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Contents

November/December 2016 | Volume 16 Issue 8

Regulars

Features

EDITOR’S DESK

2016’S DIGITAL HIGHLIGHTS

We find out what you’ve been reading online in 2016

ANALYSIS

BIO HAZARD

BREXIT – A BITTER PILL?

A look at safety in single use manufacturing

18 ON THE COVER

Natoli talks multi-tip punches

42 PHARMA AT THE MOVIES Reece Armstrong looks back at The Facility

41 PHARMAPACK 2017 Heading to Paris in January? We’ve got all the facts and stats you need

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Address changes should be emailed to subscriptions@rapidnews.com. European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals. Volume 16 Issue 8 © November/December 2016 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

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editor’s desk INNOVATION TRUMPS POLITICS As 2016 draws to a close, many of us will start thinking about changes we can make in the year ahead. A lot of people are saying that 2016 wasn’t really a great year. Music lovers mourned the losses of David Bowie and Prince amongst others. Similarly, here in the UK there was a sense of grief amongst those who voted to remain in the EU. And, even more recently, that same odd sensation was felt in the US after the election of Donald Trump. It’s a weird realisation that, as 2016 comes to a close, the world seems like a very different place. But we certainly can’t assume that all this change is bad (though I for one will seriously miss David Bowie, and I’m still not over it yet). Take for instance the changes being made by HCPs in response to the war on AMR. Public Health England statistics now show that for the first time in England, the trend towards increased antibiotic use has reversed. In fact, the latest figures show that figure reducing from 40.7 million to 38.5 million. It’s a huge, and very positive change, but the responsibility doesn’t just reside with HCPs. My partner, who works for our local council, sent me a text while she was at work the other day, saying ‘we’ve just been sent a circular advising us not to request antibiotics for winter colds. Does that sound right to you?’

Yes! It sounds very right to me! It sounds fantastic! If we’re to get on top of AMR, we need patients to play their part. But the problem is that she and all her colleagues had been given no real explanation as to why they were not to request them. They know, of course, that AMR exists and is a threat, but they still aren’t being given the full details. Where are the public service announcements, TV infomercials etc. etc.? More changes must still be made. But back to HCPs. In this issue we get an update from Isobel Finnie and Catherine Williamson from European intellectual property firm Haseltine Lake, who give us an update on the wrangles between Pfizer and Actavis over the drug pregablin, and its second medical use patent. Isobel and Catherine make the point that, in the case of second medical use patents, one major flaw in the plan is that only about 5% of doctors specify the use of the drug on their prescriptions. Where a prescription is written generically, the pharmacist is free to dispense whichever drug is available. Therefore is further change needed at the HCP end of the supply chain in order to ensure all pharmas get a fair bite of the apple? 2017 is sure to bring about change – some positive, and undoubtedly, some less so. But as I conclude in my ‘digital highlights’ feature on page 24, “innovation will trump politics in the race for better healthcare.” Dave Gray

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ANALYSIS

Patent wars Isobel Finnie, partner at European intellectual property firm Haseltine Lake, alongside associate Catherine Williamson, discuss the growing patent battle between pharmaceutical branded drugs and their cheaper, generic counterparts.

cross European c o u n t r i e s , healthcare costs are a topic of significant debate and in the UK NHS funding is a perpetually thorny issue. At a patient level, we aren’t usually too concerned if our doctor prescribes us a patented pharmaceutical or a generic version of a drug, as long as it works to help us feel better. But it’s a different story for the healthcare and pharmaceutical industries - and we need the patent Isobel Finnie, partner at European system to both reward intellectual property firm Haseltine Lake and incentivise innovation through securing a period of protected market exclusivity, which means we can continue to get new and improved drugs, whilst also encouraging competition to keep costs affordable for health services. The complexity of this balancing act has been highlighted by the issue of “second medical use patents.” This type of patent provides protection for the use of a drug to treat a particular disease (second medical use) where the drug was already known to treat another disease (first medical use). This type of new technology is particularly advantageous since the safety of the drug in subjects is already known and it is therefore

Catherine Williamson

quicker and easier to get regulatory approval for the new use. Re-purposing known drugs gets effective treatments to patients more rapidly than developing completely new drugs, and for a fraction of the cost. A series of recent UK court decisions has provided some interesting discussion and guidance on both the scope of protection afforded by these patents and how they may be enforced in the UK and the rest of Europe.

These cases involved Warner-Lambert (a subsidiary of Pfizer) and Actavis. Warner-Lambert are the owners of two patents relating to the drug pregabalin. The first patent relates to pregabalin per se, whereas the second patent is a second medical use patent relating to the use of pregabalin for treating pain. Warner-Lambert has authorisation to market pregabalin, which they sell under the trade mark Lyrica, for epilepsy, generalised anxiety disorder (GAD) and neuropathic pain. Upon expiry of the first patent, Actavis began preparations to launch a generic version of pregabalin under the trade mark Lecaent. Since the second patent (relating to the use of

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pregabalin for treating pain) was still in force, Actavis opted to launch Lecaent with a “skinny label”, meaning that the patented use to treat pain was not included in the “Summary of Product Characteristics” that must be included with the drug. However, Warner-Lambert were concerned that Actavis’ product Lecaent would still be provided to patients to treat pain, despite the fact that the use of pregabalin to treat pain was protected by their patent and authorisation had not been given to market Lecaent for the treatment of pain. In the UK, approximately 90% or more of prescriptions for pregabalin are written generically (i.e. specifying pregabalin rather than Lyrica or Lecaent). This is encouraged by the prescribing software used by GPs. In addition, only about 5% of GPs specify the use of the drug on their prescriptions. Where a prescription is written generically, the pharmacist would be free to dispense either Lyrica or Lecaent. It would therefore be very difficult to ensure that only Warner-Lambert’s product is given to patients for the treatment of pain. The courts have considered whether Actavis infringe Warner-Lambert’s second medical use patent by marketing their generic drug Lecaent, and the lengths to which Actavis should go to ensure that their product is not dispensed for the patented use. The Court of Appeal has provided guidance on the interpretation of second medical use patents. The patent in question in the present case specifically relates “use of pregabalin or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating pain”. The Court of Appeal indicated that the use of the word “for” in the phrase “for treating pain” requires that the manufacturer knows or can reasonably foresee the ultimate intentional use for pain, and does not require that the manufacturer has that specific intention or desire himself. This guidance was followed by the judge in the High Court decision announced in September last year. The judge considered that there may be intentional administration of Lecaent for pain if a pharmacist dispenses Lecaent and he or she knows that pregabalin has been prescribed for pain. However, the judge took into consideration the steps taken by Actavis to prevent Lecaent from being provided to patients for the treatment of pain and concluded that it was not foreseeable to Actavis that Lecaent would be intentionally administered for the treatment of pain except in a small number of exceptional cases, which the judge considered to be too small to merit consideration. The steps taken by Actavis included notifying pharmacists specifically that Lecaent was not licensed for the treatment of neuropathic pain. Despite this, the judge commented that, “I remain more convinced than ever that the best solution to the problem of protecting the monopoly conferred by a second medical use patent while allowing lawful generic competition for non-patented indications of the substance in question is to separate the patented market for the substance from the non-patented market by ensuring that prescribers write prescriptions for the patented indication by reference to the patentee’s brand name and write prescriptions for non-patented indications by reference to the generic name of the substance.”

patented use will rely on a suitable system being put into place by the relevant government authorities. The judge commented that patentees and generic companies should cooperate with the relevant government authorities as far as possible to assist in putting such a system into place. It is noted that in relation to the present case, software providers assisted in setting up such a system by adding an alert to prompt prescribers to prescribe Lyrica for pain. It is also interesting to note that, prior to the full trial, the judge refused a request for the court to issue an order against Actavis specifying, amongst other things, that each pack of Lecaent should include a removable notification stating that “This product is not authorised for the treatment of pain and must not be dispensed for such purposes”, and that any agreements Where a prescription is between Actavis and a pharmacy to written generically, the supply Lecaent should include the condition that the pharmacy shall use pharmacist would be free reasonable endeavours not to supply to dispense either Lyrica or dispense Lecaent for the treatment or Lecaent of pain. The judge stated that granting the request would create a greater risk of injustice than refusing it, in particular since such order would delay Actavis’ entry into the market and may also deter pharmacists from stocking Lecaent. This decision enabled Lecaent to be marketed for non-patented uses such as epilepsy and GAD without delay and without further disadvantaging the sale of Lyrica for the treatment of pain.

“

”

Since the High Court decision in September 2015, a further decision was issued by the Court of Appeal on 13 October 2016. A final decision on whether Actavis infringe Warner-Lambert’s second medical use patent by marketing their generic drug Lecaent was not made. However, the judges disagreed with the High Court judge’s decision that both Actavis and the prescribing pharmacist must know that Lecaent is being dispensed for the treatment of pain. The Court of Appeal judges commented obiter dictum that the issue to decide was whether Actavis knew or could foresee that at least some of the prescriptions written generically for pregabalin to treat pain would in fact be fulfilled with Lecaent. The Court of Appeal judges further commented that if the test of knowledge was satisfied, it should have been considered whether Actavis had taken all reasonable steps in their power to prevent Lecaent from being used to treat pain. Exactly how a system enabling generic companies to market products for non-patented uses without inadvertently infringing second medical use patents would work remains to be seen. However, it is encouraging that these issues are now being considered as the development of new uses for known drugs is growing. We await further guidance with interest.

This is in-line with an order the judge made prior to the full trial, requiring the National Health Service to publish guidance that pregabalin should be prescribed for the treatment of neuropathic pain by the brand name Lyrica. This guidance should be adhered to by doctors so far as is reasonably possible. However, the effectiveness of guidelines in preventing a generic drug from being dispensed for a

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ANALYSIS

Search and rescue Robert Gaertner, director, Europe strategy at Veeva Systems on the search and rescue mission for data integrity

“

There’s no question that the industry will continue to increase its outsourcing of critical manufacturing functions

”

nspection findings and warning letters related to externalised manufacturing operations continue to be a major risk, according to the most recent statistics. Data integrity has been continuously ranked as one of the major root causes. Leading authorities such as the MHRA and FDA have responded by publishing draft guidance on this topic to help life sciences companies ensure data is consistent and accurate. Data integrity is crucial to ensuring the safety, efficacy, and quality of drugs. And, as outsourcing continues with more critical manufacturing functions performed outside the company − and outside of direct oversight – ensuring data integrity is increasingly difficult. As data integrity issues continue to surface during plant inspections, regulatory authorities are trying to compel manufacturers to clean up data operations. In fact, business and production-control systems that were formerly only given cursory reviews have come under increasing scrutiny. With the absence of credible data, the concern is that these companies’ products cannot be trusted. Quality processes now span internal and external parties; however, many supporting systems were designed to operate only within a company’s walls. In addition, many of these applications do not work well together, often existing in siloes.

