EPM March 2019 by EPM Magazine

TRENDS FROM PHARMAPACK

THE LATEST IN DIGITAL HEALTH

WHAT BREXIT MEANS FOR MANUFACTURERS

March 2019

LIGHT SPEED LAUNCH

Launching at Interphex: Ezi-Dock Systems explains why its new UV-C Aseptic transfer system is its most disruptive technology yet: page 16

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Contents

March/April 2018 | Volume 19 Issue 2 REGULARS 5: EDITOR’S DESK Reece Armstrong examines the legacy of Scott Gottlieb and what his push towards innovation meant for the industry.

6: A SMALL DOSE A brief round-up of some of the latest developments in the industry, including the return of The MedTalk Podcast and a genetic test for AMR.

10: ANALYSIS China’s global pharma market and why manufacturers need to cure their data ills.

12: OPINION What leaving the customs union really means for the pharma industry.

16: COVER STORY Why the launch of Ezi-Dock’s UV-C aseptic transfer system is its most important yet.

FEATURES 18: PHARMAPACK Reece Armstrong looks at why the show is growing and what was trending in Paris this year.

21: FORMULATION Useful articles examining a range of methods used during drug formulation.

32: DIGITAL HEALTH Can a wearable really transform clinical trials? What can technology do to help? How AI can diagnose rare diseases.

42: PROCESS EQUIPMENT Overcoming the challenges of compound granulation and finding the best partner for hygienic control.

48: COLD CHAIN SOLUTIONS & LOGISTICS Regulatory challenges and how advancements in technology are making transportation easier.

56: CONTAINMENT The operating pressure manufacturers should choose during aseptic processing.

58: FROM THE FACTORY: This new feature looks at what manufacturers are doing to improve operations and efficiencies on the ground.

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A CHANGE IS GONNA COME The announcement of Scott Gottlieb’s departure from the FDA in March sent shockwaves throughout the pharmaceutical industry.

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The adoption of new technology is what drives industries forward, but without reassurance from regulators, companies might not be so keen to become early adopters of potentially transformative processes

For a year in which the industry has faced uncertainty over Brexit, multiple major mergers and acquisitions, not to mention a number of innovative new developments targeting sepsis, AMR and genomics, Gottlieb’s forthcoming retirement is sure to be a cause of concern for manufacturers in the US. A key figure for pharma, Gottlieb’s legacy will be grounded in his constant push towards innovation, highlighted by digital health initiatives and a recognition of the way new technologies can change current industry practices. Take the regulator’s approach towards continuous manufacturing (CM), a technology which in recent years has been touted as an important tool in modernising the pharmaceutical industry. Through the FDA’s efforts, early adopters of CM and

EDITOR’S DESK other advanced manufacturing technologies will be assisted throughout the application process for products made using these methods.

BUT WHY IS THIS IMPORTANT?

The adoption of new technology is what drives industries forward, but without reassurance from regulators,

companies might not be so keen to become early adopters of potentially transformative processes. The rise of CM for instance, while slow, is attuned to new drugs such as personalised medicines and gene therapies, both of which require different approaches to traditional batch manufacturing. More importantly though, Gottlieb recognised that transparent regulation and policies for advanced manufacturing technologies are necessary if patients are the ultimate beneficiaries. CM might be linked to reduced manufacturing footprints and more efficiency, but there’s potential that patients will also feel its benefits; specifically in relation to drug shortages. Last year Gottlieb wrote that since quality issues are the main cause of drug shortages, the centralised nature of CM “allows for issues to be identified – and remedied – more quickly.” “Advanced manufacturing techniques also allow for more flexible manufacturing capacity, which enables manufacturers to respond to drug shortages faster. With these systems, drug makers can more quickly adjust volumes based on product demand and therefore release product to the market more quickly,” Gottlieb wrote. A penchant to push new technologies onto manufacturers is what regulatory bodies need if real change is to occur throughout the industry. With the high costs of developing new drugs, coupled with the doubt of any new product actually making it to market, it’s understandable that manufacturers might be unwilling to invest in methods that aren’t thoroughly tested.

A small dose Pharma environmental regulation could lead to hefty fines The pharmaceutical industry risks high financial penalties if it doesn’t prioritise its environmental reporting obligations. The announcement comes from environmental consultancy group, Lorax Compliance, who spoke at Pharmapack Europe earlier this year.

North East Trust uses digital platform to improve clinical trials

An NHS Trust in Newcastle is using a digital platform to help improve patient recruitment in clinical trials.

research activity, the Trust sought a solution that would identify the appropriate patients for clinical trial recruitment more effectively.

Newcastle upon Tyne Hospitals NHS Foundation Trust is using software from clinical data company Clinithink to help improve its patient recruitment capabilities.

By using Clinithink’s CLiX natural language processing (NLP) platform the Trust was able to reduce the time and investment required to find and enrol patients into clinical trials. The platform works by using artificial intelligence (AI) to interpret clinical documents, automating the review of a hospital’s clinical notes and connecting physicians

The Trust has suffered from recruitment challenges in the past including delays and costs. Wanting to increase its commercial

and patients with suitable clinical trials. Professor Julia Newton, deputy medical director of Newcastle upon Tyne Hospitals said: “Working with Clinithink has changed how we deliver commercial work. We have topped the NIHR league tables for research for seven consecutive years now, we are proud of how we deliver to time and target, and we are always looking for ways to work better and more efficiently. Clinithink represents such innovation for us.”

Addressing delegates at the show in February, COO Michelle Carvell said businesses may not be aware of the full extent of environmental Extended Producer Responsibility (EPR) legislation and the changes that will be implemented from the EU’s Circular Economy Package.

PARTNERSHIP SET TO TRANSFORM DIGITAL OPERATIONS FOR CONTRACT PACKAGER Contract packaging organisation (CPO) Central Pharma has partnered with digital innovation firm, Supply Chain Wizard to help transform its digital operations. Through Supply Chain Wizard’s fully integrated digital factory suite, Central Pharma will be able to access the latest IoT technology solutions. The tools, designed specifically for primary and secondary packaging operations, will allow Central Pharma and its customers to make data-driven

decisions and increase production efficiency and productivity. Through the new digital processes, Central Pharma hopes to continuously improve its operational and quality processes for new and existing customers. Alwyn Smit, chairman of Central Pharma said: “Partnering with Supply Chain Wizard will help drive our business toward achieving its goal of having a world class manufacturing status. Our new facility in Ireland will be a Digital Factory, the Supply

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For instance, recent legislation changes like Germany’s VerpackG require businesses to register a dual reporting system, with noncompliance carrying a hefty €200,000 fine. “The pharmaceutical industry has many regulatory hoops to jump through, so it’s perhaps understandable that environmental reporting has been as less of a priority”. “Nevertheless, many pharmaceutical companies are highly globalised and export and import into numerous markets.

Chain Wizard team have been excellent in getting their software up and running which has added value to our daily operations at our UK production facility. All of our customers will benefit from having digital access to our production lines.” “We are very excited to partner with Central Pharma in their transformation journey in both UK and Ireland, and happy to see great progress towards a more digital future. This partnership has the potential to become a

As more EU countries focus on improving their packaging collection, sorting and separating capabilities, this industry, like many others, will need to prepare for these changes and consider how they will impact their operations,” Carvell said.

Genetic test developed to fight AMR

“The industry should expect further reforms over the next two years in line with the EU’s 2018 Circular Economy package,” she said. “Planning for these changes is not something to leave until the last minute.”

digital transformation success story and a model digital factory showroom for manufacturing companies to visit & learn from Central Pharma’s experience,” explained Evren Ozkaya, founder and CEO of Supply Chain Wizard. “Central Pharma is a client and partner with one of the most innovative mindsets & high aspirations to create a competitive advantage through digital transformation, and we hope this is the start of a long and successful relationship.”

A new genetic test has been developed to help determine whether people carry bacteria that can cause resistance to two common antibiotics. Researchers from American University developed the test to address growing concern around antimicrobial resistance (AMR). It offers researchers a way to monitor the prevalence and movement of antimicrobial drug resistance. The test detects bacteria carrying the Macrolide efflux gene A which causes resistance to erythromycin and azithromycin, common antibiotics often used to treat respiratory illnesses

such as strep throat. The researchers state that despite widespread resistance to azithromycin and erythromycin, antibiotics are still used a lot to treat strep throat and other respiratory illnesses. “Our rapid genetic test can help doctors better assign medication on site, and improve pointof-care diagnostics, potentially leading to better outcomes without having prescribed a patient a useless antibiotic. There’s a lot of trial and error with antibiotic use, so this is trying to take out some of the error,” lead author Megan Nelson said. “The test is able to detect the gene within 10 minutes of

assay run-time,” said John Bracht, assistant professor of biology at American University and corresponding author on the study. “Standard antibiotic testing requires at least an overnight culture and often isn't performed in routine diagnostic work. Instead, physicians guess which antibiotic to prescribe based on past experience and recommendations, and patients have to return if the treatment fails. We simplified the process of detecting antimicrobial resistance so a physician can determine whether or not a patient will be resistant to a prescribed drug while that patient is still in the waiting room. We think this is a gamechanger for treating common illnesses.”

8 THIS PODCAST’S FOR LIFE… SCIENCES

The MedTalk Podcast returns after an unexpectedly long absence with its latest episode. For new listeners, The MedTalk Podcast takes a light-hearted look at all the latest news in the pharma, medtech and digital health industries. This latest episode examines the Topol Review - a report into the effect that digital medicine, genomics, robotics and artificial intelligence could have on the NHS workforce, and its patients. This episode features comments from the report’s lead author, Dr Eric Topol and Lisa Kean, senior manager of clinical effectiveness at Wolters Kluwer, who gives her thoughts on the need for a digital workforce within healthcare. Lastly, we discuss the Med-Tech Innovation Expo – taking place in Birmingham from 15-16 May and why it’s the place to be for anyone involved in the medical design and manufacturing industry.

A small dose

Cloud-based platform to support FMD compliance

A cloud-based endto-end warehouse compliance solution has been released to help pharma companies better comply with the EU Falsified Medicines Directive (FMD) and US Drug Supply Chain Security Act (DSCSA). Released by track and trace network, Tracelink, the Smart Inventory Tracker helps improve operational efficiencies by allowing companies to verify and update the status of serialised

product, receive realtime feedback, and generate compliance reporting based on configurable workflows. The platform connects to 32 National Medicine Verification Systems (NVMS), enabling companies to meet their traceability, receiving and distribution requirements to EU FMD and DSCSA. “As we expand our business to serve all the digital supply

network needs within the life sciences industry, TraceLink provides the only end-to-end platform that enables companies to capture, process, and exchange serialised product data across a digital supply network,” said Shabbir Dahod, president and CEO, TraceLink. “Leveraging the value of our unique network platform, Smart Inventory Tracker is a complete warehousing solution that integrates with other TraceLink network applications,

enabling companies to be compliant while optimizing warehouse product inventory and minimizing disruption in their warehousing workflow.” By integrating with Tracelink’s digital supply network, Smart Inventory Tracker lets companies make realtime decisions and automate the verification of their serialised products directly from the warehouse floor.

PARTNERSHIP TO HELP ACCELERATE DRUG DEVELOPMENT A strategic partnership for chemistry, manufacturing and controls development has been signed between two pharmaceutical companies. Through the partnership, Ark Biosciences will work with WuXi STA

to accelerate drug development. WuXi STA will provide an integrated solution in process R&D and manufacturing. WuXi STA’s “end-toend” CMC platform is designed for new drug development for both API and finished dosage

forms. By working with WuXi STA, Ark Biosciences hopes to optimise manufacturing processes and reduce commercial production costs. “We’re delighted to partner with such a well-respected, worldclass CDMO such as

WuXi STA,” said Dr Jim Wu, CEO of Ark Biosciences. “WuXi STA’s enabling end-to-end CMC platform, scale, and innovation capabilities will help us to move our drug candidates from the clinical-stage to commercialization more efficiently.”

