lessons do you think the pharma industry and governments need to learn from Covid-19? GUITE: Coming out of the Covid-19 pandemic and looking ahead, the pharmaceutical industry will keep a number of key learnings in mind. One lesson learned is the need to be prepared, flexible and collaborative. Manufacturers should look to logistics partners to ensure they have a proven track record of successful contingency planning – inclusive of maintaining air connectivity and the time and temperature requirements of specialty drug product. Covid-19 has illustrated the importance of anticipating demand surges moving forward. Pharmaceutical logistics has always required widespread cross-border and cross-agency collaboration, and pharmaceutical companies should continue to collaborate with authorities and government officials to ensure patients are able to get medications in a time of crisis.


DRUG DELIVERY SUPPLEMENT

How advances in primary packaging are helping patients administer biologics at home.

HOME

T Author: ANIL KUMAR BUSIMI - senior global product manager for SCHOTT iQ Platform at SCHOTT

he rise of biologics continues to dominate the global pharma drug pipeline, yet it is the administration of these drugs that presents a challenge to pharma packaging. As biologics have become more structurally complex than their predecessors over the past decade, they require special packaging to ensure drug stability throughout shelf life. More so, a changing market has introduced the possibility of home administration for biologics, which is being driven by the goal to lower healthcare costs. This is supported by advances in primary packaging solutions. Medication now needs to be filled, stored and administered in a single container type, while at the same time allowing for easy, safe and accurate injection administration. This can be achieved with prefilled syringes (PFS) but also by using auto-injectors and wearable devices. SAFE ADMINISTRATION WITH PRE-FILLED SYRINGES The key benefit of PFS is that they make injections easier and safer for both healthcare professionals and patients. The drug is already filled in the container in its exact dose, which prevents the risk of dosing inaccuracy, while the administration process is often supplemented by auto-injection or safety devices. In addition, pharmaceutical companies can benefit from less overfill in PFS in comparison to using vials.

DELIVERY Furthermore, PFS can be used directly for aseptic filling as they are already washed, siliconized, fitted with a tip cap or needle guard, and sterilised, which saves costs and process steps. To meet the needs of biologics, available syringes made from borosilicate glass tubing were specifically developed for highly sensitive formulations. For example, the 1ml long syriQ BioPure glass syringes from SCHOTT, feature lower adhesive residues and a lower tungsten level (ICP-MS certificate available) compared to standard syringes, which supports a low extractables and leachables (E&L) profile while ensuring drug stability. The syringes come with elastomer components, which further provide a low E&L profile to additionally reduce the risk of potential drug/ container interactions during the entire shelf life. At the same time, the optimised siliconization process, which provides a uniform inner coating, improves the functionality with conventional safety devices and autoinjectors making the administration process safer for patients. ELIMINATING SILICONE TO KEEP HIGHLY SENSITIVE BIOLOGICS STABLE IN ULTRA-PURE PREFILLED SYRINGE SYSTEMS In PFS, one of the components that drugs may interact with is silicone. The substance has long been deemed a necessity to help reduce the injection force needed

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to administer drugs and make the treatment more comfortable for the patient. However, an estimated 1015% of the biologic pipeline drugs are ultra-sensitive to silicone. Pharmaceutical containers, which contain silicone, are therefore not suitable to package such drugs. When PFS refrain from siliconization of the syringe barrel, an accurate geometry of the container becomes important to maintain a consistent gliding force. This is possible, using 100% inspection of the glass tubing, which ensures tight dimensions and high cosmetic quality of each barrel. Currently, the only commercial available option for glass PFS is the syriQ BioPure silicone-free syringe system combined with GORE ImproJect plungers. The product combination consists of a PFS system with a silicone free glass barrel and plungers that eliminate the need for silicone as a lubricant in prefilled syringes. Moreover, the new and tighter tolerances go beyond ISO 11040-4 to provide a smooth self-injection, while including all mentioned benefits of the regular syriQ BioPure portfolio. FINDING THE RIGHT PFS FOR INJECTION VOLUME AND DRUG VISCOSITY The highly viscous nature of some biologics presents another challenge to packaging. The high viscosity level is the result of ensuring eďŹƒcacy of the treatments


www.epmmagazine.com

by increasing the bioavailability and the active pharmaceutical ingredient (API) concentration. In return, this means that more force is required to inject the drug. Yet if too much force is applied, the injection process may become uncomfortable for the patient and the syringe inside the autoinjector device is at risk of breaking. While the 1ml long staked in needle is considered the standard for biologics drugs, there is a trend to deploy 2.25ml PFS to also allow higher injection volume and accommodate the increasing viscosity of the biologic drugs. Hence, pharma companies can choose between 1ml long or 2.25ml syriQ BioPure PFS, which both feature high mechanical strength and are compatible with safety devices and auto injectors to make injection safe and improve patient experience.

drug stability, provide container closure integrity (CCI), ensure smooth fill and finish operations and must comply with the relevant regulatory requirements. To reduce the complexity during development and time to market, many wearable injectors rely on proven primary packaging solutions like cartridges. The containers allow designers to choose container length, volume, diameter, neck and ange design, and the stopper and plunger material. Another benefit of cartridges is that many of their functional parameters, particularly glide force, have been tested to full extent according to ISO standards.