Significant manual overhead is necessary to bridge the gap between all parties and among applications to stitch together a continuous process, which then creates many opportunities for data issues. Having the quality team review the data from manufacturing sites is a great first step. However, communication still often occurs via email, or some other uncontrolled method, in a nonvalidated environment. This could lead to an observation or warning letter. Using secure, cloud-based technology that is purpose built for the GxP area will support the end-to-end lifecycle management from drug development to commercial manufacturing, regardless of whether operations are internal or external. Every move is controlled and can be subject to oversight, reducing the risk of data being manipulated or lost amid fragmented processes and disparate systems. The GxP-regulated cloud gives life sciences companies the ability to extend data integrity across all parts of the value chain, while at the same time enabling partners to access information they need. Raw-materials suppliers, contract research organisations (CROs), contract manufacturing organisations (CMOs), brokers,

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and distributors can interact simultaneously under very controlled conditions to ensure that accurate, up-to-date information is always available to those that need it – whenever, wherever, however. Reviewing information from manufacturing sites helps detect data integrity issues; however, problems are typically more difficult to detect and have greater impact near the end of a process. Moving upstream and providing the quality team with direct access to the quality management system allows issues to be detected earlier and accelerates downstream decision-making. The quality team can review process deviations, so problems can be resolved proactively and approvals can be streamlined for improved efficiency. Providing all stakeholders with access to up-to-date, accurate data and content in a single, authoritative system instills greater confidence that operations are being executed compliantly. There’s no question that the industry will continue to increase its outsourcing of critical manufacturing functions. This shift has greatly disrupted how quality is maintained. Manual processes backed by siloed legacy technology do not make it easy to extend visibility or process control outside of the organisation. This can result in a number of large-scale quality issues and attract regulatory scrutiny globally. Establish a cloud technology foundation to transform manufacturing and quality management – and do more than just make incremental steps forward. Industry cloud solutions that manage quality content and processes bring together all stakeholders on one platform – ensuring an auditable trail of all activities with partners.

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BREXIT – A BITTER PILL?

Life after Brexit Paul Ranson, of global law firm Morgan Lewis’ London Life Science’s Practice examines how UK biopharma must now adapt to a changing landscape

t may come as no surprise that a pre-referendum ‘Brexit” poll conducted by the UK Pharmaceutical Directors Club of senior management within the UK pharmaceutical industry resulted in a vast majority in favour of “remain” with local management and head offices concerned about the possibility of the UK exiting the European Union (EU) and negative implications for their businesses.

Planning for regulation post-referendum The EMA and other EU medicinal product organisational and licensing arrangements are restricted to EU and EEA members, so the UK, if outside the EEA, will be excluded. Indeed, the EMA will, in these circumstances, be expected to move its headquarters out of the UK and relocate in one of the remaining EU countries. Nor will rapporteurs from the UK be accepted.

However, as part of the forthcoming negotiations, it would seem sensible for the UK to agree a Mutual Recognition Agreement such agreements already exist between the EU and Switzerland, Canada and Australia. The EMA will certainly regret the loss of the UK competent authority, the Medicines and Healthcare Products Regulatory Agency in so far as it is one of the most respected member

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state competent authorities and the most used rapporteur under the centralised system and reference member state under the mutual recognition and decentralised systems. A particular irony is that the new Clinical Trials Regulation introduces the possibility of a single approval for a pan-EU clinical trial which has been sought after for many years and may now come too late for the UK to benefit.

The Regulation will probably come into force in October 2018. For medical devices, a question arises whether they should retain an authorised representative or manufacturer in the UK? Similarly, should manufacturers continue to use a UK notified body? However, joining the EEA or entering into a mutual recognition agreement under EFTA, could mean that UKoriginating devices would still benefit from access to the EU market. The likelihood of an extended negotiation period means there may be little material change for at least two years and probably substantially longer. However, before any action is considered, it would be appropriate to identify all applied for or granted marketing authorisations, clinical trial approvals or legal representative status, orphan designations and supply chain licences held by UK affiliates as well as any key regulatory functions performed by them including qualified or responsible persons and siting of databases. For medical devices, one would similarly identify those products for which a UK company is either the manufacturer (CE-marking holder) or the authorised representative and where the selected notified body is based in the UK. If the UK goes the EEA route, little will need to change, even after Brexit, as all EU rules will apply within the UK wholesale with UK

companies able to apply for and hold the requisite approvals and licences. An exception is that MA approvals under the centralised route would need to be nationally implemented as they would not apply automatically in the UK. Were the UK to go the Swiss route or WTO, much of UK life sciences law is derived from EU law either through Directives implemented nationally in the UK or through EU Regulations which have direct effect. Accordingly, transitional measures could well be brought in to ensure that both the UK implementing laws and the EU Regulations would remain in force until amended or revoked. However, the MHRA would have to transfer marketing authorisation applications for which they are either rapporteur or the reference member state to other member state regulatory authorities. With goodwill on both sides, an easy solution might be a series of mutual recognition agreements in relation to both medicinal products and medical devices – as UK governance in both sectors is widely respected throughout Europe there is little reason (other than possibly political mischief making) why this would not be achievable. This would be particularly important for the supply chain to ensure importers and manufacturers would be able to release product for EU supply – and vice versa. By way of precedent, Switzerland has an agreement with the EU mutually recognising GMP licences to facilitate this. It also has

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a similar agreement leading to mutual recognition of CE-marking for medical devices. Similarly, UK notified bodies can point to existing mechanisms in place for non-EU countries including mutual recognition agreements involving the US, Canada, Australia, Switzerland and Japan. Whichever way negotiations go, there is an argument for the industry not taking precipitous action as, at worst, any regulatory approvals, licences or functions could be transferred to an affiliate within the EU prior to the effective date of the UK actually leaving the EU. Ian Hudson, Chief Executive of the MHRA, stresses that the Agency is “open for business as usual in terms of its routine regulatory work whilst the Agency works with the UK Government, industry and other EU and international regulators to consider and take forward the results of the UK referendum. This continuity is also recognised and endorsed by its EU partners and EMA leadership.”

Conclusions As an acknowledged ‘jewel in the crown’ of the UK economy, the new Government will be anxious to mitigate the impact on the UK life sciences sector and will be open to ideas as how to exploit UK industry and research base strengths in a post-EU world. The life sciences industry therefore has a real opportunity to gain a greater share of voice through a concerted lobbying camping to achieve its aims.

AL RI RT O VE AD

Material Characterisation with thermal microscopy Linkam’s Duncan Stacey shows options for pharma… In research, development and manufacturing it is vital that the characteristics of the materials used are well understood to ensure the optimum materials are chosen for the application. In particular, it is important to understand how different materials respond to changing temperature and environmental conditions. Linkam Scientific Instruments have been developing and manufacturing a range of temperature controlled stages from high to cryo temperatures for both OEM and end users for over 30 years. These are used in conjunction with light microscopes and a wide range of analytical techniques including Raman, FTIR, WAX/SAX and other X-ray techniques to visualise and characterise the properties of materials. These stages are used to help users characterize materials from polymers to biological tissue, from metals to composites over a range from -196°C to +1500°C. Each of our instruments is designed and manufactured in house by our team of highly experienced electrical, software and mechanical design engineers. The precise and accurate control of temperature of your sample has been enhanced to enable more detailed characterisation of materials. Linkam has worked with many industries to develop solutions for some of the key problems that benefit from thermal characterisation of materials such as plastics and drug development from R&D to manufacturing to QA and storage.

Fig 1a

Fig 1b

refine the parameters directly in an industry standard vial. Unlike other systems, single vials and up to seven vials can be studied simultaneously in the FDVS making it a very cost effective solution. The new LINK software provides an integrated environment and a simple solution to 21CFR11 compliance.

Fig 1a shows an image of a number of sucrose crystals in a DSC pan. Traditional DSC will provide a bulk signal from all crystals in the pan (red). However as TASC is an image analysis technique (green, fig 1b), it is possible to analyse each crystal in the pan making it an ideal technique for investigating sample inhomogeneity. Our thermal stages are widely used to characterise the thermal stability of compounds while our Optical DSC stage provides accurate enthalpy measurement and, when combined with our LINK Imaging system, allows visible changes to the sample to be analysed simultaneously. The recently launched TASC (Thermal Analysis by Surface Characterisation) module extends the imaging capability by providing the ability to analyse changes in the surface structure of materials with changing temperature. The local environment can be controlled within our stages including vacuum, pressure, purge gases and now humidity with the recent launch of our RH95 Humidity Generator. Freeze drying is a widely used technique for pharmaceutical materials to ensure they can be delivered to the point of use easily and in good condition without the use of expensive chilled storage. The development of the freeze drying process can be extremely time consuming and expensive. Our FDCS provides an efficient system for the quick and easy development of parameters required for freeze drying. The recently launched FDVS (Fig 2) allows you to further

One common factor with all Linkam stages is that they are uniquely designed to allow visualisation of the material being tested. This ensures a more complete picture can be obtained as changes to the material such as colour, shape and size can be easily seen. These can be recorded for further analysis. The Imaging Station (Fig 3) has been optimally designed for use with our stages. The Imaging Station is a dedicated imaging platform providing a stable platform for high resolution imaging while its unique ability to tilt the arm allows easy access to the Linkam stage for loading your sample.

Fig 2 Shows the new FDVS for single and multiple vial system for freeze drying

Linkam has thermal stages for measuring the thermomechanical characteristics of materials. Our TST350 is widely used to measure the tensile properties of materials at different temperature, while our CSS450 Shear stage is used to investigate the rheological properties of materials as diverse as blood, ice cream, polymers and cosmetics. Every aspect of modern life involves electronics of one form or another. The boundaries of the current semiconductor materials are constantly being pushed out and the race is on to find the next generation material. Linkam electrical stages are playing a key role in this research. These combine the standard heating and cooling capabilities of all Linkam stages with electrical feedthroughs in order that electrical characteristics of materials such as graphene and other “2D” materials can be correlated with temperature and humidity.