ANALYSIS

Why China's new legal framework will be a magnet for global pharmaceuticals Nick Beckett, managing partner and co-head of CMS Life Sciences & Healthcare Group writes about China’s approach to attracting global pharmaceutical and digital health companies.

hina is the world’s second largest healthcare market and it’s growing at a rapid rate. It could become a $1 trillion industry by 2020, according to McKinsey. As a developing country with a huge population, the government needs to ensure its citizens are looked after, and the upcoming challenge is an unprecedented one. By 2050, 80% of the world’s elderly will be Chinese. International pharmaceutical companies and tech giants recognise the opportunity that China presents, but few have been successful in establishing a meaningful presence in the country. The central reason is because China’s laws have historically been unfavourable towards international players, and in particular there has been concern about the lack of protection as regards intellectual property (IP) rights. Likewise, global corporations will only be successful in China if they spend time in the country to understand local values. This is changing through China’s focus on healthcare innovation, in particular digital health. The goal is to create Chinese global healthcare champions that can compare with success stories like Baidu, Alibaba and Tencent in the tech sector.

To make this happen, China is looking to attract global pharmaceuticals and tech companies to encourage collaboration with local corporations. The catalyst is an improved legal infrastructure enabling foreign companies to uphold their IP in specialist courts – a reassurance that is greatly needed. Further, Chinese authorities are designing an equivalent to the “Patent Linkage” regime of the US that notifies patentees of impending drug registration applications. Patentees could then respond should their patent rights be infringed. The drug evaluation authority would have the power to suspend the application by up to 24 months until a settlement or valid judgment has been reached. Similarly, the new draft amendments to the PRC Patent Law published last December introduced an extended regime whereby a protection term of up to five years may be given to an inventive patent of a drug that has simultaneously applied for marketing in China and abroad. In 2017, the National Medical Products Administration joined the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. This was widely

considered a significant step towards the internationalisation of the Chinese drug approvals process. What’s more, the government has rolled out several policies to encourage innovation, including Made in China 2025; Healthy China 2030; the Three-Year Action Plan to Encourage the Industrial Development of the New Generation of AI; and a special plan within the 13th Five-Year Plan to create a biotech industry that will account for more than 4% of its GDP by 2020. Additionally, it is building a healthcare workforce among its own population. This includes attracting its “Sea Turtles” (Chinese students who have gained a university education abroad) back to innovate at home. China’s plan is coming to fruition. There is more collaboration between Chinese and foreign companies. One example is Airdoc – a result of a Chinese company and Microsoft joining forces to create AI technology that aims to prevent diseases. It is a cloud-based algorithm that uses retina scan images to detect susceptibility signs, and the results can be sent to the patient’s phone within seconds.

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Opinion

What we do know is our membership of the customs union has helped hugely to create the current highly eďŹ&#x192;cient arrangements for UK pharma manufacturers.

WHY LEAVING THE CUSTOMS UNION MIGHT NOT BE A GOOD THING FOR PHARMA Adam Johnson, director of pharma manufacturing logistics specialists discusses why pharma manufacturers might lose out if the UK leaves the customs union. THE BACKSTOP

hether the UK should retain its EU customs union membership in the long-term is now the central issue stymying progress towards the country avoiding the default outcome of a calamitous no-deal Brexit. Extended customs union membership, as expressed through the device of the so-called Irish backstop, is a prominent feature of the draft withdrawal agreement prime minister Theresa May finalised with the EU Commission in November. The backstop would guarantee a continued invisible border in Ireland, assisting cross-frontier trade and the peace process, plus avoiding smuggling, through Northern Ireland continuing to implement the same customs regime as the republic. This mechanism would kick-in if the EU and UK had not agreed a free trade deal which made it unnecessary by the end of the envisaged transition period following our departure, currently set for December 2020. Crucially, once in force, the backstop could only be abolished through the consent of both the UK and EU.

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However, opposition to the mechanism possibly applying for many years, mainly from Conservative and Democratic Unionist Party MPs, largely explains why the withdrawal agreement was rejected in the Commons during January by a record 230 votes. The prime minister, as I write in late February, is therefore seeking to negotiate a legally-binding time limit or unilateral right for the UK to exit the backstop with the EU, to placate these critics. This is despite the EU having said repeatedly that negotiations on the withdrawal agreement will not be reopened and acceding to May’s requests would mean the device no longer being a backstop. Moreover, insistence on a permanent customs union with the EU is a key element among Labour’s conditions for supporting any amended version of the withdrawal agreement. The main objection opponents cite to a potentially durable backstop is customs union membership precludes the UK from implementing its own free trade deals with countries outside the EU. Many Brexit supporters, including numerous MPs, see this opportunity to run an independent trade policy as an important benefit to leaving the bloc. WEAKNESSES However, there are numerous reasons for doubting whether this notional advantage will live up to the claims made for it and believing Labour’s position is preferable for UK businesses, including pharma manufacturing companies. For one thing, free trade agreements with other countries typically take years to negotiate and ratify – the EU’s with Canada, which came into provisional effect during 2017, for example, took seven. In contrast, the damage to our prosperity incurred through leaving the customs union of the EU, by far our largest

trading partner, accounting for nearly 50% of our exports, would begin instantly. This truth that trade negotiations between nations are usually a lengthy business was underlined in mid-February. Then, it was revealed the government had secured post-Brexit agreements with only seven of the 69 outside countries with which we currently trade under preferential arrangements applying through our EU membership. The seven nations, which include the Faroe Islands (population roughly that of Torquay) but not relevant giants like Japan or South Korea, account for just £16bn of the nearly £117bn of British trade with the 69 states. This, of course, is despite strenuous efforts by the Department for International Trade to secure rather greater success during the last three years. On top of this, the government’s own analysis has estimated that even a postBrexit UK concluding independent free trade deals with the US, China, India, Australia, the gulf and the ASEAN bloc – a highly optimistic assumption – would add merely 0.3 to 0.6% to our national wealth. This would therefore only partly offset the economic damage caused by leaving the EU, which official estimates say will remove between 1.4 and 8.1% from our GDP growth per head, over a 15-year period, depending on what form Brexit takes. Other weaknesses in the anti-customs union case include that few people still alive have experience of negotiating UK free trade agreements, as this has been done on our behalf by the EU since the early 1970s. Other countries will also be acutely aware that we need these deals quickly, which will hardly improve our chances of securing favourable terms from them. It should also be stressed that, contrary to the impression given by some politicians, membership of the EU or its customs union does not restrict states from trading profitably with outside countries. Germany’s trade flows with

China surpassed its business with fellow EU heavyweight France for the first time earlier this decade, for example. This difference of parliamentary opinion is a major reason why, with fewer than 40 days until our official withdrawal date on 29 March, pharma manufacturing businesses, which need certainty and time to plan, still have neither. Indeed, ships are already at sea carrying goods, including very possibly pharma items, from the UK to countries such as Australia, Japan, New Zealand and South Korea, which will not arrive until after 29 March. Nobody currently knows whether tariffs or which regulations will apply to those items or even if they can be landed at all. POSSIBLE OUTCOMES All alternative forms of Brexit to withdrawal agreement ratification, including the UK re-joining the European Economic Area, remain possible, along with the country even retaining its EU membership, perhaps after a new referendum. What we do know is our membership of the customs union has helped hugely to create the current highly efficient arrangements for UK pharma manufacturers. When we at Tudor import goods from the EU on their behalf, for example, the only documentation we need is a copy of the packing list or commercial invoice and the travel document. This is a waybill for air freight, a bill of lading for sea consignments and a CMR note – the abbreviation being derived from its French full name – for road haulage. No customs clearance processes or duties apply, and no VAT is payable before goods can be moved from receiving ports or airports. Whether this almost ideal system or something like it will apply after Brexit, however, remains anyone’s guess.

ANALYSIS

TACKLING DATA TO REMAIN RELEVANT

Heather Oebel, NPI enterprise solutions manager at Winshuttle examines the changing drug landscape and why pharmaceutical companies need to go digital with their data.

he last 20 years has seen rapid development of personalised medication, higher levels of public engagement with health issues and increased demand for safe over-the-counter drugs. New market dynamics are causing an explosion in demand for product variations and fierce competition as small, agile brands enter the market. Pharmaceutical manufacturers risk becoming irrelevant if they do not keep up with the race to market while consumers will miss out on low prices if monopolies continue to dominate for newly introduced products.

New market dynamics are causing an explosion in demand for product variations and fierce competition as small, agile brands enter the market.

Unfortunately for large pharmaceutical manufacturers, introducing new products to market is a complicated process. Extensive safety measures, new legislation or even a product rebrand, can lead to a product being taken off the shelf and reintroduced in a new package, perhaps without any need to change the product inside. In international markets where each country adheres to its equivalent to the Medicines and Healthcare products Regulatory Agency (MHRA), product and packaging requirements are likely to differ. In production terms, each new product variant, even a simple packaging change, kicks off what can be a lengthy launch or new product introduction (NPI) process.

For large manufacturers who run their business on an SAP Enterprise Resource Planning (ERP) system, hundreds of data points may be collected for each new product. We recently surveyed manufacturing professionals from around the globe to understand the challenges with their NPI processes. We found that over half are hindered with slow, manual data collection processes. We also discovered that 75% are under pressure to speed up launches—no surprise given the increasingly intense market competition in the sector. A combination of rapidly changing market dynamics and slow, manual launch processes may cause pharmaceutical companies to “hedge their bets” and start the launch process for over-thecounter (OTC) product variations that may never get released. This involves collecting as much data as possible upfront, and often guessing at some data elements to move the process along.

This game of chance can have a couple of major negative consequences. Firstly, time and resources are wasted if a product is never released, and secondly, placeholder data is often not replaced with the right data, leading to possibly dangerous and costly downstream consequences, such as inaccurate dosage instructions or the omission of allergens. Digitising data collection and entry can reduce launch cycles by 50% or more, reducing or eliminating the need to start launches for unapproved products. Another benefit to a digitised launch process is the ability to build in data guardrails and approval processes that improve data quality and minimise errors. In today’s fast-paced OTC markets, large pharmaceutical manufacturers must balance speed and agility with strict regulatory guidelines and product quality standards. Digitising manual launch processes can be an important step towards meeting these important goals.

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Containment out of the Box

In researching and developing this new system the Ezi-Dock team discovered that levels of satisfaction with existing aseptic transfer processes were very low.

IMAGES: 1 Ezi-Dock’s Ezi-Flow UV-C Aseptic Transfer system 2 Assembly of the Ezi-Flow CSV system which won a Queen’s Award for Enterprise in 2013

COVER STORY

LIGHT SPEED UK-based Ezi-Dock Systems has launched what it feels will be the most far-reaching piece of ‘disruptive technology’ – an innovative aseptic transfer system using UV-C light in place of traditional vaporised hydrogen peroxide (VHP) systems.

hat makes some of the world’s leading pharma companies place orders for a new product months before its launch? That’s what happened in 2018 when Ezi-Dock Systems managing director and sales director, Steve McAleavy and Mike Brimson, began to talk to customers about their concept for a simple but highly-effective replacement for the industry-standard approach to aseptic transfer. Ezi-Dock’s design team and project partners Crystal IS, a division of the Asahi Kasei Group have progressed at light speed to develop and validate the new system which will be launched officially at Interphex 2019, New York. However, the first orders were placed long ago by pharma giants who have come to trust Ezi-Dock’s habit of developing customer driven radical ideas into game-changing process technology.

“VHP based aseptic product transfer systems have always been time-consuming and overly complex, requiring the provision of several services at the point of use,” said McAleavy. “Our approach to the contained transfer of APIs has always been to reduce complexity and cost whilst improving performance. We first took this approach with our EziFlow CSV system, and this is now used all around the world. Indeed, it’s become so readily-accepted that people almost universally refer to it as ‘an Ezi-Dock’, which is completely incorrect, but I suppose we shouldn’t complain at the brand penetration that reflects! “Aided by Crystal IS’s extensive background in UV-C technology, we have been able to adapt our existing, well-proven high containment transfer system to deliver aseptic transfer using UV-C light rather than vaporised hydrogen peroxide,” McAleavy added. “The result is a genuine gamechanger for this particular process. Essentially, we have been able to provide the industry with a safer, simple ‘plug and play’ solution that provides a massive upgrade in performance whilst using less time and fewer resources at a significantly lower cost. Indeed, if you have access to an electric socket, the Ezi-Flow UV-C system can be deployed immediately!”