ADMINISTERING LARGE VOLUMES WITH WEARABLE INJECTORS The trend of self-administering injectable drugs and the goal to reduce injection frequency is driving the development of wearable injectors or large volume injectors, which are particularly designed for subcutaneously administering injectable drugs in large volume (more than 2 mL) and/or over extended injection time-periods. While wearable injectors are not a new concept, the use in administering biological drugs is a novelty. Similar to the use of an autoinjector for self-administration, it is the primary packaging in wearable injectors that plays a key role in keeping the drug safe from contamination. At the same time, it is responsible for ensuring optimal functionality to deliver the drug, and must seamlessly fit into the device. Deciding for the right primary packaging for wearable injectors can be a daunting task as the container needs to ensure

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THE IMPORTANCE OF PRIMARY PACKAGING As an integral part of every drug, the primary packaging is responsible for keeping the drug safe until it is administered while improving the patient experience. Relying on a close collaboration early on in the process with the packaging and component supplier, pharma companies are able to find the right packaging for its drug, patient group and administration requirements. For packaging suppliers this allows them to continuously respond to trends in a timely manner and develop varied innovative solutions, which meet the market needs.

The highly viscous nature of some biologics presents another challenge to packaging.


DRUG DELIVERY SUPPLEMENT

AVOIDING THE PIT

How to avoid crosslinking in soft gel formulations.

Author: CLAUDE CAPDEPON EMEA & South East Asia application laboratory manager at Rousselot

T

he popularity of soft gel capsules continues to rise, with the latest market reports predicting a CAGR of 5.46% and a global market value of $3,276 million by 2023. Typically used to carry semi-solids, liquids, gels or paste-like fills, soft gels offer a versatile solution to active pharmaceutical (API) ingredient delivery. SOFT GEL CAPSULE DESIGN When designing a soft gel formulation, shelf-life stability, shell dissolution, and formulation versatility must all be carefully considered. Consumer experience is also key – from taste and odour masking, to swallowability. As such, gelatin is the preferred excipient for soft gel applications, due to its robust functional properties, full digestibility, and compliance with stringent regulatory requirements. Plus, as the only clean label excipient, it provides added appeal for an increasing number of consumers. However, not all gelatin excipients are made equal − manufacturing gelatin-based soft gels requires technical knowledge and specialised gelatins to ensure optimum product stability and avoid common manufacturing pitfalls such as crosslinking.

The reactions involved in crosslinking are often enhanced by the characteristics of the gelatin.

AVOIDING CROSSLINKING The formation of strong chemical linkages between gelatin chains, crosslinking can cause soft gel shells to become rubbery and insoluble, ultimately affecting the capsule ability to dissolve fully and timely. A purified, soluble protein, gelatin is a polydisperse polymer composed of three alpha chains that cross together to form a triple

helix. Along with its specific amino acid composition, this predisposes gelatin, which accounts for 40 to 47% of the total gel mass composition, to crosslinking. By understanding gelatin’s behaviour under specific circumstances, it has been possible to predict its resistance to crosslinking, and therefore develop specialised solutions to counter it. The reactions involved in crosslinking are often enhanced by the characteristics of the gelatin: viscosity in relation to molecular weight distribution and pH for example can play a key role in making a capsule become unstable and brittle. Rousselot’s research shows that crosslinking occurs as a result of inappropriate storage conditions – namely high temperatures (>30°C) and humidity (>60%), complex fills or APIs containing aldehydes. Understanding the crosslinking process and reactions led to the development of our StabiCaps

solution. Using gelatin from bovine origin, the range of specialised soft gels are designed to reach specific low viscosity profiles and low pH range in a clean label formulation, to ultimately reduce crosslinking. Moreover, additional salts have been added to StabiCaps Plus with the aim of fixing any crosslinking residue and avoid the release of amino acid groups. A STABLE FUTURE With outstanding functional properties and clean labelling, gelatin is set to remain the preferred excipient for soft gels. However, ensuring product stability for increasingly complex fills and new API technologies is a key challenge for manufacturers. Specialised gelatin soft gel enable superior performance to be maintained via increased product stability, while also opening up further API formulations options for pharmaceutical soft gel products.


DRUG DELIVERY SUPPLEMENT

How connected devices are helping patients better manage their medications and improve adherence.

T Author: ANDREAS MELINIOTIS director of Device Development at Vectura

The emergence of connected devices brings the industry to a potential turning point.

he effectiveness of any treatment is a combination of many factors, most notably patient adherence to the dosage regimen and correct use of drug delivery devices by the patient. This means that a lack of compliance and/or patient use error can seriously compromise treatment outcomes. Now, more than at any time in the past, it is possible to use relatively simple connected devices to track and report factors affecting adherence, giving healthcare providers specific and targeted data to inform decisions regarding any necessary modification of a therapy. As the availability of connected devices increases, so the effect of this data-driven therapy adjustment is likely to become increasingly apparent, which in turn will increase the desire to connect more therapies.

way, adherence should be defined as how patients follow the medical prescription. However, numerous variables influence medication use, such as the route of administration, frequency of use, taste, response to therapy and adverse events.” Another example where feedback on medication effectiveness is key to correct administration is

diabetes, where glucose levels are self-measured by patients to decide when to administer insulin. Where connected devices can provide feedback on medication effectiveness, this can be an important part of the selfadministration process. The ability of patients to selfadminister, however, depends

Making the

Connected drug delivery should be focused on areas where the impact can be greatest. For example, whereas insulin injections for diabetes have a generally high level of adherence due to immediate severe outcomes, an asthma maintenance therapy may exhibit poor adherence as there is no immediate decline in health. Using a connected drug delivery device for the latter can provide a high level of monitoring and therefore give an early trigger for intervention to prevent uncontrolled disease and eventually hospitalisation. Some therapies can be affected significantly by user technique, and identifying this can have a dramatic effect on the efficacy of a treatment, particularly if it prevents a patient being prescribed a medication at a higher level to compensate for poor technique. A recent paper reviewing inhaler adherence states, “In the simplest