Fig 3 Linkam Imaging Station shown with the DSC/TASC system for pharmaceutical use

IVF has become increasingly important as fertility and birth rates fall in developed countries. Ensuring patients get the right treatment is important both from an emotional and financial perspective. It relies on the accurate equipment to support the correct diagnosis. Linkam have recently launched a range of glass warm stages specifically designed to meet the needs of andrologists and embryologists ensuring samples are kept at the optimum temperature. Linkam Scientific works closely with a number of equipment manufacturers to provide customised solutions to meet industrial needs. These include special optical configurations for ellipsometry to turnkey systems for synchrotrons. We also work with individual users to provide custom solutions so contact Linkam Scientific to discuss your requirements and see how we can help provide a solution.

Linkam Scientific Instruments Limited Address: Waterfield, Epsom, Tadworth, Surrey KT20 5LR, United Kingdom Tel: +44 (0)1737 363476 Email: info@linkam.co.uk www.linkam.co.uk

BREXIT – A BITTER PILL?

Rise to the challenge Farzad Henareh, vice president business development EMEAA, Stericycle ExpertSolutions gives his take on the regulatory and recall challenges of Brexit

n the run up to the EU Referendum in June, one of the key debates focused on the challenges and opportunities afforded by single market regulation. But the die is now cast and we will leave the EU, which is prompting industries across Britain to consider the implications for the regulatory environment in which they operate. The other concern is what this change will mean for any product recalls. The arguments between ‘for’ and ‘against’ were lively, and none more so than the impact of EU regulations on British business. There were claims that EU regulations were costing our economy £600 million a week, and an open letter from small business leaders and entrepreneurs stated: “As entrepreneurs, we deal with the EU’s constant diet of unnecessary regulations which add to our cost base, reduce our bottom line and raise prices for our customers for no return.”1 But leaders of major British business signed their own letter in support of remaining in the EU. This acknowledged the regulatory burden stemming from the EU, but it also stated that the prime minister was working to reduce the burden and that “Business needs unrestricted access to the European market of 500 million people in order to continue to grow, invest and create jobs.”2 But what about the pharmaceutical industry? The economic impact was barely felt by the larger companies, indeed it is hard to affect the big pharmaceutical giants through sudden economic change simply because people continue to need life-saving medication. But in the area of life sciences and biotech Brexit will present challenges, mainly in relation to regulation. It will mean that the UK loses much of the influence it has on EU legislative, policy and regulatory procedures. We have to hope that we will be able to remain part of the European Medicines Agency (EMA), which approves drugs on behalf of all EU member states. Mike Thompson, chief executive of the Association of the British Pharmaceutical Industry said: “If we were to split into a UK process and a European process of drugs regulation, then global companies would make the rational decision to prioritise patients in a market where they are getting access to 500 million rather than 60 million.”3 The other issue is that the prestige of the UK’s Medicines and Healthcare Products

Regulatory Agency, which is a highly proactive part of the EMA, would also diminish. In the face of this uncertainty, leaders in the pharma sector, as in all other industries, will likely be faced with three options. The first is to ratify strict regulations of our own, but this would put British companies at a severe disadvantage and would not suit Brexit supporters who argued for easing the regulatory burden on the UK. Another possibility is to develop more lenient standards in the hope of giving businesses the boost they need to ensure they remain buoyant post-Brexit. But given the importance of the EU to UK exports, lower standards would make it challenging to trade effectively. Finally, we could adopt regulations that are in line with the EU’s established standards, which of the three, seems the most sensible. This does not mean, however, that pharmaceutical companies won’t be at the mercy of a change in processes, so they need to remain wary, particularly in the face of product recalls. In this vacuum of regulatory uncertainty, there is every reason to fear that harmful drugs will enter or remain on the market in a way that they haven’t been able to previously. For pharma businesses, this means there is more likelihood that recalls will need initiating and executing, adding another layer of complexity and straining internal resources. Recall costs could rise, but to what extent depends on the product type, scope, remedy and many other factors. Until the dust settles on the Brexit vote, the uncertainty regarding regulations will continue. In the meantime, pharma companies should take steps to prepare for each scenario, and a useful resource is our new Recall Industry Spotlight for Q2 2016. From a regulatory perspective, this means analysing current customers and reviewing supply chains to determine who might be affected and how. Businesses are braced for a tumultuous environment, but those that prepare for every outcome will be best positioned to withstand the changes.

2 3

http://www.telegraph.co.uk/news/newstopics/eureferendum/12181306/EU-referendum-200small-firm-bosses-and-entrepreneurs-tell-Britons-to-vote-for-Brexit.html http://www.thetimes.co.uk/tto/opinion/letters/article4696807.ece http://www.telegraph.co.uk/business/2016/06/29/big-pharma-might-have-shrugged-offbrexit-but-britains-life-scie/

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OPINION

Get real Martin Goldman, Chief Medical Officer, Iatros Consulting working with Orbital Media, offers a view on a new way of collecting real world data through social media

was recently asked to help a smallish company who got themselves into a bit of a fix. They had a mature medicinal product on the market that had done well over the years, but someone had complained that the promotional claims, which went to the core of the product, could not be justified. The claims were based on a clinical trial which had been done many years before and had satisfied the licensing authority. The complainant said that the trial was out of date, and more recent information from later trials did not confirm the original work. Suddenly, the company was faced with the risk of having to alter its promotion, despite the fact that the product sold like hot cakes. Looking at the sales figures, it was obvious that the product was doing something right, because you probably canâ&#x20AC;&#x2122;t fool all of the

people all of the time. The real experience was that there was customer satisfaction. The answer to the problem was to provide them with real world evidence based on the usersâ&#x20AC;&#x2122; experience of the product, and to take positive evidence to relevant bodies and get their support. Whilst the pharmaceutical industry has had almost 70 years of involvement with controlled clinical trials to support medicinal products, in recent times there have been detractors. Trials are experiments with rigid somewhat enforced rules, typically designed to answer a specific primary question usually related to efficacy and/ or safety. There are typically other secondary issues. What they can never tell you in the drug development phase is what will happen when doctors and the public get their hands on the medicine. Never underestimate the perversity

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of people. They will under and overdose on your product, they will only take it when they feel like it, and they may even crush tablets and wash them down with lashings of gin and tonic. Finally, it is possible that companies may restrict the inclusion and exclusion criteria in controlled trials in such a way that they limit recruitment to those most likely to respond to an investigational medicine. Real world evidence (RWE) is different. It is data based on what actually is happening or has happened in the real world. It is what happens when the brakes are taken off and the Clapham Omnibus of patients is permitted to freewheel with a product, and then tell you what happened. That is a bit of an oversimplification, because one of the better sources of information is the electronic medical records that exist in many places and pragmatic

databases such as the Yellow Card system and the General Practice Research Database. The data can inform you about the demography of the user population, the treatment pathways used and healthcare resources usage of the customer base. However, these can only tell you what is recorded within a healthcare system, and certainly does not tell anything about self-treatment. An intriguing alternative, which is starting to gain recognition, is the use of social media to collect RWE. Thirty eight million people in the UK actively use social media and 50% of the population actively use their mobiles to access their social media. This potentially makes social media an ideal way to find relevant patients and engage them in research. How do you find them? If there are relevant user groups or Facebook groups, it is potentially laid out

for you. Otherwise there are many email and targeting portals to access the patients, and it only needs a relatively small proportion to respond to obtain stunning numbers for research as 80% of social media users will typically engage with competitions and surveys and are therefore potentially willing to be your responders.

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80% of social media users will typically engage with competitions and surveys and are therefore potentially willing to be your responders

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Converting this asset into meaningful data is slightly more difficult and expertise is needed to tailor platforms to collect and analyse data. In addition, like with all experiments, it is advisable to have a clear idea of what you are looking for, which is typically a marketing claim or health economic outcome. With expert input, the endpoints should be identified and the syntactical and semantic interface developed and tested. Social media platforms are also an ideal way of redefining user demographics, but obviously only for those that are using social media. Using data collection platforms it has proven possible to implement a variety of previously validated and some novel patient questionnaires, which not only can collect efficacy and safety information, but also more interestingly from a marketing viewpoint can collect data on economic burden to patients and societal impact.

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OPINION

Integrative medicine what’s it all about? Robin Daly, founder of Yes to Life and contributor to The Cancer Revolution believes that the latest trend in healthcare deserves a better rep

‘Integrative’ is a new buzzword that you’re likely to stumble across quite regularly these days, if you’re in the habit of following health issues in the media. But what does it really mean? Is it really, as some detractors would suggest, just a rebrand of Complementary and Alternative Medicine (CAM) in an attempt to make it more ‘respectable’? Well the answer is a resounding ‘no’. Integrative Medicine (IM) does indeed include CAM but it also includes everything that conventional medicine has to offer. As such, it represents a significant new step, a step that very many practitioners of both conventional and CAM approaches have deep reservations about. Nonetheless, it opens up many new possibilities and, importantly, reflects a new attitude towards medicine itself. Up until now, whether a practitioner was conventional or alternative bore more relationship to religious zealotry than to anything scientific. Furthermore, respect for the personal choices of the patient was a low to zero priority. There has been out-and-out war across the seemingly unbridgeable divide between the two approaches for decades, if not centuries, with both sides maintaining that the other will surely kill you. This is a terrible situation for the most important person in the picture - the person who is ill. He or she is encouraged through threats, fear-mongering, propaganda and all the usual methods employed by zealots of all types, to become a fully signed-up member of one ‘faith’ or the other, even though they may have a far less

partisan view themselves. Friends, relatives and carers are prey to the same forces and line up on one side or the other, applying further pressure to the patient to become a true believer. People questioning whether or not to have chemotherapy, for example, can simultaneously come under intense pressure both from oncologists who are simply looking to implement what they are taught as ‘best practice’, and from alternative practitioners who are ‘certain’ that it could never, ever be part of a solution. This is a tragic state of affairs that continues to this day. Clearly both sides have much to offer as both approaches produce ‘survivors’. At their time of greatest need, people have been sold very short by this simplistic either/or status quo. But now, thankfully, a new model is emerging, one that lines up perfectly with the patient’s most fundamental question regarding any treatment: will it help me? A patient has enough problems navigating through cancer and cancer treatment without finding themselves dropped into a war zone in which winning and being right can be appear to be higher priorities than their wellbeing. What they need are not diehards who will never look beyond their fervent credos, but trustworthy allies who they can depend on for the most objective and impartial advice. So IM is a step beyond the outdated conflict, in which all potentially helpful strategies can be evaluated for suitability in any individual case, and which opens up exciting new possibilities of what can be achieved by combining approaches

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in novel ways. While still in its infancy, some of the best exponents of IM are using conventional approaches such as chemotherapy or radiation in ways that can achieve the same result while minimising or eliminating many of the terrible side effects or collateral damage that are normally part and parcel of treatment. Low-dose chemotherapy for example - as it says on the tin - combines a far lower, and therefore far less toxic dose, with treatments such as hyperthermia to increase its effect, high doses of vitamins and other natural supplements to improve resilience and combat side effects, and natural immune boosters to avoid the terrible immunesuppressing effect of the drugs. This is science - not dogma - and it’s science at its best. IM opens up a world of choice for people. Given the freedom to explore all options, outside of any agenda to conform to the practitioner’s belief system, there is space for their priorities and preferences to be both heard and accommodated. There is only one common agenda in play: the best possible outcome for them, the person who desperately needs help to recover their health. This is a truly trustworthy basis for forming the most productive type of patient-practitioner partnership. I hope this explains why Yes to Life enthusiastically supports IM, and fully respects patient choice. We see IM as the future of cancer care. And although the UK is tragically backward in embracing this desperately needed evolution in medicine, other countries are showing us the way and simultaneously reaping the benefits.