BENEFITS OF UV-C ASEPTIC TECHNOLOGY In researching and developing this new system the Ezi-Dock team discovered that levels of satisfaction with existing aseptic transfer processes were very low. “The industry knows that there is great difficulty in this area,” said Brimson. “There is a level of ‘wipe and pray’ mentality out there. What this means, of course, is lots of testing, retesting, and wasted time and product. “The plain fact is that Clostridium difficile (C. Diff ) can’t be reliably wiped away, and isopropyl alcohol doesn’t kill it. Flooding with UV-C, at the levels achieved by our new Aseptic system and verified in independent testing, kills C. Diff and E. Coli. Gassing with peroxide vapour is frankly almost medieval in comparison to using UV-C, and it’s costly, unsafe and wasteful.

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“With the Ezi-Flow CSV High Containment Transfer System we took the existing technology – expensive and low-performance split butterfly valves – and created a simpler, neater, and radically more cost-effective solution that required very little training. Taking the same view of Aseptic Transfer, we wanted a radically new approach that did away with complexity and toxic vapours and replaced them with a simple, effective process. We’ve worked in and around these production environments for many years and I can honestly say I can’t imagine that anyone will choose to continue with VHP when they realise a cheaper, easier and moreeffective solution is available.” LAUNCHING THE EZI-FLOW CSV HIGH CONTAINMENT TRANSFER SYSTEM In 2010 a discussion at a UK pharma plant revealed that the incumbent contained transfer system had been failing miserably, and the production manager could find no suitable solution, McAleavy and Brimson were eager to provide an answer. They took just three months to develop the Ezi-Flow CSV system. The system is based on a two-part passive and active, similar in concept to most split butterfly valves, but offering significant advantages in cost and performance. Both parts are interlocked to ensure operator & product safety, and the Ezi-Flow proved so easy to use and so cost-effective that take up of the design was immediate and has now continued through a series of revisions. At the start of the project, McAleavy and Brimson aimed to achieve a 1–10 µg OEL (operator exposure limit), but they actually managed to achieve less than 1 µg, which is as good as, if not better, than many split butterfly valves, according to McAleavy. “That’s how we started to make real inroads into the pharma market,” he said. “Within a few years we

were supplying 10 of the top 12 pharma companies and many had come to see us as process development partners, able to quickly develop solutions to specific manufacturing problems. “Gaining the trust of the pharma industry and developing a positive reputation for ‘disruptive’ designs that really break the mould and provide measurable benefits has been the key to speed of our expansion.”

WHAT COMES NEXT? Unlike many UK-based manufacturers currently, Ezi-Dock is looking forward eagerly to the future. “We have no great Brexit concerns,” said McAleavy. “Of the 36 countries we sell to only 14 are EU, so we’re used to any amount of regulation. Whatever happens we will cope with it. We’re more concerned at the moment with the creation of our own clean room injection moulding facility which will bring a vital part of our manufacturing in house and under our own close control.

Taking the same view of Aseptic Transfer, we wanted a radically new approach that did away with complexity and toxic vapours and replaced them with a simple, eﬀective process.

17 Visitors to Interphex, New York, will be able to see the launch of the Ezi-Flow UV-C Aseptic Transfer system at the company’s booth (3259). The show runs from 2-4 April at the Javits Center New York City and represents a significant event for Ezi-Dock. “Above everything, though, the key factor for us is the launch of our Ezi-Flow UV-C Aseptic Transfer system, which will perform a vital role in our planned growth by taking us firmly into global biopharma markets. We’re just excited to see where the journey takes us next!,” McAleavy said.

PHARMAPACK

Leaving for P As Europe’s dedicated packaging and drug delivery event, Pharmapack plays host to some of the biggest players in the industry and acts as an indication of the trending topics that will occur throughout the year. This year, Reece Armstrong caught up with Silvia Forroova, event director of Pharmapack to discuss why the show has grown so much and what to expect from the industry in 2019.

he meeting takes place outside of one the venue’s conference rooms, situated a few stories up and boasting an impressive view of Paris, the Eiffel Tower clearly visible. Being 11.30am the show has barely begun, but already the show floor is packed and stands are streaming with visitors. Forroova begins by commenting on the success of the show and why it is expanding at such a rate. “It’s actually expanding because of how the markets are developing. If we think about the pharma market in terms of innovation; what is happening when it comes to serialisation, biological drugs, containment, the technology being used in wearable devices, and pre-filled syringes are a huge topic as well. And because of the FDA approvals last year, I think it was 56, and some of them are biodrugs as well, all of these factors are trying to minimise healthcare costs more so than ever before. Whether it’s in developing countries where just making sure that there is compliance, that there is safety, self-application and selfdosing that is safe for the patient. I think all of these factors are helping us to expand the show,” Forroova states.

REFERENCES 1 https://researchbriefings. parliament.uk/ ResearchBriefing/Summary/ POST-PN-0567#fullreport

While innovation seems to be a key driver of the show and indeed the industry, increased collaboration between the varying

sectors appears to be equally as important. The latest Pharmapack report for instance indicated how larger pharma companies are now looking to acquire SMEs to boost approval times and scaleup challenges, as indicated by two large merger and acquisitions earlier in the year. On the topic of collaboration, Forroova believes that changes to drug development have led to packaging being considered much earlier in the lifecycle of a drug. “Packaging used to come in quite late in the stages when it came to drug development. Or even at the final stage. We have a pill, we have a product and it needs packaging somehow. It needs a box!” she jokes. Now though Forroova relates the rising complexity of drug molecules to a specific need in the way they’re packaged, tracked and labelled. The obvious contender for change in this instance is the Falsified Medicines Directive (FMD), which came into effect in February. The FMD requires pharmaceutical companies to comply with a number of safety features that ensure the authenticity of medications throughout the entire supply chain, limiting the possibility of counterfeit medicines making it to the patient.

Asked whether patients are aware of the dangers of counterfeit drugs, Forroova thinks that this varies depending on the country. “In Europe and the US more people are aware of counterfeit drugs and products. When it comes to patients, it’s more about making sure they never have to think about counterfeit medicines; that products aren’t safe to use or have had to be recalled. I think that’s our role here, to educate manufacturers and the packaging companies to do their utmost and to support the activities they’re planning,” she says. We briefly touch on the subject of Brexit, and whilst Forroova doesn’t want to stray too far into political waters, she understands that the UK’s departure from the EU could produce a sort of sea change within the industry. She gives the example of the advanced therapies market within the UK, where a number of major manufacturers are based. “I was reading some research on the advanced therapy medication and a lot of them especially in the EU are manufactured in the UK. So when it comes this particular segment of medication it [Brexit] could have quite a huge impact if a manufacturer leaves or if it makes other players become stronger in the market,” Forroova warns.

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r Paris Indeed, as a recognised leader in the research and development of advanced therapies, the UK could gain £9-14bn per year by 2024, a figure that is 4% higher than the country’s market share of other medicines. Considering the licensing requirements of the EU, in which license holders for medicines must be based in the EU or the European Economic Area (EEA), SMEs could very well end up relocating out of the UK. While Brexit isn’t something Forroova delves too deeply on, she doesn’t deny that it is firmly on the minds of visitors and exhibitors to Pharmapack; there’s even a conference session devoted to it. However, she’s right to say that it isn’t the show’s main focus, which she thinks is clearly represented by Pharmapack’s Innovation Gallery. Showcasing the industry’s latest advancements, Pharmapack’s Innovation Gallery constitutes everything from connected drug delivery devices to new kinds of easy-to-open blister packs. One of the most unassuming products we discuss is a glass vial that has an invisible UV print on it, which provides an anti-counterfeiting aspect to the packaging. It’s simple but wholly intuitive and is one of the best examples of how even the most modest products are changing to industry needs. “I think it really shows us the trends and how we’re trying to showcase players and an industry that is actually supportive on innovation. So this is very important, this is our mission and vision,” Forroova concludes.

When it comes to patients, it’s more about making sure they never have to think about counterfeit medicines

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FORMULATION

Give it a dry

Dr Andrew Naylor, research and development director, Upperton Pharma Solutions, explains why spray drying might be the preferred method for biotherapeutics.

iologics. Biotherapeutics. Biotech drugs. Biotechnologically produced proteins. Whichever your preferred name, it is clear that an increasing number of these modern therapeutics are entering drug development pipelines, with a growing number launched to market each year. Biotherapeutics are an important part of modern medicine as they can be designed to specifically target almost any disease mechanism, offering efficacious treatment with reduced side effects. Biotherapeutics are produced by, or involve, living cells, with a high level of control over their manufacture to ensure quality, safety and efficacy. To date, therapeutic areas include vaccines, protein therapies and antibodies. Given the high sophistication and cost of manufacture and the sensitivity of the molecules,

alongside the all too common failure of new therapeutic candidates in clinic, effective formulation development is vital. Most biotherapeutics are provided as a drug substance in a liquid state, perhaps as a slurry post fermentation and filtration, or as a nanosuspension. Typically, these are frozen to reduce instability, and only thawed when required. It may be relatively straightforward to formulate these into liquid dosage forms such as injectables or oral suspensions, but to improve stability and further exploit and investigate preferable dosage routes then a dry powder will be required. Producing a dry powder form of a biotherapeutic has many advantages over the liquid form; smaller volume therefore reduced storage space requirements, greater physical stability, the

removal of the need for frozen storage and the opportunity to explore delivery routes more popular with patients, such as oral or inhaled administration. DRYING IN PHARMACEUTICAL APPLICATIONS Spray drying is a wellestablished process widely used in pharmaceutical applications for encapsulation or to make amorphous solid dispersions. Dryers use the combination of an atomised feed solution and a heated gas to generate a dry powder, which is collected using cyclone, filter or electrostatic technology. Traditionally, lyophilisation has been used for drying in pharmaceutical applications as there is a perceived risk of exposing thermally labile APIs and biotherapeutics to the elevated temperatures of the >>>

FORMULATION

spray drying process. Yet in reality many of these molecules can be successfully spray dried without any loss of potency, which is down to the mechanism of drying encountered during the spray drying process. During spray drying the feed solution is atomised into the drying chamber through a nozzle. In pharmaceutical applications this is most commonly a twofluid nozzle, which atomises the feed into droplets using compressed air. The design of these nozzles means that the cooler atomisation air protects the liquid from the high temperature of the drying gas, right up to the point of atomisation. Once atomised the droplets dry rapidly, and evaporative cooling from the drying process keeps the temperature of the droplets low. Â Heat exposure of the product being dried is therefore minimal. With the right formulation and process development, this evaporative-cooling and rapid drying means that even the most delicate biomolecules can be spray dried with little or no loss of activity.

STABILISATION TECHNIQUES In common with other drying processes, it is usually necessary to include excipients to provide complete protection of the molecule and stability throughout the process. There are three critical points during the manufacture and storage where the biotherapeutic can be vulnerable; on solution atomisation, during the drying process, and on storage post drying. There are a wide variety of excipients that have been utilised to develop spray dried powders with excellent assay and long-term stability. Surfactants, such as polysorbates or pluronics, offer protection at the liquid-air interface during the atomisation stage, preventing protein aggregation or denaturation. Stabilisation during the drying process is achieved by the use of excipients that can form hydrogen-bonds with the biotherapeutic. Sugars such as trehalose, raffinose, or dextran are commonly used as matrix formers. Due to their high glass

transition temperatures they can offer excellent long-term storage stability. Combinations of amino acids such as histidine, glycine, proline and arginine, or divalent metal ions such as zinc, can be added to maintain the protein structure, reduce protein aggregation and minimise chemical degradation thus improving stabilisation. Once a stable, dry powder version of a biotherapeutic has been formulated, the powder can follow traditional pharmaceutical development routes, with granulation, tabletting and capsule filling common place. Spray drying has the added advantage of often producing powders that are perfectly suited for inhaled drug delivery, with excellent aerosolisation properties. Further excipients can be included in the feed solution formulation to comprise part of the spray dried powder, or blended with the powder after spray drying according to the onward application.