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upon many factors; not least education and age. For some patient groups, there are smartphone apps connected to a drug delivery device that can be designed to both prompt the user to self-administer and guide them through the administration process by listing the critical tasks and providing pictures or videos to aid dosage. Such technology and interaction provides huge levels of guidance data to patients,

and gives the opportunity to reduce user task errors and improve compliance as a byproduct of connecting medical devices. Connected devices can provide both feedback and metrics to encourage patients to comply. Gamification can be used to change patients’ mindsets, using an app or other feedback interfaces to encourage compliance, and there are

connection

suggestions to ensure long term compliance, constantly changing aspects, can keep patients interested, and have a longer-term effect than more basic systems. Currently, connected drug delivery presents as add-ons to existing approved combination products or medical devices. Good examples are pressurised metered dose inhaler (pMDI) add-on devices, which sense the user pushing the pressurised canister to release the medication. The functionality of such devices is limited as the base device has not been designed with connectivity in mind, so the options for communication between devices are restricted. Additionally, only the number of times the user has pressed the canister to release medication can be measured, but no indication as to whether the user has inhaled the medication, or whether the canister still contains medication can be registered. Without monitoring the usage and remaining doses, the system is far from providing true patient adherence information. As time progresses, delivery devices are likely to be increasingly designed with connectivity in mind, which could open up possibilities for integrated connectivity or high functionality add-on devices, but extensive market research will need to be undertaken prior to the development of next-generation devices. User needs must be fully understood and a detailed target product profile (TPP) drawn up to ensure that the top level assumptions and requirements are considered. It is likely that the functions of such a device will be different or more complicated than initially assumed, and these details are

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important to ensure that the final design meets the user’s needs. For any developer, the key is to focus on the user and the intended use, and to use these inputs to select a concept for development. Once a design is available, functional requirements can be tested, but again the developer must engage users for feedback and validate that their needs are met – and this is likely to be an iterative process to achieve a product which meets the original brief. Ensuring that regulations are met when developing connected devices depends largely on the target markets and the type of device being developed. For instance, a 510k application with the FDA for the US market can be used if a predicate device exists, as a basis for the application. This would be appropriate for a medical device but not for a combination product. A combination product that includes a fixed connected device element would need to follow a more onerous new drug application (NDA) type route. The new EU Medical Device Regulation would apply to both medical devices and combination products for European markets. The emergence of connected devices brings the industry to a potential turning point, and being able to measure ‘true adherence’ will be a first step towards unlocking the benefit of such devices. The ability to measure signals from the patient and automatically administer, or prompt administration of medication will provide a closed feedback loop that could ultimately optimise efficacy for individual patients, and ensure the robust continuation of medication, optimising patients’ treatments.


DRUG DELIVERY SUPPLEMENT

The importance of ensuring a robust parenteral packaging supply chain in unprecedented times.

Pandemic preparedness

T Author: JEFF SMYTHE - commercial development manager at Datwyler

How do you manufacture enough drug product and its packaging to vaccinate the entire world?

he year 2020 has truly been an unprecedented time for most of us, but in the healthcare world, preparing for a pandemic is par for the course. Epidemiologists have worked for years to study coronaviruses, which is now helping companies lead the way in developing potential treatments, cures, and vaccines. For drug developers, being ready to develop and mass produce drugs for a pandemic situation is an essential part of their risk management strategy. But what about the packaging suppliers that create containers, stoppers, plungers, and seals to protect and deliver these vital drugs? How do you manufacture enough drug product and its packaging to vaccinate the entire world? CAPACITY LIMITATIONS Even when operating 24/7, drug developers and their suppliers can only manufacture a finite amount of product based on manufacturing capacity. Manufacturing volumes are determined based on years of historic volumes, sales forecasting and industry projections. These projections then define the amount of staff, equipment, and building space needed to meet demand. In the case of our current pandemic, the cost, time, and square footage

needed to produce vaccines for the entire globe are more than any one supplier can handle. The solution to this problem is to qualify multiple suppliers to meet global demand. With the top packaging suppliers working transparently with the leading pharmaceutical companies to develop and produce the final product, we can proactively mitigate potential capacity limitations. SCALING-UP TO MAXIMUM CAPACITY Even with all major suppliers working to qualify multiple vaccine solutions, each supplier must also consider the diďŹƒculty in scalingup production to meet maximum capacity. First, suppliers need to consider that the Covid-19 vaccine is not the only essential drug product being manufactured in 2020. Life-saving medications still need to be produced and distributed to patients during the pandemic, which means that suppliers must find a way to continue meeting current demand while also using excess capacity for the Covid-19 vaccine. In some cases, suppliers will need to invest in new equipment, raw materials and more staff to handle the increase in volumes. For faster scale-up, find suppliers

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with continuous manufacturing improvement capabilities already in place and excess capacity that can be used for vaccine production. AVAILABILITY OF RAW MATERIALS Raw materials for parenteral packaging components are sourced from all over the globe, and procurement can be interrupted now that country-wide shutdowns and shipping and travel restrictions are in effect. Drug developers should partner with suppliers that have a global procurement and supply chain already in place to ensure raw materials can be sourced no matter the situation. Additionally, drug developers should build packaging inventory now to hedge against lead times and potential capacity constraints. To mitigate these risks and prepare for future emergency situations, drug developers and packaging suppliers need to work together early in the development process and put into place risk mitigation plans for every scenario. Together, we will find a solution to this global pandemic and have plans in place to prepare for future unprecedented times.