ON THE COVER

Multiple benefits Natoli takes a whistle-stop tour through the benefits and considerations of switching to multi-tip punches for tablet production

ulti-tip punches are a cost effective way to increase tablet output without the need for additional tablet presses, decreasing total press run times and ultimately minimising operating costs. The use of multi-tip punches follows a similar principle as a single tip tool for the rotary tablet press but there are special designs and operating techniques that must be understood for a successful tableting process. Before we jump into the discussion lets first go over the common features that are offered for multi-tip punches. Two common multi-tip tool configurations for B and D tooling are assembled and solid type tools with both having their advantages. When choosing which configuration best fits your needs, some things to consider are tool type (B or D), tablet size, number of tips and particle/ powder characteristics. Assembled punches consist of a punch body, caps and tips which allows the replacement of tips without having to purchase the whole tool body. The solid design offers easier cleaning, minimised assembly times, reduced rust potential and less risk of cross contamination. Rotating heads are a common feature for multi-tip punches, and are preferable on lower punches, as it can increase the life of the tool and press parts. This feature provides a two-part punch configuration where the head rotates independently to the punch body. The advantages of the rotating head include extended tool life as it provides a changing contact surface for enhanced head wear versus a single point contact on rollers and cams. Rotating heads also reduce the torsion stress on the lower punch tips as it contacts the compression rollers. As some tablet presses do not offer lower punch guide keyways, a rotating head may be a critical feature when using multi-tip punches. This is of particular concern when compressing very small tablets known as micro or minitabs where the lower punch tips are fragile.

This article will point out the critical stages of the rotary tablet press process and describe what impact multi-tip punches have at each step and how to overcome the common challenges found in the tablet compression industry. Case studies will also be provided to address the impact multi-tip punches have on compression and ejection forces.

DISCUSSION Die filling stage: Hopper level Product is initially loaded into the hopper of a tablet press and the powder must have adequate flow properties to successfully enter the feeder system. The amount of product in the hopper will determine the head pressure of the powder and this pressure can impact tablet weight. Keeping a constant head pressure can help minimise weight variation issues. When multi-tip punches are installed on the press the rate of product consumed is significantly increased and requires loading the hopper more often.

Feeder speed The feeder delivers the powder from the hopper to the die table. The speed of the feeder is set to maintain a constant charge of powder in the feed system and is affected by turret speed, number of turret stations and tablet weight. With the use of multi-tip punches more product will be drawn from the feeder requiring a higher feeder speed than is used for single tip punches.

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Die fill process The lower punch is pulled down from the fill cam to allow overfill of the die cavity. The excess powder is then pushed out when the punch reaches the dosing cam. The lower punch tip to die clearance must be within tolerance to create a partial vacuum to assist in the die filling process. It is important to monitor punch tip wear and perform regular punch maintenance as this can create a number of issues. A worn out tool, or a low quality tool that is not within specification, can cause weight issues and punch binding as materials buildup on the die wall. Multi-tip punches can exacerbate these issues and require special attention to tool quality. The selection of the proper fill cam is critical for single tip and multi-tip tools. Powder over-blending is a common issue when the fill cam size is excessive and the recycled material re-enters back into the feeder and is potentially over blended from paddle feeders mixing. This over blending phenomenon is potentially minimised when dealing with multitip punches as the powder feeder residence time is significantly reduced. As the number of tips are increased on a punch and the appropriate size fill cam is installed the over blending potential is minimised. Minitab or microtab compression is a common application for multi-tip punches. When tablets are smaller than 4mm in diameter, one should consider reducing the lower tip length. An undercut die is provided with the shortened lower tip length and this may cause catastrophic failure if the incorrect fill cam is installed. Tooling manufactures are very experienced in this modification and working directly with them will ensure proper tool design and tablet press set up.

powder is uniform in fill. Monitoring the compression force per station with a force transducer allows the operator to determine weight variability. This tool allows the operator to optimise the feeder paddle speed by setting the speed to slowest setting but still producing consistent tablet weights. Multi-tip punches add complexity to the compression force measuring system as the force transducer is typically installed in the compression roller pin or strain gages are fitted on the compression assembly. For a single tip tool the force measurement is acting on a single compressed tablet but the force reading for a multi-tip tool is related to all of the compressed tablets on that punch. It is of special importance that the multi-tip punch working lengths are within tolerance since these force systems have no way of determining which tip is causing the issue.

Case study - what impact do multi-tip punches have on the compression force? At the Natoli Institute for Industrial Pharmacy Research & Development located in the Arnold and Marie College of Pharmacy at Long Island University in Brooklyn, New York, a series of experiments were conducted to study the compression force impact from a single tip, two tip and four tip 0.25â&#x20AC;? (6.35mm) round tool. The tools are illustrated in Fig. 1. A direct compression blend consisting of 25% w/w of APAP and 74.5% SMCC 50 with 0.5% magnesium stearate was used for the study.

Pull down cam Immediately following the dosing cam is either a tail over die or pull down cam. Both are designed to keep the powder in the die cavity before the upper punch enters the die. The pull down cam will pull the lower punch down, allowing the column of powder to drop below the top of the die surface. This prevents powder loss from die spillage caused by high turret speeds and resulting centrifugal force. When utilising multi-tip punch as with shortened lower tip lengths and undercut dies it is imperative that the pull down cam doesnâ&#x20AC;&#x2122;t pull the lower tip from the die cavity. This modification should be treated similar to that of the fill cam.

Compression stage: Pre compression Pre compression is a de-aeration stage. This allows the removal of air and initial consolidation of particles to help with the main compression process. Common tablet issues including capping and low tablet strengths can be resolved by adding a small amount of pre compression. A multi-tip application may also benefit from the use of pre compression but with the increased number of tablets produced, the press speed can be reduced. This reduction in speed increases dwell and total compression time, possibly eliminating the need for pre compression.

Figure 1 - 1, 2, & 4 tip tools used in study

A compaction profile study was performed on a bench top rotary tablet press at 25RPM turret speed. Tablets were collected at varying force levels for each tool configuration. Resulting tablets were measured for thickness, weight and breaking force.

Main compression The final compression force on the rotary tablet press is a result of the amount of powder in the die cavity and the distance between the upper and lower punch tips. For concave punch tips it is the deepest measureable point in the punch face that is critical. This is the difference between the punch working length and overall length. The overall length is the distance between the head flat and top of the cup where the working length is the distance between the head flat and bottom of the cup. It is the working length that is critical in providing a constant displacement between punches under the compression roller. Assuming a concentric pressure roller and punches that are within working length tolerance, the resulting compression force will be similar for each turret station if the

Figure 2 - Tablet breaking force vs. compression force

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Serialisation - best practices for global commercial supply in an evolving market

WEBINAR Date: 09/02/2017 Time: 15:00 GMT Price: Free Established and developing serialisation regulations vary from country to country, and PCI offers insights into meeting country specific requirements based on extensive experience supplying commercial serialised medicines to established and emerging global markets. Serialisation requirements are rapidly progressing and evolving in established and developing countries around the world. Having supplied commercial serialisation for a number of years, PCI’s Ian Parsonage, senior director of global serialisation, shares his experiences in developing PCI’s serialisation technology platform along with developing and executing PCI’s strategy for supplying commercial serialised products to domestic and emerging markets across the globe. Drug counterfeiting is on the rise and regulatory deadlines are approaching fast. The pharmaceutical supply chain will soon be at a critical point to ensure patient safety. From drug manufacturers to distributors, all supply chain partners will need to make crucial decisions to upgrade their production lines in compliance with traceability deadlines. PCI offers experience and expertise in serialising commercial drug product and has invested significantly in expanding its overall global capacity to support pharmaceutical and biotech clients looking to supply commercial drug products into Europe, the United States, and global emerging markets including China, Brazil, South Korea, Turkey and others. Established and developing serialisation regulations vary from country to country, and PCI offers insights into meeting country-specific requirements based on its extensive experience in supplying commercial serialised medicines to specific global markets. Join us for this free webinar to: • • •

Understand the complexities of supplying commercial serialised products to domestic and emerging markets across the globe. Understand the requirements for the fast approaching regulatory deadlines in various countries. Understand the key considerations when choosing an outsourcing partner for implementing a successful serialisation strategy.

Speaker: IAN PARSONAGE, Senior Director, Global Serialisation (global engineering), PCI Pharma Services HOSTED BY: EPM Content Team

Register Now www.epmmagazine.com/webinars Can’t make the date? Sign up anyway and we will send you an on demand copy after the event.

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European Pharmaceutical Manufacturer is a highly regarded brand covering the pharmaceutical manufacturing supply chain from conception to production, keeping readers informed of the latest news, opinions, developments and breakthroughs in this innovative and technologically advanced sector.

ON THE COVER Figure 2 depicts the compaction profile for the three tools. It is clear that the compression force increases to achieve the same tablet breaking force when the tips are increased. One might think that since the area of the tool has doubled, it would require twice the force to achieve the same tablet breaking force. This is illustrated in Fig. 3.