SUMMARY Biotherapeutics are an important part of modern medicine, delivering treatments to serious illnesses including cancer, rheumatoid arthritis and heart disease. However, development can be challenging. There is a need to store bulk drug solutions frozen due to poor stability of solutions at ambient temperatures. Liquid dosage forms are also less favoured by consumers, therefore drying of the delicate biotherapeutics is necessary. The fast, semi-continuous and scalable qualities of spray drying offer clear advantages over the slower lyophilisation process. Inclusion of excipients into liquid feed solutions can protect even the most delicate of molecules from the spray drying process, opening the technique to complex biologics. Once dried, the product can then follow traditional formulation development pathways, with manufacture of conventional oral or inhaled products with superior stability. Rapid throughput by spray drying can accelerate formulation development timelines, enabling faster access of medicines to patients.

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FORMULATION

Harder, faster, Peter Nelson, technical operations director at Catalent Micron Technologies examines why micronisation may be the answer to poor water solubility in drugs.

REFERENCES 1 Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications. International Journal of Pharmaceutics, 2011, 420 (1): 1-10 2 Catalent Webinar, Particle Size Reduction, 2018. [Last accessed 22/01/2019] 3 Effect of surfactants on the solubility and intrinsic dissolution rate of sparfloxacin. Mbah, CJ and Ozuo, CO. 3, Mar 2011, Pharmazie, Vol. 66, pp. 192-4.

ver the past few years everyday items such as computer chips and mobile phone batteries have been shrinking. Size reduction technology is also commonplace in drug development, where reducing the particle size of a promising active pharmaceutical ingredient (API) can help to overcome a hurdle facing 70% of drugs in the pipeline: poor water solubility.

we apply the basic theory of micronisation, one may logically assume that a smaller particle size will produce an accelerated dissolution rate. However, micronisation is a multifaceted process. While it may directly alter particle size, it could also have secondary effects on other characteristics that influence API performance.

Traditional oral dosage drugs are delivered into the circulatory system through absorption in the gastrointestinal tract (GIT). However, a challenge arises if drugs cannot permeate through the GIT into the bloodstream. Another potential issue is when slow rates of dissolution result in drugs not fully dissolving before completing their transit time in the small intestine, missing the ‘window of absorption’. Particle size reduction counters this by relying on the simple mathematic principle that reducing an object’s size will increase its relative surface area. This can consequently improve the particle’s rate of dissolution, ensuring that sufficient quantities of the active ingredient reach the bloodstream.

PARTICLE SIZE MATTERS It’s critical to understand exactly how micronisation can impact a drug’s performance. One important characteristic affected by micronisation is agglomeration between particles. The increased surface and amorphous area created by micronisation can cause a sticky situation for drug developers. Agglomeration is where particles stick either to each other or to a surface, adversely affecting powder flowability, making the micronised drug difficult to handle. It can also reduce the effective surface area of the micronised particles, cancelling the benefits provided by size reduction.

Micronisation is particularly effective at improving the efficacy of drugs that are dissolution rate limited. This is an extremely versatile and straightforward process for improving the solubility of drug candidates. Micronisation typically uses fluid energy jet mills to break down an API to produce micron-sized particles. But how small do we want our micronised particles to be? If

Smaller particle size may also negatively impact a drug’s performance through influencing wettability. Micronisation can often lead to particles having a high energy state, making particles hydrophobic and reduces the wettability of a drug; an important precursor to dissolution. Changes in particle agglomeration and wettability are two examples highlighting how it is possible to overmicronise a material. This can increase the risk of delays, or even

failure, when commercialising a promising drug compound. Drug developers can mitigate these issues by determining the optimum micronised particle size of a compound as early in the pipeline as possible. If possible, all drug powders should undergo rigorous characterisation to determine the optimal particle size and their respective characteristics. While the amount of API material a drug developer has available could limit this, up to 10 trials can be performed with as little as 100g of an API. HOW TO DEDUCE THE BEST PARTICLE SIZE It is crucial to quantify the physical characteristics of an API to enable drug developers to identify the optimal particle size for optimal performance. A perhaps obvious but important tool used to achieve this is particle size analysis. A widely used technique to accomplish this is laser diffraction, which is often preferred for its repeatability, rapid measurements and high sample throughput. However, laser diffraction cannot deduce all physical traits that can impact a drug’s performance, such as agglomeration. Microscopy is a simple technique that can accurately deduce the physical appearance of a chosen sample. It also creates limited disruption of agglomerates during sample preparation analysis. Surface area analysis is another useful analytical tool, and like microscopy, the sample preparation is not disruptive to agglomerates.

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stronger... smaller?

Although the impact of micronisation on the amorphous content and crystallinity of a sample is often negligible, it may be a concern for drug developers. As changes in these characteristics may negatively affect a drugâ&#x20AC;&#x2122;s performance, it is important to allay these fears. Crystallinity and amorphous content can be quantified through powder X-ray diffraction if the sample has a high amorphous content or through vapour sorption if the amorphous content is predicted to be below 5%. The short-term stability of an API must also be considered when selecting an optimal particle size. All of the characteristics detailed above may not be static properties. Quantifying these variables at intervals of days, weeks, and even months, ensures that the optimal particle size remains stable in the short term.

Techniques such as comicronisation with a surfactant like sodium lauryl sulphate (SLS) can also improve the solubility and intrinsic dissolution rate of an API, since SLS is a surface active agent. Another tool used to improve these characteristics is cryogenic micronisation, where the drug is stored overnight at room temperature before being processed at -50Â°C. Smaller is not always better when micronising a drug. However, the optimal particle size can be determined through micronising an API to varying degrees, and subsequent rigorous physical characterisation and formulation development. By undertaking this during early phase and scale-up, a working particle size specification can be established early on for subsequent R&D and early phase batches.

Micronisation is particularly effective at improving the efficacy of drugs that are dissolution rate limited.

FORMULATION

AN EGG-CELLENT APPROACH Phil Morton, chief technical officer, Albumedix discusses the effects that albumin can infer on APIs in formulations, and the proposed mechanism behind them.

evelopment of safe and stable formulations is a challenge of pharmaceutical drug development, and the choice of excipients can become an important factor for their successful formulation. For hardto-formulate active pharmaceutical ingredients (APIs) this becomes more critical and can be the determinate of whether such a drug candidate gets discontinued in development or becomes a successful pharmaceutical. Albumin has been shown to offer benefits over other excipients in the formulation of various APIs, and can help overcome certain formulation challenges. FORMULATING DRUGS WITH ALBUMIN Human albumin is the most ubiquitous protein in blood and is present at amounts around 40 g/L. Its role in blood is the shuttling of numerous smaller entities such as metals, hormones, fatty acids and toxins. However, it also makes up about 75% of the colloidal oncotic (or colloidal osmotic) pressure of blood and the single free cysteine of albumin (at position 34) makes up the majority of the reducing equivalents present in blood. All these properties are traits which are functional in employing albumin in formulation. Albumin has historically been used in a range of different formulations.

Originally, plasma sourced human serum albumin was employed, but there has been a shift in the industry towards the use of chemically defined (recombinant) human serum albumin. Recombinant products are advantageous due to factors such as: the absence of animal- derived products, certainty of supply, high purity, absence of host-derived proteases, high homogeneity, high free thiol content, absence of known or unknown human pathogens, batch-to-batch consistency and the presence of an established regulatory pathway.

instead of the API during oxidative stress. The thiol of cysteine 34 is positioned in a crevice in the albumin protein, which shields it from the solvent and specifically from larger molecules. This confers a relative low reactivity and properties as a scavenger of predominantly highly reactive oxidation species, such as radicals, rather than as a general oxygen scavenger. Cysteine 34 of albumin therefore does not readily become oxidised and can be handled with no specific precautions during formulation process steps.

Albumin in formulation has been reported to prevent: • Surface adsorption • Aggregation • Fibrillation • Oxidation And to improve: • Solubility • Lyophilised cake formation • Dissolving properties of API from lyophilised powder.

2. Surface covering ability

The mechanistic properties of albumin can be categorised into four benefits: 1.Oxidation protection capability This stems from the free thiol moiety of cysteine 34 – an unpaired cysteine residue – which is present in its reduced form and can become oxidised

Albumin has a predisposition to cover both hydrophilic and hydrophobic surfaces. Historically, albumin has been used to cover the surfaces of medical devices to increase their biocompatibility. Studies have shown spontaneously formed albumin coverage to be in the order of a single albumin molecule in height, with only 1-2 mg albumin needed to cover 1 m2 of surface. This property is utilised for low dose/high potency drugs, where the dose could otherwise be difficult to control due to its surface adsorption during production, handling and storage. Another effect of albumin covering the surfaces is that it can hamper surface-induced unfolding and aggregation events of the API. >>>

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FORMULATION

3. Direct interaction ability Albuminâ&#x20AC;&#x2122;s promiscuous binding properties have resulted in the reporting of numerous APIs binding either in a simple 1:1 ratio, or other more complex ratios. This ability can convey multiple effects on the formulation. For instance albumin can, by direct binding, improve solubility of otherwise difficult to solubilise molecules or prevent otherwise detrimental interactions of molecules that could have given rise to unfolding and aggregation. There are also indications of albumin having the ability to bind to the exposed hydrophobic end of growing fibrils, thereby curtailing their propagation. 4. Indirect interaction ability Albuminâ&#x20AC;&#x2122;s positive second viral coefficient means that it will try to avoid interacting with itself in solution, effectively instigating oncotic pressure in blood. The effect also makes for another potential stabilising property of albumin. As the albumin is spaced out evenly in the solution, it hampers the general movement and flexibility of other entities in the solution. The decreased flexibility of the entities in the formulation can translate into increased stability of these entities. The effect on this for formulation is not easily conceived or illustrated, but small-angle X-ray scattering (SAXS) has shown co-formulated proteins to have lower flexibility when formulated with albumin, without there being any direct interaction.

ADVANCING TOMORROWâ&#x20AC;&#x2122;S FORMULATIONS Despite the clear advantages, the use of recombinant proteins as excipients has only seen significant growth relatively recently. Pressure from regulatory bodies and the better understanding of the high-performance capabilities of recombinant human albumin are likely to push these products into the pharmaceutical mainstream. By continuously expanding our knowledge of albumin formulation mechanisms, important but hardto-formulate APIs will progress more quickly through the pharmaceutical pipeline.

By continuously expanding our knowledge of albumin formulation mechanisms, important but hardto-formulate APIs will progress more quickly through the pharmaceutical pipeline.

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INTERVIEW

Breaking up With manufacturers now stockpiling medicines and potential border delays between the EU and UK looking likely, the uncertainty surrounding Brexit is causing a lot of consternation. To gain a global perspective, Reece Armstrong caught up with Dr Paul Peter Tak, a venture partner at Flagship Pioneering and the former senior vice president of R&D, development leader and chief immunology officer at GSK.

ailing from the Netherlands, Dr Tak’s involvement in life sciences is well regarded. A professor of medicine, Dr Tak is also on the board of directors at two biotech companies based in the UK, and his work at Flagship Pioneering helps create new biotech companies in Cambridge, Massachusetts (US).

the uncertainty of the UK leaving the EU, and perhaps even in that very disruptive way, should not be underestimated,” he says.

When discussing the UK’s situation with the EU, Dr Tak sees Brexit as something which presents a lot of dangers to the country’s healthcare system.

“There’s a reason that pharmaceutical companies like to be in the UK and that’s the very strong science. But science is dependent on people,” Dr Tak says. “In the long-term, Brexit has a potential impact on biotech and big pharma because they are dependent on the collaborations with the best academics; they recruit the people from academia, they work together with academia, they get ideas from academia and collaborate on clinical trials. If you do clinical trials, you need to be able to first get the medicines and a very hard ‘no deal’ Brexit may lead to disruption to the access of medicines from Europe to the UK and vice versa.”