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DRUG DELIVERY SUPPLEMENT

EPM speaks to Phillips-Medisize about the promise of connected health in drug delivery for patients, pharmaceutical providers, and the healthcare industry. WHY IS CONNECTED HEALTH IMPORTANT TO DRUG DELIVERY? It’s important to get as close to the point of actual medication administration and the events that surround it. Self-administering medication, while it sounds very straight-forward, is actually very challenging and emotionally draining for patients who have chronic and debilitating conditions. Why? One reason is because when some individuals take a prescription pharmaceutical to manage their health, it psychologically reminds them that they’re ill. The goal is to help patients take their medication as prescribed to improve adherence and manage their condition.

Answers by: Kevin Deane - vice president of FrontEnd Innovation and Connected Health, Phillips-Medisize

WHAT ARE THE KEY BENEFITS OF A CONNECTED DRUG DELIVERY SYSTEM TO HEALTHCARE PROVIDERS? How can healthcare providers determine the effectiveness of treatments without understanding how, or even if, patients are taking their prescribed medication? When trying to provide a continual diagnosis and treatment plan for patients, the healthcare provider (HCP) needs to assess how the prescribed medication is working over time. The HCP may only be able to draw upon conversation with the patient to determine how they are taking their medication. However, patients often don’t remember the details of how well they’re adhering to their medication, which presents an incomplete picture of what’s actually happening. The advantage of a connected drug delivery system is that it provides accurate information about when, at what level and exactly how patients are taking their medication, compared to the original prescription. This data helps to provide a clearer

indication of how well the treatment regimen is working and whether adjustments are required. WHAT ABOUT THE ADVANTAGES OF A CONNECTED DRUG DELIVERY SYSTEM TO THE PAYER? Traditionally payers have been reimbursed for prescription drug treatments based on consumption, not necessarily effectiveness. Now the model is shifting toward pay by result. A connected health system provides a deeper understanding of whether patients are taking their medication in the way that has been prescribed by the physician and how effective the treatment is in managing their condition. Having a more detailed view of actual health outcomes may provide a better measure for reimbursement. FINALLY, WHAT ARE THE BENEFITS TO PATIENTS? From the patient perspective, there are two key benefits. First, a connected health system gives patients a better understanding of how they’re administering their medication, whether they’re taking it in the right way and at the right point in time. Automatic timers and alerts embedded in the drug delivery device, for example, remind them when it’s time to take their medication. Many injections require or suggest site rotation in order to limit the impact on different areas of the body, and a good connected app is able to offer that guidance to patients as well. Second, a connected health system provides a lifeline back to the healthcare community. Once patients leave the safe environment of a hospital, they’re faced with managing their condition by themselves, which

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can make them feel isolated or alone. A connected drug delivery system links them back to a level of healthcare support and has the tools needed to address questions and manage their condition more effectively when remote from a hospital or clinical setting. WHAT IS THE ROLE OF PATIENT SUPPORT PROGRAMMES, AND HOW CAN A CONNECTED HEALTH SYSTEM COMPLEMENT THEM? Patient support programmes (PSPs) are generally third-party programmes sponsored by a

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pharmaceutical company, but function as separate entities and are resourced by clinicians and nurses. Their sole responsibility is to support patients in selfmanaging their condition in the home environment. They’re often very knowledgeable about the particular disease in which they’re supporting patients and typically communicate via phone, email and text with patients, following a set of defined guidelines. Up until now, however, PSPs lacked true visibility into measuring the impact of their interventions on patient behaviour and medication adherence. Connected health systems capture real-time data to show evidence of how well patients are adhering to their

treatment regimens and whether they require a higher level of support. This data can be viewed through a PSP web portal or dashboard at the individual level to personalise PSP outreach, as well as at a community level to further identify and triage those patients within a given territory that need more support. In essence, the system shines a light onto specific individuals and groups that aren’t taking their medication as expected so that a PSP can tailor intervention to get patients back on track.

are effective in capturing and displaying medication information. The next step is utilising this data to define and implement successful interventions. It is one thing to identify that someone is not taking their medication effectively, but it is quite another thing to affect a positive change in behaviour; a virtuous circle that improves adherence to medication, leading to better outcomes and reduced overall healthcare spend. This is the goal that everyone in this area is targeting.

WHAT ARE SOME FEATURES OR FUNCTIONS OF CONNECTED HEALTH SYSTEMS UNDER EXPLORATION? We are building systems that

WHAT FUTURE TRENDS WILL BE PIVOTAL TO SUCCESSFUL CONNECTED DRUG DELIVERY? There are four main trends shaping the future of connected drug delivery. First, as explained above, is understanding more about what motivates patients, so that we can define and implement successful interventions. The second trend is around scalability, moving from small pilot studies to large global programmes and shared infrastructure where we can start to benefit from economies of scale. This will help implement connected health solutions at a lower cost base, so that they can be used more broadly in the market. The third trend is around integration. As healthcare continues down the path of digital, medication adherence data will be shared from proprietary systems to leading EMR systems, allowing HCPs to view this data from anywhere. And, fourth, analytics is going to be a key driver for connected health systems going forward. We’ll see a trend in how patient data is used more effectively to understand patient behaviours tied to drug performance and even the relationship between taking medication and improved health outcomes. This will guide more tailored and personalised care delivery at both the individual and patient population levels.

ON THE PATIENT 39

A connected health system provides a lifeline back to the healthcare community.


EPM speaks to Lionel Maritan, associate director of research and development at Becton Dickinson (BD), about the company’s Intevia 2.25ml autoinjector which is set to launch at the end of 2021 or the start of 2022.