The results clearly show a significant increase in ejection force with the increased number of tips but it is not doubled or linear. The properties of the powder play a major role in the ejection forces. When lubrication is excessive the ejection force will not increase with increased compression force since the friction is reduced. This profile finds value in the development arena where lubrication can be optimised. Lower levels of lubricant can reduce capping potential, improve tablet strengths and disintegration/dissolution times.

Figure 3 - Pressure calculation

Figure 4 below is the compaction profile normalised for the tablet geometry and punch tip area. This gives a clearer picture of the resulting tablet strengths at different applied compaction pressures. If in fact the force is doubled when the tool area is doubled then the plots would superimpose. At the same compaction pressure, the 2 tip tool configuration results in a 19% increase in tablet strength, and another 19% increase in strength from 2 tips to a 4 tip configuration. In this case study the applied pressure or compression force would be less than double to achieve the same tablet strength.

Figure 5 - Ejection force vs. compression force

Tablet take off The final step on the rotary tablet press is the tablet take-off or tablet removal from the lower punch face. Common problems associated with tablet take off are sticking and picking issues. There are many techniques available to remediate these issues including steel composition, punch face coatings, and logo designs, but when dealing with multi-tip punches the punch overall length is of particular importance. Most tablet presses are designed so that the lower punch tip is flush with the top of the die table to ensure a smooth tablet removal process. Some presses are designed to protrude the lower tips at 0.5mm or more. If the overall lengths are not consistent within a set of punches the tablet removal process may have issues with the tips damaging the take off bar or even the leading edge of the feeder. If the punch tip is slightly below the die table surface the tablet might fracture at the take off bar. For multi-tip punches it is favorable to provide a flush tip situation versus a slightly protruded tip since the latter can cause tablet damage from the trailing protruded tips contacting the leading tablets that were removed from the take off bar. This case study has provided some exciting and intriguing information about the necessary compression forces for multi-tip tooling. As interesting as this data is, there is still much to learn about multi-tip tooling. To better our understanding, Natoli will be engaging in these multi-tip-related studies in the future.

Figure 4 - Tablet strength vs. compaction pressure

Ejection After the tablet is compressed the ejection cam will push the lower punch upward to eject the tablet. The ejection force is a combination of the residual radial die wall and coefficient of friction between the tablet belly band surface and the die wall surface. Excessive ejection force levels will cause premature wear to the lower punches, cams and may cause visual striations on the tablet’s belly band. Multi-tip punches will increase the belly band surface from the increased number of tablets which will inherently increase ejection force. Common ways to reduce the ejection force is added levels of powdered lubricant to the formulation (i.e. magnesium stearate), tapered dies and lined dies of different materials.

- What impact do multi-tip punches have on scalability –Studying the impact of compression and ejection forces from the R&D to manufacturing press.

Case study continued - what impact do multi-tip punches have on the ejection force?

As a tablet manufacturer, it is imperative to have a full understanding of available options for rotary tablet presses and the impact of each manufacturing. If you are considering multi-tip punches, be sure to work with a reputable tooling manufacturer to discuss all options and determine which solutions will work best for you.

As previously mentioned, as the number of tips are increased on the punch, the number of tablets ejected also increases and an increase in ejection force is expected. If the contact area is doubled, one would assume the force would be doubled as well. The results are depicted in figure 5.

- Multi-tip output comparative study for powders that require slower turret speeds – Multi-tip punches can provide longer dwell/slower turret speed without sacrificing tablet output. An output study will be performed on a single-tip and subsequent multi-tip. - The effects of over blending in the feeder with single-tip versus multi-tip punches – Investigating deteriorating tablet strengths and disintegration results for single-tip and multi-tip format punches due to over blending.

For more information, contact Natoli Engineering Company, Inc.

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REGULATORY AFFAIRS

Safety first Akhila Krishnan, senior director - regulatory affairs, at the ELC Group shines the spotlight on the latest guidance for medical device safety

he regulatory landscape of medical devices is changing in sync with the overall global regulatory requirements, which are in a period of rapid change. The US recently finalised its guidance on “ISO 10993 and Biological Evaluation of Devices”, which includes details of risk-based biocompatibility approaches, chemical assessment and biocompatibility test article preparations for devices utilising nanotechnology. In the EU, draft medical device guidance as well as In-Vitro diagnostic regulations were published in June 2016. These guidance updates are designed to set high standards of quality for medical devices, to meet the common safety concerns that might be associated with the device. The major areas updated in the EU medical device regulations (MDR) are as follows: • Medical devices available in the EU will be subject to the MDR. The MDR will also be applicable to all devices for which the manufacturer does not claim a medical purpose.

“

of Unique Device Identification (UDI) will significantly enhance the effectiveness of post-market safety, improve incident reporting, corrective actions, and monitoring by authorities. The UDI will also help to reduce medical errors, identify counterfeit devices and facilitate stock management. • Authorised Representatives will be held jointly and severally liable for defective medical devices, prompting these organisations to scrutinise non-EU based manufacturers more carefully before accepting their business. Authorised Representatives are also likely to more thoroughly and frequently monitor such clients’ compliance, and seek insurance policies to cover added residual risks.

Assuming late 2016 or early 2017 as the publishing date, the MDR will come into effect in late 2019 or early 2020

• All manufacturers selling in Europe will be required to establish risk management systems (RMS), quality management systems (QMS) and to be assessed by notified bodies. Class I Device Manufacturers who self-certify devices are exempted from being required to have their QMS assessed by a notified body. Once satisfied, the notified body issues a CE certificate to show that the products assessed meet the requirements. No medical device can be placed on the market within Europe without a CE mark.

• As per the draft MDR, certificates issued prior to final implementation of the MDR – tentatively scheduled for late 2019 or early 2020 – will have a maximum validity of five years. However, all CE Mark certifications issued before implementation of the new regulations will automatically expire four years after the new regulations come into force. • All manufacturers involved in the manufacturing of medical devices should have in their possession complete and updated technical files relevant to the medical device. • Major labeling changes with respect to Unique Device Identification (UDI): codes must be included on all medical device labels based on internationally recognised principles, including definitions that are compatible with those used by major trade partners. The traceability

”

• Clinical evidence requirements: for clinical evaluation, manufacturers may rely on a clinical data of a similar device for which equivalence against the proposed device can be demonstrated. Equivalency can be established when they can prove that technical, biological as well as clinical characteristics are equivalent. If no equivalency is established then manufacturers may only use data from clinical investigations. Rules for conducting clinical investigations in effect will be stricter than before.

The list is not exhaustive, and there are many other updates that will be clearer once the final guidance document is published and implemented. Following publication, there will be a three-year transition period. So, assuming late 2016 or early 2017 as the publishing date, the MDR will come into effect in late 2019 or early 2020. Prior to MDR finalisation, guidance developed by international organisations such the International Medical Devices Regulators Forum (IMDRF) should be taken into account for global harmonisation of regulations that will impact safety protection worldwide and facilitate free trade. Finally, in regard to the recent referendum indicating Britain’s exit from the EU region, all eyes are on this evolving situation to determine how this will impact the overall regulatory framework of the EU region; whether this will lead to major modifications in the MDR is yet to be seen. Whatever the outcome, one thing to be ensured is that public health is not impacted by exit, and for this the MHRA will have to continue to work closely with the EMA.

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2016 DIGITAL HIGHLIGHTS

12 months in headlines To satisfy his inner geek, our editor Dave Gray takes a dive into the world of web traffic analytics to see which EPM online stories you were reading over the past 12 months

DECEMBER 2015

JANUARY 2016

Sanofi and Boehringer make a trade

GSK goes digital

As last year drew to a close, our online readers were monitoring Sanofi’s plans to acquire Boehringer Ingelheim’s consumer healthcare business as part of a swap for its own animal health business.

Perhaps one of GSK’s New Year’s resolutions was to pursue the digital dream? It would certainly explain why in January we reported that the firm was said to have engaged technology player Qualcomm in negotiating the terms of a joint venture. Speculation was driven by multiple media outlets that the discussions between GSK and Qualcomm could be geared towards the development of a digital device for pharmaceuticals.

Olivier Brandicourt, chief executive officer, Sanofi, said: “In entering into exclusive negotiations with Boehringer Ingelheim, we have acted swiftly to meet one of the key strategic objectives of our roadmap 2020, namely to build competitive positions in areas where we can achieve leadership.” By August 2016 it was announced that European regulators had approved the deal, subject to Sanofi divesting certain products.

In March, the group confirmed a strong drive into technology. In an interview with IEEE Spectrum, GSK executive Moncef Slaoui told the magazine that the company expects to begin clinical trials with ‘bioelectric treatments’ as early as 2017.

FEBRUARY 2016 Martin Shkreli lays into Pfizer

Pharma in 3D

Nicknamed “pharma bro” and “the bad boy of pharma” in the press, Martin Shkreli became something like the Donald Trump of our industry. Responsible for disproportionate price hikes of an HIV drug his company acquired, the controversial character enjoyed courting the mainstream media with his outrageous statements.

In March, the first FDA-approved 3D printed drug was made available for the treatment of epilepsy. Aprecia Pharmaceuticals’ Spritam (levetiracetam) tablets, for oral suspension, entered the marketplace as an adjunctive therapy in the treatment of certain seizures. Don Wetherhold, CEO of Aprecia, said: “Spritam is designed to transform what it is like to take epilepsy medication, and is the first in a line of products we are developing to provide patients and their caregivers with additional treatment options.” Spritam is formulated with Aprecia’s proprietary ZipDose Technology, which combines the 3D printing and formulation science to produce rapidly disintegrating formulations of medications.

In February he spoke out against Pfizer, and our readers tuned in. Defending his own reputation, he said of the big pharma giant: “At Pfizer’s clinical world headquarters they don’t have one lab in there, they don’t have any research going on, this company has cut billions of dollars of research and they raise [drug] prices all the time.”

MARCH 2016

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APRIL 2016

MAY 2016

Pfizer drops Allergan plans

Things get personal

Back in April the top story amongst online readers was related to the US issuing new plans to limit tax inversions – deals in which US firms seek to merge overseas companies and take profits abroad, side-stepping US tax rates.

In May readers were engaged in a thoughtful piece authored by Dr Hakim Yadi, CEO of the Northern Health Science Alliance. Dr Yadi spoke to EPM online about personalised digital medicine and the behaviourome – some of the most debated buzzwords around in 2016.