“The whole confusion around Brexit I see as a big risk for healthcare in the UK, for the NHS, for academic research and a risk for biotech and pharma,” Dr Tak says. One of the most obvious consequences of Brexit is an increase in the already substantial vacancies within the NHS. Dr Tak sees Brexit’s psychological impact of having the potential to cause EU citizens to not feel welcome in the UK. “The UK needs skilled people and the only way to get skilled people is to be able to offer long term stability to talented people, their careers and their families. But also, they need to feel at home right, and they need to feel part of the community, not like an outsider. I think the psychological impact surrounding

The impact of Brexit on people is something which Dr Tak feels particularly strongly about, especially when it comes to the academic workforce.

Dr Tak’s worries don’t stop there though. Academic research in the UK risks having large gaps in funding schemes due to Brexit, not to mention the loss of networking opportunities with EU peers. “Science is all about networking, working together and if that would be disrupted it’d have a big impact,

not only related to money, you can’t compensate everything by giving money to academics, they need to be part of these networks,” Dr Tak says. Not that money isn’t an important factor for research. The EU’s Horizon 2020 programme for instance has provided the UK with €5.1 billion in funding since 2014, amounting to 14% of the programme’s €70 billion budget. Thankfully, the strength of the UK’s pharma and biomedical industries means that the government shouldn’t be too willing to leave any gaps in funding, Dr Tak hopes. “I would think that the UK government will be quite keen to compensate as much as possible because the whole pharma and biomedical infrastructure is so important for the UK economy,” Dr Tak says. “But you don’t know what happens on the long term. What would happen if the UK, after a hard no deal Brexit, would go into a recession? The UK government has always been invested and supportive of science and pharmaceutical research but things may become more difficult if the economy goes down.” Perhaps most importantly though is that the UK would lose its important voice in helping shape the EU research agenda.

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Brexit “You need to have a seat at the table where the decisions are made. What are we going to spend the billions of research on in Europe? I think it’ll be important to be involved in the networks in the future and to have a seat at the table and be influential,” Dr Tak says. For this to happen, the UK would have to become an associate country, similar to what Norway has done, Dr Tak states, though this still wouldn’t be as ideal as being part of the EU. As an ‘Associate Country’, the UK could still participate in Framework Programmes much like EU Member States. Crucially though, the UK would have a limited ability to

influence any decisions related to European research funding. We speak further on the issues that Brexit has already brought up; the closure of the EMA and the subsequent loss of 900 jobs, and how multi-country clinical trials will be made more difficult for UKbased pharma companies, due to increased administration and costs. Increasingly though it becomes clear that much like the debate surrounding Brexit, Dr Tak simply isn’t sure what is going to happen. And while his experience offers an informed perspective, he isn’t so sure that the UK public have been made aware of any of the potential implications of Brexit on life sciences.

"I look at it as a global citizen, a Dutch passport holder, a UK resident and tax payer, working in the UK and US. I think it’s sad for such a fantastic country that a big decision could be made that is not completely and optimally informed. I would think there is a responsibility for politicians and also people in these different sectors to try to be objective about it and to lay out what the implications are of different scenarios. There could be benefits, there are also clearly disadvantages and risks and that needs to be explained to the people to make an informed decision. I think that is what real democracy is about,” Dr Tak states. Despite all of the negative connotations surrounding Brexit, Dr Tak isn’t willing to discount the UK as an exciting place for science. “I don’t exclude the possibility that the UK will continue to be attractive. It completely depends on what Brexit is going to look like, what the consequent disruption will be and what the UK government will do to make it attractive to do biomedical and pharmaceutical research in the UK.”

There’s a reason that pharmaceutical companies like to be in the UK and that’s the very strong science.

DIGITAL HEALTH

CLINICAL CANDIDATES Carla Balch, CEO of TransMed Systems discusses the recruitment problems in clinical trials and what technology can do to help.

ven with a large number of clinical trials available to cancer patients today, there remain many trials that have no patients, and many patients who are not enrolled in trials. According to ClinicalTrials.gov there are more than 292,000 active research studies open for patients; with 33,000 of these being studies for cancer. However, the reality is that more than eight out of 10 clinical trials don’t finish on time; half of trials don’t meet recruitment goals, potentially leading to failed trials; less than 1% of the US population participate in clinical trials, many patients aren’t aware that participating in clinicals trials is an option at the time of diagnosis, and that trials for cancer and Alzheimer’s disease have trouble finding patients for their studies. Clinical research is the most fundamental component of efforts to advance the treatment of disease – including cancer – through better, more accurate diagnoses and drugs. But faced with critically low enrolment, researchers are experiencing a crisis in research and discovery. If you can’t find the patients, you can’t run a trial. It’s that simple. Researchers depend on data from hundreds of thousands of patients to make clinical breakthroughs. They need to find those patients

who are in hospital beds or being seen in clinics – and who are not enrolled in trials – right now.

and consider clinical research participation as part of their care plan.

WHAT STANDS BETWEEN SITES AND PATIENTS For those who seek to participate in trials as clinical research sites, the difficulties are also abundant. Screening for eligible trial patients can be a tedious and error-prone process for sites, akin to searching “many haystacks for many needles.” The most time-consuming element is matching patients to the clinical trial’s eligibility requirements, often a manual process that takes a significant amount of work and time. And more complex eligibility criteria make it even more difficult to find patients who qualify and want to participate. The search process calls for an automated method to sift through the thousands of patients who may not be right for the trial, so researchers can concentrate on the ones that are.

A WAY FORWARD To overcome all of these challenges, we have to improve conversations between patients and healthcare providers. To find the right patients, we also need to change the level of awareness, education and access in terms of how healthcare professionals discuss clinical trials with patients. A survey of 2,000 physicians and nurses by the Tufts Center for the Study of Drug Development found that nearly all physicians (91%) and the majority of nurses (72%) feel somewhat or very comfortable discussing the opportunity to participate in a clinical trial with patients. And yet physicians refer fewer than 0.2% of their patients into clinical trials, while nurses refer even fewer. This is where sponsors, contract research organisations (CROs) and investigative site personnel have a major opportunity to engage healthcare providers as partners in the clinical research process.

Patients have mixed perceptions of clinical trials; they are concerned with time and travel commitments and enduring long enrolment periods when they are already dealing with difficult diagnoses and faced with uncertain outcomes. It can be scary. Addressing such concerns with education and better information at the point of care can help patients understand

Patient recruiting also can be improved through the use of technology and automation to identify and match eligible patients. Automation and technology can help clinical site personnel discover a wealth of information about the uniqueness of a patient population in terms of geographic location, as

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well as an individual patient’s age and gender, their type and stage of disease, treatment history and other medical conditions that affect that patient’s ability to participate in a clinical trial. The right technology, insights and expertise can help harness the power of knowledge to dramatically improve this process for everyone, from sponsors to patients. It is essential that the recruitment process be a collaborative partnership between healthcare providers, sponsors, CROs and patient advocacy groups – all working from a central clinical trial enablement platform to bring promising and lasting solutions to cancer and other critical illnesses, all striving to improve the standard of care for patients everywhere. Their shared mission must be to ensure that every patient has access to the best treatment option, which is often a clinical trial. Achieving consistent and sustainable long-term success in clinical research depends on effective use of real-world evidence. Through collaboration – and the proper technology – research teams can more quickly and easily identify which trials are right for their patients, ensuring no patient is overlooked for a clinical trial, and empowering the medical community to progress today toward treatment that will save lives tomorrow.

Automation and technology can help clinical site personnel discover a wealth of information about the uniqueness of a patient population in terms of geographic location.

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DIGITAL HEALTH

The future of clinical trials? Reece Armstrong looks at why a new wearable could be a game-changer for clinical trials.

new wearable could mark the future for clinical trials through the better use of real-world evidence to support the approval of new therapies. Healthtech company Shimmer’s wearable sensor Verisense includes a wrist-based Inertial Measurement Unit (IMU) that can capture biometric data, such as activity and sleep. In addition, seven sensors can be placed on different parts of a participant’s body to study complex musculoskeletal or neurological conditions. The platform is designed to place the minimum burden on participants. A base station provided with the platform is placed in a location the user visits every day and is used to capture data. More so, a six-month battery life ensures users aren’t constantly charging the wearable, which can even be worn in the shower or bath. Clinical trial sponsors are given access to raw participant data, which can then be transferred to an electronic data capture system to ensure data integrity. In addition, algorithms provide validated metrics and a monitoring dashboard shows the status of all clinical sites. The launch comes shortly after the FDA announced a new framework to support the use of real-world data in approving drugs and biologics. In recent years, digital health products such as wearables have

largely focused on consumer needs, blending health tools and alerts into user-friendly smartwatches. Now with major tech companies such as Apple developing more healthtech services, it makes sense that a company like Shimmer would aim to transform the clinical world. More so, the rise in wearable technology means that there is now a potential to garner patient data that is produced outside of the clinical space and which can measure a patient’s quality of life far more accurately. And while wearable technology has massively progressed in recent years, offering features including fall detection and electrocardiograms, Shimmer states that current devices can’t offer the specific requirements of a clinical trial. “An effective clinical trial solution has to meet very specific requirements, such as providing access to raw participant data and purpose-built management tools, while placing the minimum burden on sponsors, sites and participants,” Geoff Gill, president of Shimmer Americas said. “This can’t be done by simply repurposing consumer wearable devices or other current devices. We started by systematically understanding the needs of sponsors, sites, and participants, then designed Verisense from the ground up to meet those needs. The initial feedback from customers has been overwhelmingly

positive. Starting in March, customers are planning to use Verisense in trials for Alzheimer’s disease, Parkinson’s disease, cancer-related fatigue, and stroke.” The use of Verisense in clinical trials will be particularly important for chronic conditions like diabetes, which require access to real-world participant data. “There is a growing demand from pharmaceutical companies, regulators and payers to factor real-world data (RWD) into healthcare decision making. They want to ensure that new therapies, especially those for chronic conditions, deliver objective improvements to participants’ health and quality of life,’ Gill added.

DIGITAL HEALTH

A RARE FIND Dr Peter Fish, head of clinical partnerships at Mendelian discusses why artificial intelligence (AI) could be the key to diagnosing rare diseases.

ncreasingly, technology seems to be at the heart of daily life, from hailing cabs and fitness trackers to online marketplaces. As with many other industries in the last few years, digital innovation is increasingly reshaping access to healthcare and how clinicians operate, with GPs available for consultations over video chat and digitalisation named as a major priority in the NHS’ longterm plan. Yet as advanced technology continues to help the majority of people lead healthier lives, it’s important to consider how it can be used to diagnose and treat more complex cases like rare diseases. Many think rare diseases only affect a small number of people and that you are unlikely to ever meet someone with a rare disease, much less be afflicted yourself. In a sense, that’s true, with some rare diseases, like Progeria, so unique in number that they may only affect a handful of people per country. However, it is estimated that rare diseases affect 350 to 400 million people globally and around 1 in 17 people will have a rare disease at some point in their lives, meaning that as a group, rare diseases are actually far from rare and have wide-reaching repercussions. Currently in the UK, it takes on average 5.6 years to even be diagnosed with a rare condition, many of which may be chronic,

life-changing or fatal. During these years, patients undergo a distressing diagnostic odyssey of sorts, on average visiting eight physicians, including four specialists. Patients endure many tests, from imagery or blood tests to more invasive practices, and often receive misdiagnoses - sometimes multiple times before finding an answer to their condition. While frightful and frustrating for individuals, it’s not only patients who feel the consequences of such inconclusive hospital visits, but also clinicians, healthcare systems worldwide and ultimately, taxpayers. Last year, a Mendeliancommissioned report looked at the cost and resource impact in the last 10 years and found that, while undiagnosed, rare disease patients have cost the NHS significantly more than £3.4 billion, as existing diagnostic pathways for rare diseases are inefficient and large amounts are spent on inconclusive tests. However, with the advancement of digital innovations in the healthtech space, AI could be the answer to this growing issue. While technology is being used to discover new drugs, increase genomic testing and improve quality of life, it can also be used to filter and flag possible rare diseases to physicians much earlier in the diagnostic journey, benefitting patients, providing

information, and reducing unnecessary costs along the way. DIAGNOSES THROUGH AI Artificial intelligence solutions can conduct an audit of lengthy research in a fraction of the time of doctors, scanning the latest discourse and updating local knowledge on a daily basis. For example, technology can source information from a multitude of different resources globally to give clinicians and patients a clearer picture of symptoms and possible causes in relation to rare diseases. Generally, clinicians use pattern matching with regards to patient data (height, weight, medical history, etc.) to form a diagnosis, but can only measure hundreds, or at most thousands, on their own. Using Mendelian, clinicians can computationally, and in seconds, use tens of thousands of data patterns to generate a ranked list of diseases that can be focused on to find a diagnosis. In many cases, clinicians may never have heard of or seen cases of these diseases before and may not naturally have considered them in the patient in question. IMPLICATIONS FOR WIDESPREAD USE It’s good news that there is progress in the right direction currently, AI solutions are being trialled by the NHS to help GPs identify patients with rare or hard to diagnose conditions. Already,

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a grant from Innovate UK allowed for the implementation of Mendelianâ&#x20AC;&#x2122;s specialised screening system in select clinics, providing augmented intelligence with data analysis to flag those that match potentially unique conditions. Once the technology has analysed a patientâ&#x20AC;&#x2122;s symptoms, they are then flagged to the GP who has various options, including referring the patient to a specialist or recommending further analysis and testing. Flagging patients with certain criteria or symptom patterns may also aid drug trials down the line, as only 5% of rare diseases currently have a drug treatment or cure. As clinical trials require a minimum number of patients, at times there often arenâ&#x20AC;&#x2122;t enough diagnosed patients for trials to be initiated. Instead, such studies must collect a sample size by reversing the process: searching for symptoms rather than already diagnosed patients, a process which can be expedited through such AI identification solutions. As with anything, the first step to solving a problem is to name the issue. With the help of AI solutions that expedite diagnoses, around 400 million people across the world may begin to fight back against their rare condition faster than ever before, providing research, awareness, and efficient drug therapy for rare disease patients to come.