A PA NLESS APPROACH M

Author: Ian Bolland

aritan begins by explaining that the new product is still in its development phase and will be dedicated to injecting drugs at a higher volume compared to previous devices the company has launched. The 2.25ml disposable autoinjector is a combination product designed to deliver a range of viscous drugs for patients suffering from chronic diseases. Since chronic disease patients undergoing biologics treatments often need to inject frequently, the device has been designed for home use and to be easy to hold. Used with pre-fillable syringes, Intevia works through a two-step process, with the patient first placing the autoinjector on their skin before pressing a button once to deliver the prescribed dose. Though designed for home use, it has had the input of healthcare professionals during human factor studies whilst being tested on patients with chronic illnesses. BD hopes its new autoinjector will be able to provide less painful delivery of any dosage but Maritan admits that delivery has to be considered in combination with the drug itself when it comes to pain level.

LIONEL MARITAN - associate director of research and development at Becton Dickinson

“What we are doing, in fact, is trying to establish specific requirements when we launch this new development to keep reasonable injection, so not too fast and not too long as well,

and to find the best compromise between flow rate but also the injection time when you are using an autoinjector. “We are combining these two limits, and have tried to design between them, to keep a good compromise between the pain and the ability for a patient to inject themselves in a reasonable time.” Designing a new autoinjector does come with its challenges, as Maritan explains it is a case of replacing manual steps by automatic means, and given the higher volume of medication carried within this autoinjector, the challenges can be seen as greater compared to the existing products that BD has in smaller volumes. Comparing it to a 1ml autoinjector, Maritan explains how “the challenges are much higher because you want to inject two times the volume.” More so, development challenges are presented by the need for the company to afford a broad range of drug viscosities that are accessible with its autoinjector technology. “Your design is at the limits and you need to find the right combination of component subsistence to maximise the performance without compromising the basic functions. “If you need to inject higher volumes at higher viscosity you


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need more power force. The higher the power, the higher the challenges are and the side-effects you need to manage at the system level. “For the technical challenges we are putting more constraints on the autoinjector and you have to manage all these constraints by finding the right technical solutions and by selecting the right components.

“With an autoinjector you integrate a preferable syringe, you integrate stoppers, so you integrate a lot of well-known components not only used in autoinjectors, but used in other systems, and you need also to select the right components to ensure the system functions.” There are many things to take into consideration when it comes to opting for specific parts and the materials used to assemble them to form the injector, including the barrel and the stopper. Maritan explains that any plastic parts will be produced with moulding technology, a barrel will be produced using a specific forming process, and stoppers are produced via a specific forming process. “We have to specify to make sure these components are correctly manufactured at the right quality level and with the right specification. “We have a lot of knowledge and management of all the components and sub-systems that are part of the autoinjector. Not only the autoinjector components but the syringe plus the stopper, so we are managing all the components. We are specifying all of the components to be sure that the system will operate as it should do in the end with patients.”

The challenges can be seen as greater compared to the existing products that BD has in smaller volumes. 41


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WHAT'S

TRENDING

READY FOR CHANGE Why pharmaceutical trials are ready for major changes.

B Author: PAUL BRAGAN senior partner at Wakefield Research

y necessitating social distancing and limiting travel, the Covid-19 outbreak has interrupted many ongoing clinical trials, with over 400 suspended since March 1st. To ensure the continuation of certain trials during the pandemic, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) relaxed clinical trial regulations in March and stressed that patient monitoring, patient consultations, and confirming patient consent can all now be accomplished remotely. Wakefield Research believes that this development will lead to remote trials becoming an important component of the pharmaceutical industry. Already we are seeing significant developments. Science 37 recently partnered

with AiCure, Medable partnered with MRN, and Bioclinica has joined forces with VivaLNK to develop better remote trial offerings that will support trial sponsors throughout the pandemic. This wider adoption of remote trials will achieve: 1) greater efficiency for trial sponsors, 2) a more diversified pool, and 3) continual monitoring. 1. GREATER EFFICIENCY FOR TRIAL SPONSORS A move from in-person to clinical trials will save substantial costs for trial sponsors. Currently, CRAs who travel to trial sites must be reimbursed for transportation, housing, and meals. These costs add up quickly and, consequently, onsite monitoring of clinical trials costs up to 30% of the entire clinical trial costs, according to FDA data. Moving to remote trials will be of great benefit to sponsors as it will make it easier for them to launch new trials and to invest in additional drug research and development. 2. A MORE DIVERSIFIED POOL Remote trials can also eliminate geographic barriers, making it easier to recruit a diversified participant pool with greater representation of minority and rural participants. Achieving diversity in clinical trials is extremely important as it gives crucial data about the potential effects of a given drug on individuals of different populations. Access to such a large population of participants through remote trials also aids in trial recruitment and retention, leading to better results.

3. CONTINUAL MONITORING With remote trial capabilities, participants are now able to consent to treatment electronically and receive medication and monitoring equipment from pharmaceutical companies through the mail. In time, trials may also utilise smart watches and other wearable devices to continually monitor trial participants and check-in with them virtually in a timely manner whenever issues arise. Aside from saving time, this can also limit the risk of infection. However, the recent shift to remote trials will not completely eliminate inperson pharmaceutical trials. Predominantly remote trials will likely require occasional inperson check-ins or monitoring visits. Also, certain high-risk trials, such as those in oncology, will continue to necessitate more frequent in-person interactions. Remote pharmaceutical trials will also face some potential difficulties. Certain participants may feel anxious about rarely meeting with researchers faceto-face, or they may not take their trial as seriously when it is conducted remotely. Further, pharmaceutical companies will have to ensure that they are in full regulatory compliance during remote clinical trials. This might prove challenging initially, as much of the remote trial infrastructure is still being developed. Nonetheless, a greater emphasis on remote trials in response to Covid-19 will bring permanent change, with it the potential to make many types of trials faster, more efficient, and more successful than before.