As a result, Pfizer’s long-discussed deal to buy botox maker Allergan, which was described as the biggest pharmaceuticals deal in history, was scrapped. Predicting that the deal would fall through, Professor John Colley of Warwick Business School had said: “The move to limit tax inversions by the US government has wiped $20 billion off the share price of Allergan which broadly equates to the tax benefit arising from Pfizer merging with Allergan.”

He explained: “In the future having information on the genome, proteome and metabolome will not be enough, we are going to need a way of understanding a patient’s behaviourome if we are to prescribe the most effective drug, device and digital solution to help manage or treat a patients condition.”

JUNE 2016

JULY 2016

One word: Brexit

Brexit, Brexit and more Brexit

Just like pretty much every other media outlet in Europe, our news in June was dominated by Brexit. On the 23rd Britain voted to leave the European Union. Our coverage focused on the opportunities and risks for the sector.

I’m afraid to say that by July, neither our content team nor our readership were quite finished discussing Brexit. But for readers in the UK, one story in particular heralded some good news.

As we reported, one key study from research firm GlobalData found that the vote to leave will have significant consequences for the pharma sector in regulatory impacts, R&D, access to talent, IP rights, and market access.

In July GSK announced £275 million of new investments at three of its manufacturing sites in the UK to boost production.

We also covered the reaction from the industry across social media, with one user tweeting: “Terrible day for Britain. Can’t believe it: #EUreferendum #Brexit has won. Who will house European Medicines Agency? Hello Denmark?”

In a clear effort to soothe some post-referendum anxieties, the UK’s business and energy secretary, Greg Clark welcomed the news: “An investment of this scale is a clear vote of confidence in Britain and underlines our position as a global business leader.”

AUGUST 2016

SEPTEMBER 2016

Back to business

Switched on

And, breathe. We made it through June and July, and whilst uncertainty rages on, so does innovation. In August, we brought you news of Check-Cap, a clinical stage medical diagnostics company developing an ingestible capsule for preparation-free, colorectal cancer screening.

Another contribution from a member of the EPM online community. In September, Christian Hebenstreit from Medidata Solutions told us about the huge interest in digital health in Europe and outlined ways for the pharma sector to make the most of the opportunity.

It wasn’t just the novel idea that made this group worth writing about. In August it announced that it has entered into an agreement with GE Healthcare to develop and validate high-volume manufacturing for X-ray source production and assembly into Check-Cap’s capsule.

His advice? It’s simple: “Companies need to go the extra step with strong feasibility studies to promote adoption by patients, healthcare providers and government payers in each country and prove that these sensors and apps are not only safe but effective tools for understanding disease and treatment.”

It may look like a pill, but a drug it ain’t. This company is being backed by one of healthcare’s major players to develop technology for prevention.

OCTOBER 2016

NOVEMBER 2016

Doctors without borders

The Trump card

In October non-profit organisation Doctors Without Borders/Médecins Sans Frontières (MSF) rejected Pfizer’s offer to a donate a significant number of pneumonia vaccines (PCV) to aid the children they serve.

At time of writing, we’re right up to date, so what has our online family been reading in November? It’s not hard to guess, as we saw with Brexit in the summer, once again politics has overtaken innovation in the headlines, for better or worse. Trump has been critical of the pharma sector, and blamed Medicare in the US for failing to negotiate on prices. “We don’t do it. Why?” Trump said. “Because of the drug companies.”

Jason Cone, executive director of Doctors Without Borders in the United States argued that donations can involve multiple rules and conditions that can negatively affect vaccination campaigns. Donations from pharmaceutical companies can often include restrictions on which patient populations and what geographic areas are allowed to receive the benefits. Cone further stated that donations can undermine efforts to increase access to affordable vaccines and also deter new manufacturers from entering the market.

It’s a little early to say what the long-term impact of the new US administration will be on the industry, however one thing is for sure: innovation will trump politics in the race for better healthcare.

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13:5

CONTAINMENT

Keep it all in Sylvain Querol (MEng), tendering manager, Europe, at Powder Systems Limited on how to achieve high containment for HPAPI small-scale production

ver 25% of the total drugs produced worldwide are being classified as highly potent. The High Potency Active Pharmaceutical Ingredient (HPAPI) market is rapidly growing creating new opportunities in a competitive landscape. Process technology providers need to keep up with stringent regulations to meet the market demand for high containment solutions. Targeted therapeutics using HPAPIs and cytotoxic drugs show effective treatment at low concentration. HPAPIs and cytotoxic drugs account for a quarter of the entire API market, but are rapidly growing thanks to their numerous advantages compared to traditional therapeutic products. They cover major therapeutic areas from oncology, cardiovascular, anti-diabetic to antibody drug conjugates (ADCs) and have become the key focus of researchers and manufacturers. Oncology treatment is one of the main drivers behind this growth with around 60% of the HPAPIs being developed for cancer treatment. HPAPI is the fastest growing segment of the worldwide API market, but the US FDA announced a shortage of FDA-approved manufacturing sites. Manufacturing technologies need to evolve to maintain the protection of operators but also the integrity of these highly potent compounds regarding cross-contamination risks. Occupational exposure limit (OEL) for APIs classified as highly potent is less than 10µm/m3 per eight hours time weighted average (TWA). The growing demand for HPAPIs and cytotoxic drug manufacturing causes significant challenges relating to the production process. These

products can lead to serious occupational hazards if not handled safely. Patient and operator health and the environment have to be protected from these hazards. A special focus is required for R&D and lab development operation. Many innovative drugs for targeted therapy are still at early stages and their toxicity levels are often unknown, so additional precautions should be taken. New containment strategies need to be implemented in HPAPI manufacturing plants to address these risks and strengthen safety requirements. Accurate OEL levels need to be defined along with testing and validation methods. How material is transferred from one process to another and what type of process equipment will CMOs have been eager be required is the first step to evaluate the best containment solution suitable for to adopt singleuse systems compared to traditional HPAPI manufacturing.

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dedicated systems that

CMOs have been eager to adopt single- are not practical for use systems compared to traditional multi-product facilities dedicated systems that are not practical for multi-product facilities. A survey from 2015 from BioPlan Associates showed that cost became a growing concern amongst manufacturers. Indeed the operating cost linked to consumables are inhibiting CMOs to increase the use of disposable technologies. The main concern with single-use technology is the risk of breakage of flexible bags and loss of production material. An issue that is of higher importance with HPAPI production is the health of the operator being at risk, and highly valuable product being potentially lost.

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Regulatory concerns, especially regarding leachables and extractables, is next on the list of issues to consider when adopting single-use technologies. In contrast, the use of rigid high containment systems, mainly gloveboxes or isolators working under negative pressure, is the safest protection for HPAPI manufacturing. Containment technology is not always readily suitable for small-scale production though. Installing such isolators for every transfer point and process equipment would not be practical. Latest innovations are focused on the integration of entire process lines including all the process equipment inside a single high containment rigid process isolator or suite of connected isolators. A process isolator provides a fully integrated synthesis and formulation process of HPAPIs, cytotoxic, ADCs and any other potent compounds. Process steps such as lab scale reaction, hydrogenation, filtration, drying, chromatography, dispensing, packing and weighting of clinical trial batches are performed safely in one single system. CMOs and pharma manufacturers are adopting such approaches for the containment of their lab and kilolab scale HPAPI manufacturing.

Enclosing for what benefits? Rigid isolators provide a physical barrier and containment of fragile glassware while guaranteeing high level of operator safety from toxic liquids and dust, but also vapour and solvent. The targeted OEL will depend on the required operations and quantities but for typical applications of less than 1kg the enclosed installation can achieve OEL down to the nanogram levels of 20ng or less per meter cubed, eight hours TWA. Enclosing the production line allows operator intervention in a safe manner onto the glassware or reaction rigs. Manual handling is necessary when developing new products or producing contract batches as the operator needs to adjust and modify the installation to meet the process needs such as changes of fittings, valves, etc. Most synthesis processes are streaming in a closed system within reaction rigs and products are transferred through pipework and tubing. High containment isolators provide an additional protection layer in The overall capital case the closed process is unsealed to adjust fittings, but also allow for fast and expenditure will therefore easy access without having to wear heavy be reduced by adopting personal protective equipment (PPE). high containment systems Removing heavy PPE is one of the key advantages of using isolator technology. Enclosing all of the production process within an isolator eliminates the need of PPE and multiple decontamination chambers. The cleanroom does not require complex design to accommodate several rigs as all glassware is enclosed in the isolator chamber. The overall capital expenditure will therefore be reduced by adopting high containment systems.

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During HPAPIs and cytotoxic drug manufacturing, the critical points are the open solid handling steps, generally at the upstream of the production line and, in most cases, at the end with the final or intermediate dried product. All these steps require extreme containment because of volatile dust in the air during sub-dividing and charging or raw materials, or offloading of the final powder. Even when handling small product quantities, there is a high risk of exposure and, more importantly, of cross-contamination when transferring the product from one step to another. Providing a unique isolator for the entire process reduces greatly this risk. During the entire process, products are never in contact with the external environment, eliminating any risk of cross-contamination.

New technology adoption Integrating the whole production line in a high containment isolator provides undeniable benefits to a safe and efficient manufacturing of HPAPIs and cytotoxic drugs. However, designing and manufacturing large isolators is more than putting a box around process rigs. Initial process understanding is paramount to achieve high containment performances. Integrating full process lines is all about project management and communication with the different suppliers involved. The isolator manufacturer needs to understand how the operator will use the different process equipment to design a suitable solution. The integration relies on glassware skids to provide a robust configuration as versatile as possible especially for multiproduct and contract manufacturing. Glassware is one of

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the fiddliest apparatus

The containment solution designer should to integrate; the turnkey undertake a detailed technical review with the end users to clearly outline the provider needs to pay proposed operation of the equipment to great attention to understand how the equipment will be used the ergonomics and under what conditions. This allows for the development of bespoke solutions to create a synergy between user requirements, technical regulations and equipment manufacture. The containment provider should have process engineers with hands on experience of operating such integrated equipment, such knowledge is invaluable for high quality engineering. The product quantities, handling instruction, access points, utility connections and cleaning methods are examples of process aspects to be known and fully controlled.