Flagging patients with certain criteria or symptom patterns may also aid drug trials down the line, as only 5% of rare diseases currently have a drug treatment or cure.

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FMD ROUND-TABLE

Getting on track With the EU’s Falsified Medicines Directive (FMD) now in effect, pharmaceutical manufacturers must comply with strict regulations designed to ensure counterfeit medicines don’t enter any stage of the supply chain.

PM spoke to a number of pharmaceutical manufacturers to get their thoughts on what FMD means for the sector. Q: WHAT’S THE NEXT STEPS FOR MANUFACTURERS? Daniel Tedham, managing director at The Wasdell Group “The next major step for manufacturers to start exploring is full aggregation capabilities. While it increases the complexity of your supply chain there are numerous benefits to aggregation and implementation will allow companies to fully realise the benefits of serialisation and full track and trace abilities. Ultimately aggregation allows for faster passage of products through the supply chain.”

Jean-Marie Aulnette, vice president of EMEA sales at TraceLink “Eventually, the industry will move to a state where serialisation is ‘business as usual’ and companies will start searching for supply chain efficiencies and opportunities to deliver better services by improving communications with partners and patients. CMOs and

serialisation vendors specifically will have to deliver additional value and use serialisation to create competitive services, otherwise their customers will look elsewhere.” Q: WHAT ABOUT BREXIT? Staffan Widengren, director corporate projects at Recipharm “When the United Kingdom (UK) leaves the European Union (EU) on Friday 29 March, it could be that the UK market does not require serialised products, whereas the EU will uphold the regulations. This means that when drug products are transferred from the UK to the EU market, they will still need to comply with FMD requirements. >>>

FMD ROUND-TABLE

Ultimately, the operational approach of pharmaceutical firms will depend on whether the UK remains part of the current European Medicines Verification Organization (EMVO) or European Medicines Verification Systems (EMVS), like many of the European Election Studies (EES) countries, or if they decide to adopt a new and separate system.” Dexter Tjoa, director corporate strategy at Tjoapack “The FMD deadline also fell just before the UK’s exit date from the EU, which has created an additional level of complexity for the pharmaceutical industry. The UK will legally have to comply with the EU FMD requirements until 29th March 2019, however, there remains some uncertainty around what the impact will be on the UK once it leaves the EU. The Medicines and Healthcare products Regulatory Agency (MHRA), has outlined its commitment to remaining aligned

with the EU regulations. To honour this commitment, access to the European Medicines Verification Systems (EMVS) will have to be negotiated to ensure a seamless working relationship between the UK and the EU.”

This can lead to improved processes for inventory management, product recall management, secure distribution and product authentication. It could even be utilised in preparation for the advent of smart factories.”

Q: IS THIS A STEPPING POINT FOR NEW TECHNOLOGIES?

Jean-Marie Aulnette, vice president of EMEA sales at TraceLink

Alberto Negri - sales and marketing director - SEAVision “As compliance becomes widespread and the industry feels the full force of the new regulations, the technologies and systems that companies have implemented for serialisation will start to bring additional benefits that have the potential to reshape the industry. Once new systems are in place and fully operational, the regulatory pressure is off and there is an opportunity to review processes and begin exploring some of the added value that can be realised from the data collected from new systems.

“To date, the collective pharma industry has been very focused on the costs associated with serialisation and is yet to see its potential. Ultimately, having all the additional data being created by serialisation in data lakes will enable a number of opportunities, for example the digital transformation of recalls to derive crucial business intelligence. Better supply chain visibility and providing more information to patients are just the first steps – within the next two-three years we’ll see truly revolutionary technology such as artificial intelligence being used to deliver predictive analytics for supply and demand forecasting.”

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PROCESS EQUIPMENT

Tip your cap Andrew Turner, regional sales manager, Hanningfield Asia-Pacific, looks back at the success of capsule transfer systems, and why they’re a must have for any manufacturer.

t is 1999. The Euro has come into use, ‘The Matrix’ is in cinemas, Bluetooth technology is launched, and the world is paranoid over the potential implications of the Millennium Bug. At the rear entrance to a large pharmaceutical plant in Ireland, a young sales engineer stands by his wooden crate, checking it over for damage in transit. His rugged good looks and chiselled jaw hide his apprehension over the day ahead. The site, the product, and to some extent the application is all new to him, and he is very aware that he and his machine will be under scrutiny for the remainder of the day. The pressure is on to perform. Slowly he opens the crate, removes the chocks, and carefully wheels the mobile frame out into the morning sunshine, then recloses the wooden flap. “Here we go”. The stainless steel glints as he pushes it up the ramp and into Goods Inward. Out of breath he takes a minute to look the machine over. With the many unknowns facing him that day, there was one thing he could rely on without concern, and that was that he knew this piece of equipment would not let him down. He had done this many times before, all over the UK

and Ireland, and knew that once plugged in and plumbed up, it would quite simply do the job. It was reliable, efficient, easy to set up and dismantle, and could be readily adjusted to suit specific site requirements. He took a deep breath, allowed himself a wry smile, and looked forward to seeing the faces of his audience as they watched it at work later that day. Ok, so the author of this article will never make a novelist, and the truth has been stretched in parts. There were no rugged good looks or chiselled jaw – and still aren’t, and there probably wasn’t much sunshine either. However, the rest is true. The machine in question was a capsule transfer system for the automated transfer of hard-shell capsules. Put simply, it will move any size of hard-shell capsules from point A to B in a gentle manner, eliminating the risk of the capsule halves separating or the shells being damaged in transit, as could potentially be the case with manual handling, vacuum transfer, or mechanical conveying methods. Many manufacturers at the time had been using bucket elevators to load capsule filling machines. Not only were the capsules being damaged in transit, but this loading

method required a sorter, and a change in capsule size required a change in sorter tooling. A less aggressive and less clumsy means of conveying needed to be developed, without losing throughput capability, and ideally without requiring a sorter. First drawn up in 1992/93, the basis of using air to convey capsules was a new concept at the time. Despite this, the capsule vacuum transfer system has remained virtually unchanged since – after all, if it works, why change it? The design was always intended to be ergonomically friendly, with the principle of operation kept as simple and efficient as possible; a large hopper holds a store of capsules which fall into a transition piece, introducing them into the flow of air immediately below the hopper. It then conveys the capsules by blowing them along the convey tubing towards their destination, in a gentle and controlled airflow. Variations on the basic design also exist for ex-rated areas or for the conveying of filled capsules. This is all mounted to a discrete mobile stainless steel frame, along with a single-phase blower and push-button control panel. The simplicity of the system, and the quality of build / finish ensure reliability, performance,

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repeatability and longevity – rare attributes in today’s fast-paced disposable world. High throughput rates and the ability to integrate level sensors and low-level alarms (audible, visible etc.) make it a supremely versatile unit, and ideally suited for the automated loading of high-capacity modern capsule filling equipment, as used in the pharmaceutical, nutraceutical and food industries. With a level sensor to maintain a constant feed, operator intervention is potentially only required to periodically top up the hopper with empty capsules. Clean-down is a dream – ask the young sales engineer from 1999 – the whole assembly comes apart by means of quick-release tri-clamp couplings and can be readily washed and reassembled in a short space of time. The young sales engineer reclosed the over-centre clamps on the crate, a satisfying feeling at the end of a rewarding day. His capsule transfer system had not let him down and had transferred the capsules quickly and without damage to the filling machine buffer hopper. Job done, another end-user impressed by the simplicity and efficiency of the machine. Whether your capsule transfer requirement is for a new installation or to streamline an existing process, this versatile system should be at the top of your must-have list. The combination of ease of use / clean-down, simple controls, operator-friendly design, compact size, adaptability to suit particular applications, quality of build, and reliability in operation all make it a true success story.

Clean-down is a dream – ask the young sales engineer from 1999 – the whole assembly comes apart by means of quickrelease tri-clamp couplings and can be readily washed and reassembled in a short space of time.

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PROCESS EQUIPMENT

COMPOUNDING THE PROBLEM David O’Connell, director of Scientific Affairs at PCI Pharma Services looks at the ways in which pharmaceutical manufacturers can overcome challenges in potent compound granulation.

harmaceutical granulation is a common technique for solid oral drug production, whether as tablets, capsules or granules for use in bottles or sachets. Multiple granulation methodologies can be used to address the requirements of a wide range of Active Pharmaceutical Ingredients (API), irrespective of potency. Granulation combines individual formulation components (API, diluents, binders, disintegrants) into a single uniform particle. The various techniques include wet granulation; dry granulation; fluid bed granulation; and hot melt granulation. Granulation is of benefit when overcoming challenges such as active content uniformity; densification of formulation; powder flow properties; compression properties; controlled API release profiles; and API bioavailability. Best practice granulation is performed using aqueousbased solutions, combined with appropriate investment in high quality, specialist granulation equipment including high shear mixers, one pot processors, roller compactors and fluid bed processors.