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DRUG DELIVERY SUPPLEMENT ADVERTORIAL

STEPWISE

TO FUTURE RESPIRATORY CARE More than 500 million people worldwide suffer from Asthma and COPD. These major chronic decisions lead to more than 3 million deaths per year. Also, the associated cost burden is significant and exceeds €150 billion in the USA and Europe taken together. A major driver for this disastrous status is insufficient adherence to controller medication, which even after the first prescription has been filled ranges between 30% and 66%. Connected, external “add-on” devices for Asthma and COPD inhalers track patient adherence and connect patients to their physicians and other healthcare providers. In clinical studies, these devices have demonstrated to improve adherence to Asthma and COPD medication and therewith clinical outcomes . Despite the fact, that they also offer advantages for other key stakeholders, like physicians, payers and pharmaceutical

companies, their market adoption has been poor so far. The reasons, we at H&T Presspart believe, are that a stepwise approach to connected respiratory care is needed and that the short-term requirements for mass adoption have not been fully met yet. Long-term connected devices might be “purpose-designed” like a Tesla electric car is around its electric drivetrain, track technique via advanced sensors and might even actively regulate device characteristics, such as the flowrate. For a short-term market success, devices also need to have embedded electronics, but should be simple, intuitive, costefficient and represent limited changes to the status quo. In an effort to realize a broad market adoption in a stepwise manner, H&T Presspart and Cohero Health formed a strategic device development and marketing partnership. As

H&T PRESSPART'S EMDI CONNECTED INHALER

a result, the companies created the first market-ready, fullyembedded, connected metered dose inhaler solution: H&T Presspart’s eMDITM powered by CoheroTM. The eMDI device design is inline with the requirements stated above: It is an evolution of existing metered dose inhaler technology and its connective hardware and software are fully-embedded. The changes to existing MDIs form and function are minimal. As a fully disposable, non-reusable unit, the eMDI secures that users do not need to do anything other than press and breathe, as with their standard MDI. Also, the electronic componentry is separated from the medication delivery pathway and the device incorporates an FDA-approved mechanical dose counter. With our partners, we hope that we can pave the way for a broad market adoption of connected technology in respiratory care. A change is needed, as “drugs don’t work in patients who don’t take them”.

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1 Akdis CA et al., “Global Atlas of Asthma”, EAACI, 2013. 2 GARD, “Chronic respiratory diseases”, http://www.who.int/gard/ publications/chronic_ respiratory_diseases.pdf 3 Akdis CA et al., “Global Atlas of Asthma”, EAACI, 2013. 4 WHO, “Burden of COPD”, http://www.who.int/ respiratory/copd/burden/ en/ 5 Ford ES et al., “Total and state-specific medical and absenteeism costs of COPD among adults aged ≥ 18 years in the United States for 2010 and projections through 2020”, Chest, 2015, 147, 1, 31-45. 6 CDC, “Asthma in the US”, https://www.cdc.gov/ vitalsigns/asthma/ 7 Gibson GJ et al., “The European Lung White Book: Respiratory Health and Disease in Europe”, European Respiratory Society, 2013. 8 NICE, “Smartinhaler for asthma – Medtech innovation briefing”, NICE, 2017. 9 NICE, “Smartinhaler for asthma - Medtech innovation briefing”, NICE, 2017. 10 Jung B, Shears D, “Embedded connected metered dose inhalers meeting requirements for mass adoption”, ONdrugDelivery, 2017, 76, 6, 44-48. 11 Jung B, Shears D, “Embedded connected metered dose inhalers meeting requirements for mass adoption”, ONdrugDelivery, 2017, 76, 6, 44-48. 12 C. Everett Koop.


Smartphone app connectivity to allow real-time tracking and care management

Mechanical Dose Counter

Introducing the next generation MDI For more information contact H&T Presspart: www.presspart.com eMDI@presspart.com

H&T Presspart are pleased to introduce the first market-ready, fully-embedded, intuitive and connected metered dose inhaler (eMDITM) established to optimize care of patients ensuring from asthma and COPD. The eMDITM integrates seamlessly with BreatheSmart from Cohero Health, the only respiratory disease management platform that enables tracking of both controller and rescue medications, along with clinically accurate lung function measurement, in real-time.


DRUG DELIVERY SUPPLEMENT

The key considerations when designing safety syringes for use outside of the healthcare setting, drawing on OMPS’ experience with its UniSafe pre-filled safety syringe device.

S

ince the 1990s, there has been a significant increase in the use of biologics to treat a variety of diseases. In fact, the global pharmaceutical market for biologics is expected to be worth over $400 billion in 2023, doubling in size over a 10-year period. Simultaneously, some of the most important and lucrative biologics have reached their patent expiration date, allowing biosimilars to make an entrance and increase competitiveness, further boosting the use of these drugs. This growth has presented the industry with a number of challenges related to drug delivery; as proteins, the molecular structure of biological drugs can make it challenging to develop suitable formulations for effective patient self-administration.