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Glassware is one of the fiddliest apparatus to integrate, the turnkey provider needs to pay great attention to the ergonomics. The best way to address ergonomic design requirements is to work with the operators and glassware suppliers at the beginning of the project to review a fullscale mock-up. Typically the containment provider will build an exact model of the isolator in a robust but flexible material and will include all the glassware. The mock-up should allow for flexibility to change the glove port position of the window enabling a ‘try and test’ study resulting in the best ergonomic solution for the process handling. The positioning of the glove ports is a key ergonomic consideration. The window, usually glass, is the main physical barrier between the operator and the process. Through this rigid barrier the operator needs to perform all the necessary handling with ease of access to avoid breakage or product spillage. For optimal ergonomics and visibility, full-length windows on both sides of the isolator are recommended. The ergonomic features drive the design of the isolator as much as the process flow. The isolator design needs to be modular and provide handling assistance such as sliding rails, strategically placed connections plate, mounting frame, etc. Ergonomics have a considerable impact on the cleanability of the isolator. Automated clean-in-place (CIP) systems, such as spray balls, are not appropriate in large isolators. They generate a lot of liquid waste and cannot guarantee 100% coverage with reaction skids obstructing the spray flow. It is recommended to do manual wiping first to eliminate any solid residues and then rinse down locally using integrated wash hoses and spray guns. This brings us back to the ergonomics and being able to reach all critical areas of the isolator for clean down through the restraint and protection of the gloves. Special features are necessary when it comes to cleaning glassware such as additional sinks and washing chambers for handling and cleaning glassware manually. Glassware is fragile and potential broken glass waste needs to be considered. Manufacturing plants may require decontamination capabilities not only with water or detergent but will require solvent inlets to address this requirement, linking back to the process understanding.

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PURIFICATION & FILTRATION

Stay in line Engin Ayturk PhD, senior R&D manager at Pall Life Sciences reviews the challenges of downstream process optimisation and advantages of single pass tangential flow filtration (SPTFF), looking at a broad range of results with inline concentration A growing need for downstream process optimisation The fast-growing global biopharmaceutical market1 is both attractive and daunting for pharmaceutical firms. While large molecule drugs have the potential to generate significantly higher revenues than traditional small molecule medicines, producing these complex molecules in a cost-effective and timely manner is a difficult challenge. To address this, industry has sought to make steps in the biopharmaceutical production processes as efficient as possible. For example, significant improvements in upstream monitoring technologies and culturing techniques have increased productivity and efficiency and allowed manufacturers to achieve high titers. Unfortunately, for efficiency-focused biopharmaceutical firms, advances in downstream technologies have been slower to emerge. Consequently, the focus now is on improving how the products of upstream processes feed into later purification steps.

Continuous bioprocessing is viewed by many as a potential solution, and this approach is attracting significant attention because switching from batch to continuous manufacturing has been shown in many industry sectors to lead to significant savings in cost and time, greater efficiency and improved product quality and consistency2. With integrated, automated continuous processing, unit operations are directly connected to one another with better process controls, eliminating intermediate hold steps and reducing waste and the likelihood of human errors and equipment downtime; this results in more efficient and quality operations with smaller physical and environmental footprints. Technologies that can facilitate continuous processing, most notably single-use solutions that enable the integration of downstream unit processes, are of interest. Suppliers have been working to deliver solutions that enable continuous processes. In particular, inline concentration of dilute solutions prior to various downstream purification steps, such as continuous chromatography, facilitates

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continuous manufacturing while increasing productivity and reducing operating costs.

Enabling efficiency with concentration The efficiency with which the products of upstream processes are captured and concentrated affects the efficiency of the overall production process. Traditionally, concentration in biomanufacturing involved direct and/or normal flow filtration operations by running feed streams through a membrane or bed that traps the solids in the filter and allows the filtrate to pass through. Such processes can be used to concentrate product to a limited efficiency; however, they require significant additional handling and frequent replacement of blocked filters. In contrast, widespread adoption of tangential flow filtration (TFF) enabled the feed stream to be fed across the surface of the filter rather than into it. One advantage of the approach is that filter life is extended. However, because it involves the recirculation of the process fluid, TFF can lead to degradation and/or aggregation of fragile (shear-sensitive) biologic molecules.

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Single-pass TFF (SPTFF ), in which the recirculation loop is eliminated by a unique flow path design and the staging of cassettes in a serial and parallel configuration, overcomes the limitation of conventional TFF. Using this approach, bioprocess fluids pass only once through the pump and module; the reduced residence time and shear exposure eliminates mixing and foaming issues and can lead to reduced risk of product damage or aggregation. In addition, if pressurised vessels are used to flow the process fluid through an SPTFF module, concerns over sensitivity to pumping can also be eliminated. Reducing the volume and increasing the titer of bioprocess fluids enables the adoption of smaller tubing and equipment sizes for unit operations downstream of the SPTFF concentration step. Perhaps most notably, the adoption of single-use technologies is often possible, which is attractive because they can provide significant savings in both capital and operating expenses, allow for reduced setup and switching times between processes, and reduce the risk of cross-contamination.

Moving toward continuous processing In particular, continuous processes provide the greater flexibility in manufacturing needed today to accommodate the shift to more targeted, niche, smaller-volume biopharmaceutical drugs, as The application well as the constantly changing of the SPTFF market needs. An increasing technique number of branded and generic allows for better biologics manufacturers and contract service providers control of the purification steps have pursued the concept of semi-continuous processing on a commercial scale, and have sought to integrate these processes over the next several years. From this perspective, it is possible that within five years fully integrated bioprocesses will be implemented at the production scale.

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The application of the SPTFF technique allows for better control of the purification steps by normalising the protein concentration from cell culture to chromatography and maintains the process productivity and economical gains afforded by continuous chromatography. Furthermore, it enables significant process cost reduction without the need to improve the upstream perfusion process, thus facilitating the move from batch to continuous mode and increasing speed to market. The Cadence Inline Concentrator (ILC) system from Pall Life Sciences, based on SPTFF technology, incorporates Delta regenerated cellulose membranes that offer high flux, high selectivity, and low protein binding. Yields are higher due to improved product recovery and reduced working and hold-up volumes compared with TFF — the line sizes are 2–3 times smaller and the feed flow rates are 5–10

times lower3. The modules can also help eliminate or reduce the size of intermediate storage tanks and the associated cleaning of tanks when used for in-process volume reduction while achieving typical concentration factors of 2–4 times (or more).

Broad applications for SPTFF In addition to its use as an alternative to TFF and for the concentration of clarified cell-culture fluids prior to chromatography, SPTFF technology can be used to optimise other downstream processes by performing product concentration at ideal process points. Examples include concentration between different chromatographic purifications, inprocess volume reduction, and in some cases, final biologic drug substance concentration. Product recovery of at least 99% can often be achieved after processing with inclusion of a buffer flush of a single system hold-up volume. The scalability of the performance of Cadence ILC modules of different sizes has been demonstrated [3] by evaluating fluxes and concentration factors, which determine the processing times, membrane areas and tank sizes required for larger processes, over a wide range of processing conditions. As a result, end users can directly scale up processes modeled in the laboratory to process development, pilot and production scales. Furthermore, although they are single-use systems, Pall has shown that Cadence ILC modules can be reused5 several times with minimal change in performance in terms of seal integrity and volumetric concentration factors.

Advantages of SPTFF To demonstrate the broad applicability of the SPTFF technology, the technical team conducted numerous studies with different feedstocks and with the ILC system coupled to other downstream unit operations. In one study, the inline volume reduction of a highly viscous feed stream consisting of a suspension of nanoparticles used in therapeutic drug delivery applications was evaluated6-7. The volume reduction was needed to enable the scale up of an ultrafiltration/diafiltration step from a 10 m2 membrane to a 40 m2 membrane without the need to scale the 400 L stainless steel hold tank due to floor space limitations. A 30 kDa Cadence ILC module was shown to provide a stable process at a feed pressure of 30 psig (2.0 barg), resulting in a feed flux of 22 LMH, a permeate flux of 16 LMH, a 3.7 times volumetric concentration factor, and an actual concentration factor of 4.1 times based upon solids content, which met the process target. In another study, the combined use of SPTFF and multicolumn chromatography for continuous mAb capture from a clarified CHO cell culture fluid via Protein A affinity sorbent

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was demonstrated8. Clarified feedstocks containing low MAb concentrations (≤1 g/L) were used to mimic a typical product titer achieved from perfusion cell culture. In another case4, a 1000 L batch of 0.4 g/L mAb in clarified CHO feedstock was concentrated using the Cadence ILC system before a capture step to reduce the size of the existing chromatography column and hardware (i.e. 60 cm column) yet retain a total Inline chromatography processing concentration time of four hours. A fiveallowed a threefold mAb concentration was achieved using a 17.5 m2 fold reduction in SPTFF module before loading chromatography onto the smaller size (i.e. 30 cm) membrane costs column. The four-fold reduction in sorbent volume resulted in approximately $500,000 in savings. Further cost savings were realised through a four-fold reduction in buffer consumption, considering an identical number of CVs was used for the non-load (i.e. wash, CIP, re-equilibration, etc.) steps.

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In another example [4], a 3.5 m2 SPTFF module was operated at a four-fold volume reduction capacity with a membrane chromatography step for capturing recombinant proteins at a 500 L scale. Inline concentration allowed a three-fold reduction in chromatography membrane costs and a two-fold reduction in the total processing time. Buffer consumption was also marginally reduced.

Next steps It has long been recognised that continuous processing has the potential to revolutionise biopharmaceutical production. The problem has always been the technical challenge of implementing such processes on an industrial scale. The major challenge has been that improvements in upstream culturing techniques and technologies have outpaced those downstream, creating a bottleneck and preventing the implementation of truly efficient continuous processes. Innovations like SPTFF are a significant step towards addressing this bottleneck and helping manufacturers optimise their downstream processes, reduce costs and bring products to market faster. References: 1

http://www.mckinsey.com/industries/pharmaceuticals-andmedical-products/our-insights/rapid-growth-in-biopharma

Konstantinov K. and Cooney C., (2014) White paper 4: continuous bioprocessing. International Symposium on Continuous Manufacturing of Pharmaceuticals, May 20-21, 2014, MIT-Cambridge, USA.

Pall Application Note: USD 3004.

Pall Application Note: USD 3003.

Pall Application Note: USD 3005.

Pall Application Note: USTR 2913a.

Ayturk, E. and Casey, C. BioProcess International Industry Yearbook 2015-2016 pp.43-44.