Additional capability of high shear granulation and fluid bed processing allows production of high potent products (with an OEL down to 0.01 µg/m3). Containment performance is proven using Standardised Measurement of Equipment Particulate Airborne Concentration (SMEPAC) testing. The granulation suites should include totally contained engineering systems with no open powder handling. These suites might include both small-scale (eg 1-5 kg) and large-scale (eg 20 – 120 kg) equipment. Traditional physical assessment of the granule from the operator is not required as end-point of granulation is determined reliably from data obtained. Data is converted into userfriendly batch reports: Figure 1 graphically indicates the power and torque of the impeller blades which, with relevant operator

training, can determine the endpoint of a granulation process prior to over massing of the product. The figure also demonstrates the granulation fluid addition rate. The granulation bowls are geometrically similar with similar design of impeller blades, meaning products developed at smallscale can be easily and efficiently scaled up to large-scale. It is vitally important to use precise mathematical scale-up modelling to ensure successful larger batches. Modelling includes the scale-up of the speed of the impeller blade, the granulation fluid addition, mixing times and bowl volumes. The impeller blade speed can be altered by choosing the most appropriate model to obtain a similar physical granule (tip speed, Froude number or constant shear stress). >>>

PROCESS EQUIPMENT

Similar models can be performed for fluid bed granulation assessing the required air flows and spray rate calculations. This can be used to deliver a low API concentration within the formulation via the granulation fluid. Other elements of fluid bed granulation include low porosity density (particles remain more spherical) and end product bulk density that is similar to the starting material. This process is also utilised for pellet and tablet film or modified release coating. One pot processing is another granulation technique where product drying is performed using a jacketed bowl. The bowlâ&#x20AC;&#x2122;s insulated water jacket is used to raise the temperature, evaporating the aqueous media and drawing moist air away using a vacuum system with a condenser. During the drying phase, the impeller blade is rotated incrementally, moving the colder material to closer proximity of the heated jacket wall. It is important that the one pot processor also includes a heated bowl lid to aid drying, an in-bowl camera and a sample chute which prevents heat loss when taking samples or visualising the product. When considering options for contained manufacturing FIGURE 1: Example of wet granulation report from high potent HSM

Scale-up models can provide a faster path to large-scale manufacturing with the similar physical and chemical properties as the developed granules. outsourcing, it is important to seek a partner who can offer a wide range of one pot processors; from small laboratory to large-scale equipment. Scale-up models can provide a faster path to large-scale manufacturing with the similar physical and chemical properties as the developed granules. Both the high shear granulators and one pot processors can be used to perform hot melt granulations. This type of granulation introduces a waxy bioavailability enhancing excipient to poorly soluble APIs, assisting in the dispersion of the granules into a fine particulate suspension aiding absorption within the patient. Roller compaction compresses powder blends between two rollers under pressure with the resulting compressed material being sized by a dry mill. Roller

compaction is used to overcome formulation problems such as moisture or heat sensitivity. The resulting granule is densified with a larger particle size and better powder flow in relation to the starting material. The best quality granulation technology allows fully contained roller compaction for the processing of highly potent APIs, with the ability to perform small development batches at 10g/hour and the capability to scale-up to 100 kg/hour. This provides a distinct advantage in executing scale-up activities from development through clinical trial manufacture and subsequent commercial production. In line with other state-of-the-art equipment, such systems perform feedback loops for optimal control of ribbon thickness produced from the rollers. In summary, the development and manufacture of highly potent drug substances bring a number of challenges, but not insurmountable obstacles. Even if the decision to outsource is clear, the choice of partner is crucially important. The granulation methods available have to offer clients maximum flexibility and the service providerâ&#x20AC;&#x2122;s record of compliance with global regulatory and safety standards, as well as experience and capacity for working with highly potent products, are good indicators that the service provider will be able to expeditiously bring the molecule to market and maintain supply of the product over time.

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COLD CHAIN SOLUTIONS & LOGISTICS

Chill Pill

As temperature control packaging companies develop solutions that answer tighter regulations governing wide-stability products, Clive Bryant, global product and marketing director for Softbox Systems, looks at the challenges they must face.

t seems almost inconceivable in a sector so often lauded for its innovation and progress, that pharmaceutical companies could be left wanting for a low-cost, rudimentary parcel shipper that protects temperature-sensitive products below 30°C. But here we stand. It would be jumping the gun to apportion blame and put packaging companies in the firing line. Their focus has typically been on developing solutions to answer increasing regulatory pressure that is being applied elsewhere in the cold chain sector. What is abundantly evident is that we are in the throes of a temperature compliance era that has accelerated in tandem with regulatory demand and industry growth. Next up: widestability guidelines. USP general chapter and ICH quality guidelines cover Good Distribution Practices for the storage and transportation of pharmaceuticals products. The guidelines involve a number of temperature ranges such as 2-8°C, 15-25°C, 20-25°C and 2-30°C. Where a storage temperature is stated on a product label, it would need to be shipped under controlled and monitored conditions. COMPLIANCE GOES FURTHER — AND WIDER Although there are different interpretations of what constitutes

CRT, Good Manufacturing Practice compliance refers to it as the customary working environment temperature of 20°C to 25°C. Excursions between 15°C and 30°C that are experienced in pharmacies, hospitals, warehouses and during shipping are also acceptable. The aim, however, according to a US Pharmacopeia CRT Range Expansion stimuli article, is to “standardise the definition of CRT to remove uncertainty and promote long-term value to industry.” This includes a revision of the guidelines that take into account and permit ranges supported by stability data, for example ‘store below 30°C.’ Regulators are now seeking assurances from manufacturers not only on the quality, safety and efficacy of products throughout their shelf lives, but also during the shipping process to the end customer. Is this an issue for pharmaceutical companies? Not exactly. Together with their packaging allies, they have a habit of stepping up to the mark. But it certainly presents a challenge, particularly when trying to find cost-effective packaging solutions. Falling into the widestability category are lower cost products such as over-thecounter medicines and routinely dispensed prescription products. Pharmaceutical companies, along with pharmacies, dispensing

doctors and clinical trials companies can be left scratching their heads as to what level of thermal protection they should use when shipping label-claim products. INVISIBLE, UNTIL NOW So how has all this slipped under the radar? The reasons abound. But we have to acknowledge that it’s easy to get lost in the noise of a saturated space. The rapid rise of the emerging markets, the geographical diversity of growth, an ageing population, the ascent of biologics, and an era of transparency and security have all been contributing factors in pushing the compliance machine into overdrive. It was perhaps only a matter of time before legislation was tightened in the wide-stability category. Without being subject to the more stringent regulations that have befallen other temperature-sensitive pharmaceuticals, historically it may have been deemed safe to ship such medications naked or in simple cardboard shipping boxes, perhaps in a vague expectation that they will reach their destinations in good condition and within their storage label claim. The hour for guarantees, however, is perhaps upon us. RELIABLE, AFFORDABLE AND RECYCLABLE, PLEASE The capability and materials are there to produce a workable

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solution and this has now been seasoned with intent. But in truth, it’s only half the battle. When you look at the volumes involved, it’s not hard to understand why the world’s leading pharmaceutical companies are all asking the same question: “How much do I have to pay for a basic, simple-to-use, widestability shipper?” As the packaging innovators rally to offer a low-cost compliance remedy, they must be mindful; the real agenda comes with a further twist. ENTER THE ENVIRONMENT. The pharmaceutical sector has taken a leadership position in the sustainability movement with commitments to eliminating waste, re-use and recycling. While leading temperature control packaging (TCP) companies are mirroring this, there is some ambivalence where the term “recycling” is concerned. Expanded polystyrene foams, for example, can only be ground and reprocessed into new polystyrene products, effectively recycling them. Alternatively, polyurethane products such as insulation panels can be repurposed or upcycled into building materials — but programmes are not always readily available, leading to challenges in disposal. These can be further complicated by regulations that increasingly require imported packaging to be re-exported to avoid local disposal or recycling. Performance TCP systems that employ vacuum insulation panels and phase change materials offer a greener alternative, when linked to full re-use programmes which help to achieve sustainable costeffectiveness. But as welfare wins over waste, there’s an increasing need for 100% kerbside recycling. This allows materials to be picked up in containers acceptable to, or prescribed by, local municipalities.

A NEXT-GENERATION SOLUTION IS OUT THERE In the quest for a panacea that satisfies all the criteria, there are some encouraging early signs. Thermaflute-type insulation could have a pivotal role to play. This cardboard material is used to create effective insulation layers, replacing traditional methods. It is a game changer. And it would allow consignors of temperature-sensitive pharmaceuticals to comfortably meet regulatory compliance without impacting on the environment. What’s more, expectant pharmaceutical partners will be anticipating features inherent in traditional shippers that save on costs, like ease of assembly and a flat-packed design that maximises storage space.

Naturally, whatever TCP systems materialise from this undertaking, they will have to be qualified to recognised industry standards and rigorously tested to uphold the wide-stability temperature range for pre-defined shipping durations. The lower cost, totally recyclable, rudimentary shipper that performs with complete reliability for widestability products is poised to see the light of day, no doubt in different configurations. Start your engines, ladies and gentlemen. The race is on.

We have to acknowledge that it’s easy to get lost in the noise of a saturated space.

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COLD CHAIN SOLUTIONS & LOGISTICS

COMING IN FROM THE COLD

Sanjay Vyas, corporate vice president & Global SBU head of Clinical Trial Supplies & Logistics, PAREXEL International discusses the challenges in transporting certain medicines and how advancements in technology are making things easier.

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growing number of drugs have a stringent stability profile and, with that, a certain bestpractice temperature range that must be adhered to. Temperature monitoring of medication has become increasingly important; regulation changes have imposed an increase in what must be monitored, and an increase in complex, fragile, highly valuable medication has added to the difficulty of this task. For any Investigation Medical Product (IMP) to be stored and administered safely, clinical trial sponsors must control the temperature conditions of the IMP throughout the supply chain and this means maintaining full visibility throughout the transportation process. TRADITIONAL APPROACH Transporting any IMP means exposing it to several different

environments. From shipping to storing at the trial site, one thing that must remain within the stability profile is temperature. While minor alterations in temperature are to be expected, any drastic single change or cumulative out-of-range exposure must immediately be flagged to a sponsor. Historically, this was done via a USB temperature logger packed with the shipment at the distribution depot, the status of which is checked when the shipment arrives and is checked-in by the receiving clinical trial site. A simple LED indicates whether the logger has recorded a temperature excursion or not, and full details of the temperature history of the journey from depot to site can be retrieved from a PDF download from the logger, and then manually entered against the shipment in the IRT (Interactive Response Technology) or RTSM (Randomisation and Trial

Supply Management) system. This which would then use the temperature information to decide whether the shipment is in good condition or needs to be quarantined while the temperature deviation is investigated. However, there are some downsides to this approach. Firstly, loggers are only used to track temperature during transport from depot to site, so once removed from the shipment and processed, monitoring then relies on temperature logging devices used at the site. This means there could be gaps in the temperature history and it makes complete cumulative temperature history difficult to obtain. Another issue is that any temperature deviation is not known until the logger is unpacked at the site. If thereâ&#x20AC;&#x2122;s only a short time between the IMP shipment arriving at the site and the next

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APRIL 12 - 14, 2019

COLD CHAIN SOLUTIONS & LOGISTICS

patient visits requiring those medication kits, there’s a risk of being unable to dispense to the patient because there’s insufficient time to order and receive a replacement shipment. This is a particular risk for treatments that are both temperature and time sensitive (short shelf-life) such as gene and cell therapies. The USB logger approach also creates a burden for site staff. It means that they need to manually transfer data from the logger into the IRT or RTSM, which also has the potential to introduce delays and errors. DIGITAL TRANSFORMATION The industry is now investing in new ways to monitor temperature more effectively using new and transformative technologies. Smart packaging is increasingly being used by pharmaceutical companies and many logistics groups offer temperaturecontrolled shippers, to ensure that the medication won’t have experienced an excursion whilst in shipment. Furthermore, Bluetooth-enabled temperature monitoring solutions provide sites with wireless solutions to check the temperature status of an individual pack. Then there’s RTSM and IRT mobile applications, which can scan for loggers in the vicinity and then notify sponsors and site-staff of any packs which need to be quarantined, thus saving time. Not only does this improve the shipment arrivals process, but it also provides a solution with no “gaps” in monitoring. Another available solution that saves site-staff time is near realtime temperature trackers which can be placed into a shipment and monitor IMPs from packaging at depots through transit to clinical trial sites. This innovation in clinical supply chain management allows a

It has therefore become vital that sponsors choose technology that not only reduces the burden on sites but provides more complete data on the temperature conditions that IMP has been exposed to.

quick response to any temperature complications, which can reduce safety risks for patients as well as manufacturing and shipment costs for clients. It has therefore become vital that sponsors choose technology that not only reduces the burden on sites but provides more complete data on the temperature conditions that IMP has been exposed to. Using technology that communicates with the RTSM system via Bluetooth enables users to be mobile in their tasks, reducing the time they need to spend on temperature checking, and increasing the time they have available for patients. BARRIERS TO ADOPTION Given the benefits described above, why isn’t this technology already being applied widely today? There are several challenges that can arise in deploying these internet -based technologies including: • Lack of mobile network or Wi-Fi coverage means some sites have trouble with apps and devices that rely on internet connectivity. • Import / export regulations make it either impossible or difficult to import the transmitting loggers or to be able to get them returned from the sites.