For patients, a device with a minimum number of components is less intimidating and easier to use, while for manufacturers, a simple product is easier to reliably integrate into manufacturing processes.

devices that encourage treatment compliance by being simple, effective and safe to use. ESSENTIALS OF SAFE DEVICE DESIGN Regulations in the US, Europe and beyond require employers to protect their staff from the risk of needlestick injuries from

A consequence of this is that biologics and biosimilars are mostly administered subcutaneously. Small volumes of drug are injected into the subcutaneous layer of the skin to allow absorption and subsequent distribution around the body. Many chronic neurological, cardiovascular and auto-immune conditions, such as Crohn’s disease, rheumatoid arthritis and psoriasis are now treated by subcutaneous injection, as well as infertility and growth disorders. As subcutaneous injection is a far less complex process than intravenous injection or infusion, this procedure is often conducted outside the hospital by patients themselves in their home environment. However, for self-administration to be successful, patients must be provided with drug delivery

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exposed needles or sharps. As a result, many needle protected safety designs are now available across a wide range of medical products. However, more recently the focus has extended to providing safety products in the home environment where patients, carers and relatives can all be at risk of needlestick injuries. In this setting the design and ease of use of a safety device is integral to the therapy as a whole, especially since it may also have an impact on patient adherence. A crucial element of safe design is simplicity. For patients, a device with a minimum number of components is less intimidating and easier to use, while for manufacturers, a simple product is easier to reliably integrate into manufacturing processes.

UniSafe’s design consists of only four moulded plastic components, and no spring, which can be simply assembled with a prefilled syringe to create the final combination product. A simple design such as this is also advantageous for drug manufacturers as the resulting efficiencies in their production process facilitates scaling up and increasing capacity. A second important safety element is enabling automatic, or passive, deployment of the needle-shielding safety mechanism. During drug administration, once an exposed needle has been removed from the injection site, the user is still at risk of injury. To resolve this issue, UniSafe’s safety shroud fully encases the needle and it is automatically positioned as the user completes the injection procedure. Once injection is complete, the needle retracts into the safety shroud without any additional user steps. Since the procedure is the same as the usual injection technique with a standard syringe, the patient can focus on their injection and still be protected from potential sharps injury. Unique to UniSafe’s design is the mechanism that retracts the needle into the safety shroud. To date, safety syringes on the market have typically been designed with an internal spring, which activates the safety mechanism. However, using a spring comes with challenges. There is a risk that devices can pre-activate during transit; in addition the manufacturing process is complex where the spring is added to the device under high tension. UniSafe does not rely on a spring, which not only eliminates these issues but also adds to the overall simplicity of the device. Furthermore, the absence of

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a spring allows the patient to clearly see the contents of the syringe prior to administration and to confirm that the full dose has been delivered afterwards, a further critical element of safe medication delivery. Finally, safety devices should prevent the syringe plunger at the rear of the device from being completely removed. Removal can lead to drug leakage and wastage and in turn possible missed injections, as well as opening the door to tampering or re-use of devices that are single-use only. THE FUTURE OF SAFETY SYRINGES The design of safety devices is constantly evolving to better meet patient and healthcare professionals’ needs. In particular, there are ongoing efforts to identify opportunities for greater sustainability and increase device connectivity. Syringe-based devices such as autoinjectors are typically single-use only and are used by patients with reduced dexterity who need a larger device than a prefilled syringe to self-administer medication. The UniSafe platform is evolving with sustainability as a key consideration and future developments will include autoinjectors that can be reused rather than requiring disposal in clinical waste after each use. Increasingly in the future, autoinjectors will also include connected devices, allowing the transfer of information between patients, clinicians and payors. There is a growing need for this level of functionality in the pharmaceutical industry; measuring and improving adherence to therapies is of increasing importance to both improve patient outcomes and reduce drug wastage and unnecessary costs.

Author: GEORGE I’ONS - head of Product Strategy and Insights at Owen Mumford Pharmaceutical Services (OMPS)


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High quality, secure and reliable. All traits that set Denny Bros apart as an established clinical trials supplier as well as a pharmaceutically-accredited company. Working closely with customers every step of the way, we recognise the importance around quality control and consistency to ensure there is no variation in quality. We are also acutely aware that the cost and reputation implications can be significant so we employ a variety of quality procedures to guarantee peace of mind for every customer. For instance, to ensure there are no discernible differences, we use very little colour within our clinical trials work. We have the creative ability to come up with original ideas while always being aware of the sensitivities and discreetness around labelling for clinical trials. WHAT OTHER THINGS DO YOU HAVE TO CONSIDER WHEN CHOOSING A CLINICAL TRIAL SUPPLIER? Trials may change during the process and suppliers will need to be equally adaptable. Multi-page label printing servicesExtending a trial may require expiry dates or other information to be tailored to your precise changed during the requirements process. Automated label inspection, especially at the point of on-demand printing, will be a logical and necessary development in adaptive trials.

Alongside this, the extension of a trial may require a new supplier to come in but with no obvious visual changes to the labelling requirements. This means any CT supplier must be flexible, often move and react fast, and have the ability to make amendments, often at short notice. Tracking of detailed information throughout the CT process is very important and clear labelling is essential to help towards this. Our labels ensure vital information remains on pack and can be ideal for repeat reference. Pharmaceutically-accredited, Denny Bros is also equally adept at managing clinical trial requirements for relatively small volume. As well as offering no minimum order quantity, our customers know that we will apply the same rigorous standards when producing just a handful of products as we do for tens of thousands. Our labels ensure products are both compliant and effective and Denny Bros prides itself on being able to provide many special print features such as batch numbering, removable information panels, holograms, tamperproof and anti-counterfeiting features, overprinting and braille. The end result? Denny Bros has an established track record for delivering perfect labels on time and to budget that meets all requirements and industry standards. Find out more about how Denny Bros can help by visiting www.dennybros.com/.