• Getting sites to return the loggers. Newer transmitting loggers are often more expensive and are reusable but there have been difficulties in getting sites to return the loggers, which adds costs to the supply chain. • Introducing new ways of working at the site. While the mobile apps have clear benefits for reducing burden on sites and improving data accuracy and safety, they are a significant change in working for the site, and require provisioning of devices to the site staff unless a Bring-Your-Own-Device (BYOD) policy is employed, which has its own concerns with data privacy and security. While there are some barriers to adoption, these are likely to deplete over time as more mobile and internet-enabled technologies are deployed at clinical trial sites, and the volume of temperature-sensitive IMP managed by sites increases. Ultimately, these developments must be employed to reduce the burden of medication management tasks on site staff and improve visibility of the supply chain to help ensure continuity of uncompromised IMP supply to patients in clinical trials.

REGULATION

Erick Gaussens, ProductLife Group’s chief scientific officer, reports on a recent pharmaceutical roundtable which examined why streamlining data management between regulatory and manufacturing needs is a pressing concern for manufacturers.

THE MASTERPLAN M

aintaining separate information systems to manage product data no longer serves life sciences firms. Compliance, cost-efficiency and improved agility depend on building closer links between enterprise resource planning (ERP) and regulatory information management (RIM), and reducing the number of separate instances of the same information being captured, stored and updated. On the panel were: > Steve Gens, managing partner, Gens & Associates > Kelly Hnat, principal, K2 Consulting > Jesper Kihl, VP for global regulatory affairs, LEO Pharma > Jan Vindberg-Larsen, senior director and head of global regulatory affairs, Lundbeck > Erick Gaussens, chief scientific officer, ProductLife Group (PLG) > Catherine Gambert, senior consultant for regulatory affairs and regulatory information, PLG > Loetitia Jabri, regulatory and pharmaceutical platforms associate director, PLG. Noting that product and regulatory information has an ever greater role to play in the efficiency and strategic direction of life sciences businesses, the debate panel considered how companies could make more of this. In Gens & Associates’ latest market research into companies’ regulatory information management (RIM) activities, the improvement of data

management and connections to other functional areas is now a major priority. Yet, many firms are held back by the scale of change to processes and systems involved, Steve Gens noted. But they have little choice now. As things stand, just 14% of companies have connected RIM and enterprise resource planning (ERP) systems. Most information gathering and verification still happens manually, creating a huge data management burden and scope for business risk. If information about a change control process doesn’t flow between regulatory and manufacturing, for instance, it can cause hold-ups in international markets. As PLG’s Catherine Gambert warned, “When a product gets stuck at the border because the information printed on the box isn’t the same as that in the regulatory documents, it becomes a serious issue.” In the medical device sector, data quality and consistency will prove increasingly critical too, as regulators impose stricter regulations around device traceability, and as the digital health movement gathers momentum, PLG’s Loetitia Jabri noted. One of the growing issues for all life sciences organisations is the speed and frequency with which data can change and need to be updated across all departments and systems. “The objective is to make sure we all use the same source of data,” Jesper Kihl of LEO Pharma said. “We recognise the potential benefit of having more

integration.” Over the last year, LEO Pharma has updated its labelling practices, for instance, so that there is more end-to-end visibility and a seamless data flow. It is now looking at applying the same treatment to other parts of the business. At Lundbeck, the regulatory affairs organisation has developed an effective infrastructure for collaborating more readily with production, allowing the two parties to share information more effectively. An SAP system is used for assessing all changes to products, including business cases; these are evaluated by commercial, regulatory and production teams before implementation. The ability to work from the same data is also prompting broader collaboration. “We’ve also established a product committee for our marketed products,” Jan Vindberg-Larsen said. “The committee governs any major cross-functional activities and ensures alignment between regulatory affairs, production, and commercial operations on goals and priorities.” It helps that modern software systems are now being built to be more open, in support of easier data exchange and process traceability. In Gens’ 2018 survey, two-thirds of respondents said their companies expected to start to automate the regulatory-clinical connection over the next two years, while just over half said they would start to connect and automate regulatory supply release and product change control processes.

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REDUCE, REVIEW, REPURPOSE An increasingly popular approach to streamlining data management is ‘master data management’. Here, the emphasis is on creating and maintaining a single, reliable record of the product truth, which can be repurposed in multiple different ways by different teams, as needed. When a company treats data as a corporate asset and maintains it in the form of definitive master data, the whole organisation stands to benefit, the panel agreed. Jesper Kihl, explained how his team at LEO Pharma has used the broad demands of IDMP to highlight the fuller potential for greater efficiencies and closer connection between functions. Down the line, a more joined-up approach to product data promises to make everyone’s life easier, makes processes slicker, and drives out cost and risk, while supporting greater market agility.

One of the growing issues for all life sciences organisations is the speed and frequency with which data can change and need to be updated across all departments and systems.

COLD CHAIN SOLUTIONS & LOGISTICS

Pressure point Tony Rhodes, sales manager at Telstar's Technology Centre for Barrier Isolation System discusses what operating pressure manufacturers should choose during the aseptic processing of potent materials in isolators.

his is a question that is posed regularly and divides opinion on which approach is the correct one. Individually there is no question what route should be taken and most would agree that an isolator designed purely to provide a grade A environment for an aseptic filling or manufacturing process must be designed as a positive pressure system, to maximise the protection of the product ‘within’ from external contaminants. From a containment stand point an isolator solely designed to protect the operator from hazardous API’s must be designed as a negative pressure system. Increasingly however we are being faced with a combination of both scenarios, for example an aseptic filling process of high potent product and therefore we have a dilemma; do we opt for negative pressure to protect the operator first and run the risk of introducing particulate into a grade A environment or do we opt for a positive pressure system and run the risk of exposing the operator to potentially harmful particles. Isolator Enclosures;- “Enclosures that are sealed to some standard of leak tightness, that contain within them a qualified controlled environment, at variance with the surrounding conditions.” By definition an Isolator enclosure leaks; how much it leaks is dependent upon a number of

factors, not least the nature of the design, workmanship and build quality. So whether an Isolator manufacturer would choose to provide a negative or positive pressure isolator in ‘our combined aseptic / potent scenario’ may well depend on their current designs as well as their past experience. For many isolator manufacturers the standard approach is to provide a positive pressure isolator to protect the product but at the same time great emphasis should be placed on the design and build of the inherently weak points to ensure the operator is protected in equal measure, both during normal operation and in case of any unlikely breach condition. In this context it is assumed all isolator enclosures would be designed and tested to a level of leak tightness to international standards ISO 14644-7 / ISO 10648-2 to either class 2 or class 3, dependent upon their size and geometry. In which case it is important that the weak points are designed correctly to ensure the leakage rate is maintained at all times, therefore many hours of research and development needs to expended on all these points to create reliable designs that produce positive results time and time again. Coupled with the mechanical design should be intelligent control systems to regularly monitor conditions ensuring the system and its components are maintained

to the highest standards. And should the unthinkable happen and there were a breach, for example a glove tear or seal burst, the control system would enter into an alarm condition, whereby the isolator operating system would revert to negative pressure and immediately induce inflow through the breach. The response time from initial alarm to full negative breach condition, limits the potential exposure to the operator to an absolute minimal time period; typically 5 to 10 seconds is common dependent upon the size of the isolator enclosure, which could be considered an extremely low risk especially when extrapolated over an eight hour long term or even a 15 minute short term exposure period. Of course this is all theory and only extensive testing in controlled environments would either prove or disprove whether there really is a risk to the operator given this scenario. As already mentioned what approach a manufacturer adopts is based on their own experience, which is also true of Telstar’s approach to provide a positive pressure isolator for an aseptic / potent application based on its long history of providing aseptic and containment Isolators and based on its programme of R&D, but to back up this stance the company embarked on inhouse trials to start testing this theory out.

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In 2017/18 the company launched a programme of testing using a third party environmental monitoring company to monitor operator exposure whilst dispensing a placebo material in a single chamber 3 glove Isolator. The chosen isolator design was taken from its standard Pura range which is capable of being run in both positive and negative modes and was tested at different operating pressures. The isolator was first tested to class 3 leak tightness ISO 10648-2 as opposed to class 2, to obtain a worst case scenario and be more reflective of a larger filling line test level.

CONCLUSION

TEST RESULTS (SUMMARY) OPERATOR EXPOSURE MODE

Highest exposure (Âľg/m3)

Mean Exposure (Âľg/m3)

Negative Pressure

0.229 (run 1)

0.070

Positive Pressure

0.148 (run 3)

0.061

All the results given above are tasked based and are not time weighted averages. Excessive spillage was noted in some runs particularly on run 1 of the negative mode, however in real situations the same situation could occur, therefore it was felt that although the test was simplistic it provided a snapshot of what could arise in practice.

Coupled with the mechanical design should be intelligent control systems to regularly monitor conditions ensuring the system and its components are maintained to the highest standards.

In this case the negative pressure mode returned the highest reading, however the mean exposure was very close, but slightly better in the case of the positive pressure mode. Given some runs had excessive spillage (mainly on run 1 negative) as stated above that may account for why the positive mode performed better in this trial, however it is acknowledged that the opposite effect could also occur. Of course this is only the start of this process and more test data is needed, but already it can be concluded from these results that a welldesigned, well-sealed enclosure will perform equally well from an operator protection perspective whether operating in a positive or negative regime.

FROM THE FACTORY

SMOOTH SAILING In the first article of our new ‘From the Factory’ series, Ajit Kanetkar, head of process technology & training at ACG explains why adopting new technologies is not always a swift transition.

he pharma manufacturing industry has witnessed considerable change over recent decades, such as new drug delivery systems, automation, new regulatory changes and more. And looking at the transformation one would believe that the industry has enthusiastically welcomed all changes with seamless transition. The reality is different. Apprehension in relation to costs, uncertainty when it comes to adoption or regulatory considerations often means that the actual transition to new technologies is not so swift. Typically the majority of pharma companies adopt a ‘wait and see’ attitude and follow those who take a lead in acquiring new technologies. Pharma manufacturers need to consider many factors when updating processes or technologies.

Regulatory changes The introduction of regulations that require assurance on areas such as: validation, reproducibility and the availability of PAT tools ought to nudge a company into looking for a technology upgrade. Market factors • The business potential for products made with a particular technology may lure some companies to acquire necessary technologies. • The creation of capacity for a technology: a company might have an existing basket of products that might be categorised into one delivery system such as modified release pellets. A new technology cannot be commercially viable if only acquired for one to two products. The company must manufacture at least three to five similar products, or

have a firm plan to develop & launch more products in this category. They would then be more open to absorbing new technology and the creation of fresh capacity. • Introducing new manufacturing processes and technologies means companies can produce products using complex processes or high-end technology, which can ward off some competition. Companies may also be propelled to opt for a technology to keep pace with competition making comparable products and who have moved to such technologies. Commercial and operational factors • It may be necessary to have a technology upgrade to improve efficiencies and consistency in output. This can contribute to better assurance levels, reduction in rejection and rework and more assurance in product quality. • Some companies are willing to take the investment risk when it comes to adopting new technologies. This

is provided they get an assurance from the supplier, or a technology partner with expertise to provide support from feasibility studies through scale-up, stability, validation with process optimisation, to commercial manufacturing of the products. • The proximity of the technology supplier can often be paramount. The presence of a manufacturing base with service support from a known supplier in the region opens customers up to considering exploring a new technology. Most new developments over recent decades have related to the hardware used to improve operational efficiencies or a new delivery system with a focus on scalability, ease of validation and data acquisition, storage, retrieval, recipe management and security. However new factors are driving another change that is being adopted with speed by the pharma industry unlike adoption of technologies for core processing and packaging. This is not surprising as they are being driven to maximise the use of resources and do not require changes in existing processes.

The Reality of Continuous Pharmaceutical Manufacturing 26â&#x20AC;&#x201C;28 March 2019, near Newcastle, UK

GEA, Siemens and Perceptive Engineering will host an inaugural three-day conference to examine the fact and fiction of continuous manufacturing (CM) in the pharmaceutical industry, addressing user experiences and the current status of continuous pharmaceutical processing. Confirmed speakers include representatives from AstraZeneca, Bayer, CMAC, GSK, Janssen, Merck, RCPE, UCB Pharma, University of Sheffield. For more information and to register for the event gea.com/events

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