WHY CHOOSE DENNY BROS? • Years of successful CT label manufacture • Manufacture of all components under one roof • High quality and controlled manufacturing site • ISO accreditations • Experienced and dedicated staff • Continuous Quality Control

ANTIMICROBIAL COATINGS

• Flexibility and ability to respond quickly • A number of controls including spectro colour control, separated artwork file control and Eye-C file checker.

CLINICAL TRIALS

EXTREME TEMPERATURES

• A significant range of products including multipage and single panel labels, variations for any container type, temperature-specific materials and variable data printing.


CONTRACT MANUFACTURING

49

EPM speaks to West Pharmaceutical Services about the essentials in contract manufacturing and the trends affecting manufacturers.

Quick Questions with Patrick Malone, vice president, Operations, Contract Manufacturing at West Pharmaceutical Services EPM: Why are more pharma companies outsourcing their manufacturing requirements? MALONE: Outsourcing is a strategy that many pharma companies use to remain competitive, reduce infrastructure and overhead expenses, and improve their operational efficiencies. It also allows them to focus on formulation and drug development and provides the flexibility needed in a fast paced, ever-evolving market. EPM: How are CMOs preparing for advances in manufacturing such as continuous & Industry 4.0? MALONE: Industry 4.0 typically refers to the use of data and automation in manufacturing. Simulation, additive manufacturing, data & analytics and augmented reality are technologies that are currently being used to create

“smart factories” where systems, machines and people work together to rapidly design or create something while improving efficiencies and eliminating errors. CMOs are getting their house in order - through Improvements in infrastructure. It is important to have the right infrastructure, security, systems and data storage - not to mention, an exceptional talent pool to support these technologies and market growth.

biosimilars. Due to the capitalintensive nature of the business and complex manufacturing requirements, pharma will continue to rely on CM partners that can offer an integrated approach to services from packaging, testing, filling, device assembly and final packaging – both for commercial and clinical production. This is all in an effort to mitigate risk, streamline their supply chain and meet time-to-market expectations.

EPM: What advice would you give to customers working with CMOs for the first time? MALONE: Strategic partnerships should be mutually beneficial and collaborative in nature. Partnering with a CMO can have many benefits, including innovative strategies that mitigate risk and improve time to market. Understand if the CMO is a leader in their given market - do they offer end-to-end solutions, and can they support scale up strategies including clinical trials, HF support, regulatory, analytical testing and device manufacturing and lifecycle management?

EPM: What are some of the biggest regulatory hurdles CMOs working in pharma face? MALONE: CMOs contribute information and data to their customer’s regulatory filings and are responsible for ensuring all quality requirements are met. Regulatory requirements vary across different countries so a CMO must understand the regulatory landscape and align to their customer’s product distribution strategy. An agile quality system is a requirement in meeting a broad set of regulatory requirements. Timing and uncertainty around regulatory clearance/approval can also present a challenge to CMOs. Clear communication with the customer around this timing is important as CMOs need to effectively plan their capacity to support their customer launch and market expansion needs.

EPM: What trends are you expecting to occur within the CMO market over the next few years? MALONE: We expect to see increasing demand for biologics and generics, as well as


50

UK approves Covid-19 treatment after promising clinical trial

A

n anti-inflammatory drug has become the world’s first treatment shown to reduce the risk of death for Covid-19 patients. Dexamethasone has been hailed as a breakthrough by the UK government and will now be part of standard treatment for Covid-19 patients requiring oxygen and ventilators. The drug is being tested as part of the Recovery trial, with data from 2,104 patients showing that dexamethasone reduced the risk of death by 20% for those on oxygen and reduced it by 35% for ventilated patients. The drug was initially suggested to the government by the New and Emerging Respiratory Virus Threats Advisory Group (NERVTAG), before being trialled through Recovery. The findings come from Oxford University branch of the Recovery Trial, who released the data on Monday (16 June). Health Secretary Matt Hancock said: “I’m absolutely delighted that today we can announce the world’s first successful clinical trial for a treatment for Covid-19. This astounding breakthrough is testament to the incredible work being done by our scientists behind the scenes. I want to thank the brilliant scientists at Oxford University, the thousands of patients who took part in the study, and my own team, led by professor Jonathan Van-Tam, who has done such a brilliant job driving this work.”

TALKING POINTS

Talking points RESEARCH UNDERWAY TO FIND CAUSE OF CHRONIC FATIGUE SYNDROME D ata visualisation company Zegami is collaborating with researchers in Oxford, Bydgoszcz (Poland), and Valencia to try and find what causes Chronic Fatigue Syndrome (CFS), otherwise known as Myalgic Encephalomyelitis (ME).

by SoftCell Biologicals. The project will use Peripheral Blood Mononuclear Cell (PBMC) data obtained from the UK ME/CFS biobank, which Zegami will then visualise in order to differentiate samples and identify patterns and trends.

The largest of its kind in Europe, the project will take place over a four to fiveyear period with the help of $750,000 in funding provided

The researchers hope that the project will lead to the first ever medical diagnostic test for ME/CFS and potentially new treatments or a cure.

OUTSIDE EPM

F

ind out what the long-term impact of Covid-19 will be on the medical technology sector in this article by Dr Andreas Ostrowicki, managing director of BGS Beta-Gamma-Service in Germany. Make sure to read the full article on www. medicalplasticsnews.com

COMING UP ON EPM

M

ed-Tech Innovation News editor Ian Bolland speaks to pharmaceutical supplier Abcam about the company’s latest collaboration to image live cells and improve the therapeutic viability of molecules.


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Diagnostics & Analytics

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Profile for EPM Magazine

EPM June/July/August 2020  

EPM June/July/August 2020  

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