Pall Application Note: USD 3002

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POWDER PROCESSING & HANDLING

Take a granular approach Christine Banaszek, application engineer, Charles Ross & Son looks at the different options in planetary mixers for granulation

hroughout the pharmaceutical and supplement industries, granulation is a processing step that can vary quite significantly from one manufacturer to another. The basic objective is the same: to combine raw materials and create bonds between particles so they can be easily compressed into tablets having a uniform composition. However, equipment used for dry or wet granulation and subsequent drying, as well as the techniques for ensuring optimal density, particle size, flow and compression characteristics, ultimately rely on the properties and interaction of each ingredient. In this context, manufacturers stand to benefit from a re-examination of their granulation procedures, especially when developing new formulations, exploring alternative raw materials or upgrading legacy equipment.

Among the various technologies well-proven for granulation requirements is planetary mixing. The classic double planetary mixer offers an efficient way of preparing powders

for tablet making. It moves batch materials by rotating two identical blades on their own axes as they orbit on a common axis. The blades continuously advance along the periphery of the mix vessel, removing material from the walls and transporting it towards the interior. Wet granulation requires the addition of binding fluid to powders that are very fine or fluffy, or difficult to blend with other solids. The resulting wet mass is subsequently dried, and sometimes passed through a mill to produce granules of a certain size. A major advantage to the double planetary mixer is its ability to execute multiple operations in a single vessel: dry powder blending, liquid addition and coating, heating and vacuum drying. In a double planetary mixer, the orbiting blades impart a very gentle but thorough folding action that carefully mixes minor or trace ingredients even if the product is not free-flowing. After a short mixing period to homogenously blend the starting dry ingredients, liquids may be added through a manifold on the mixer cover. With the use of a metering pump, liquid flowrate is accurately controlled while the batch transforms into a wet

granulated state. Double planetary mixers routinely satisfy the requirement of product uniformity and particle size enlargement (granule formation) in the wet massing phase of many granulation recipes.

in tandem with one or two disperser blades (saw-tooth disc or sharp-edged chopper) installed on a high-speed shaft that also orbits around the vessel. The planetary disperser can accomplish multiple phases of a wet granulation procedure including powder blending, wet massing, drying and milling (particle size reduction).

The final stage of the process is typically vacuum drying to remove excess moisture. As heat and vacuum are applied, the stirrers continue to mix the granulation at lower speeds, just enough to ensure uniform temperature while maintaining the size of the granules. Vacuum drying offers a fast and reliable method for drying heat-sensitive materials without fear of thermal degradation.

In a double planetary mixer or planetary disperser there are no shaft seals, bearings, packing glands or stuffing boxes submerged in the product zone. Agitators are raised and lowered in/out of the mix vessel by a hydraulic lift, enabling easy access for cleaning between batches. A reverse lift design â&#x20AC;&#x201C; where the mix vessel is raised to meet the agitators and lowered after mixing â&#x20AC;&#x201C; is also available.

Manufacturers that have successfully transferred their process from multiple pieces of equipment to a double planetary mixer report significantly shorter cycle times, some by as much as 60%. In addition to simpler handling, cleaning and maintenance, the risks for product contamination and batch-to-batch inconsistencies are also minimised when the granulation process is streamlined. For granulations that require higher shear to break up agglomerates, a planetary disperser is recommended. In this style of mixer, a low-speed planetary stirrer works

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Conclusion Dry powder blending, granulation and drying are unit processes which have traditionally required separate pieces of equipment. The flexibility to complete multiple operations in a single machine provides a competitive advantage to manufacturers seeking to improve product quality, consistency and yield, reduce processing time and simplify maintenance. By eliminating transfer steps, processing is more streamlined and less labour-intensive.

POWDER PROCESSING & HANDLING

Pump up the volume Volumetric powder filling technology could streamline your process and increase productivity – that’s according to Marta Romaniuk and Richard Lewis, from Biopharma Group and John Rakucewicz from Kinematics & Controls Corporation

ncreasingly, industry appears to be driven by a manufacturer’s demand for ‘stream-lined’ processing, whilst maintaining the level of product integrity expected by their customers – whether this be taste, consistency, texture, or API activity. The field of accurate powder filling is a good example, where the propensity for companies to move away from more time consuming, laborious, and in some instances, inefficient procedures has become far more pronounced. In this environment, every effort is made to save material, eliminate waste, and increase operational efficiency, whilst satisfying the regulatory and EH&S requirements. As a result, a vast amount of technology, and various methods have been applied in an attempt to accurately measure and dose specific volumes of powdered material. However, due to the slow and arguably, inaccurate nature of many traditional techniques such as hand filling, operators have sought new ways to maximise efficiency, minimise loss of product efficacy, and, ultimately, protect their sustainability and position in the market place, economically. For instance, while the net weighing fillers prove to be accurate, they are particularly slow in operation. The time taken to achieve an ‘acceptable’ volume of target material, with these ‘simpler’ dose methodologies of manual hand filling/weighing techniques appear to have become out-dated in the contemporary fiscal and time dependent climate, with preference towards the implementation of modernised technology.

This is undoubtedly due to the fact that filling by hand means an operator must literally take up product with a spoon, spatula, or similar, before weighing to ascertain how near, or more typically, how far away, they are from the target volume. Of course, the length of time per dose can obviously be considerable, and creates a high probability of variance from dose to dose. Henceforth, the popularity of using powder filling instruments to assist has expanded across many markets, from pharmaceutical to diagnostic reagents, cosmetics to powdered metals and food. Another aspect to consider is the evolution of product understanding, to, again, satisfy regulatory and customer demands. For example, quality by design (QbD) is a model which has become quite pervasive in manufacturing environments, driving the end user to consider and identify individual but inherent material characteristics, prior to application of suitable filling technology. This nature of understanding may be accompanied by product reports to convey the reason a particular product is dispensed in a particular way e.g. corroborative data that can then be reviewed by auditing regulatory bodies. A level of enhanced documentation that will definitely serve to benefit both the product manufacturer, and their customer. For these reasons, in-depth review of specific sample properties, process requirements and techniques are now regularly requested and carried out to gain that required knowledge. The goal of this assessment is to ensure consistent and accurate extraction of the required dose at a satisfactory processing speed and end-product quality, accompanied by a documentation trial. Users therefore need a partner willing to provide such a level of detail.

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Where traditional auger fillers may have their place in large doses filling applications of dry powdered or granular products, they lack the level of precision required for the delivery of small incremental doses with closetolerance, repeat accuracy. At the other end of the spectrum, the volumetric powder filling approach has a proven record in the delivery of highly accurate, reproducible, and swift dosage. Here, material is drawn-up in to an orifice of known dimensions using an integrated vacuum system. The optimal filling system and procedure is then determined by the application for which they are used, and on the properties of the process material, such as: • Bulk density • Free flowing or non-free flowing • Coarseness, concentration gradients and uniformity of powder • Container type The measuring tool selection has to consider both your dosage, plus the size and shape of primary containers, which might, in turn, affect the operator’s ability to dose their desired volume per minute, hour, or the working day.

At the Kinematics & Controls Corporation, the first step is a comprehensive sample test protocol, designed with six-sigma levels of quality in mind, recommended to identify the key powder and container characteristics. The outcome should provide a clear understanding of the following: • The level of vacuum required to pick up and adequately pack material, without compromising its structure • The depth of the product in the given dosing ‘gun’ to calculate the volumetric measurements • The level of tolerance expected when applying these aspects to the dose • A full written report can then be issued, for customer interpretation Please note, it is prudent we highlight that when these details are identified they only need to be applied once, allowing the operator to conduct a working shift of accurate and repeatable dosing for that individual sample. These simple, accurate, high-speed and low cost Kinematics powder fillers have a rugged construction modular design where the entry level machine 4400/VC console forms part of both the Model 4400/TX & the Model 5500/TX. All systems are capable of running for long periods of time, with low maintenance while accurately measuring and dispensing the powdered material in to desired containers. Various Kinematics systems are available to simplify operation and increase productivity, as described below, and all are supplied complete with extensive build diagrams, wiring configurations, and FDA approved parts, where required.

In addition, the variation in size of different powder particles, from several microns to more granular volumes, must be taken in to account during the selection of not just the base machine and volumetric dosing barrel, but the filter type too, which may also improve the dosing capacity.

By identifying a suitable filling solution for target powdered material at the outset, companies can minimise potential for operational problems over time, significantly reducing manufacturing expenditure, while building the client confidence in scale up capacity.

In some cases, the presence of larger filter pores i.e. 40um as opposed to 20um, may improve the airflow through the dosing gun and aid in the products compaction, thus reducing potential product waste by simultaneous dose and filter purge. During the dosing process, the residue powder inside the dosing chamber and on top of the filter will be expelled accurately by applying a user defined pressure.

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Due to the slow and arguably, inaccurate nature of many traditional techniques such as hand filling, operators have sought new ways to maximise efficiency, minimise loss of product efficacy, and, ultimately, protect their sustainability and position in the market place

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BIOPHARMA

Strict but supple Robert Harrison, pharmaceutical industry manager of industrial software group COPA-DATA, explains how industrial automation solutions could change the face of biopharmaceutical manufacturing in the years to come

iopharmaceuticals represent the fastest growing sector of the pharmaceutical industry, making up about 20 per cent of the market. Annual growth rates of the biopharma subsector are around eight per cent - double that of more traditional pharmaceutical sectors.

Turning challenges into opportunities

Flexibility

Reducing costs

The entire pharmaceutical industry - including biopharma - is under constant pressure to deliver cost effective new drugs. On the one hand, manufacturers need to develop small batches of personalised medicine very quickly, while on the other hand, the industry has to provide low cost and high volume production of common products like insulin or malaria vaccines.

Newly evolving drugs and treatments, changes in industry standards and rising energy prices are some of the main reasons why biopharmaceutical manufacturing requires more flexible processes and production lines.

There are many ways in which intelligent automation helps reduce costs in the biopharmaceutical production. It can ensure expensive materials are not wasted, processes are streamlined.

Traditional brick and mortar facilities are struggling to meet industry requirements. Instead, manufacturing on demand or modular facilities are being developed to respond to increasing industry needs.

Industrial automation software helps biopharmaceutical companies visualise all the manufacturing activities and process stages, which is essential when analysing production and energy efficiency. It allows process managers to identify the most intensive stages and visualise how to optimise the overall operation.

However, biopharma is less mature than conventional pharmaceutical production and few companies in this sector have in-house manufacturing capabilities. This pushes cuttingedge process innovation and operational efficiency to the CMO (Contract Manufacturing Organisation), supporting the trend of smaller, more agile facilities concentrating on flexibility, cost efficiency and speed. Process technologies have advanced over recent years, breaking down production facilities to evolve the modular concept of standardised functional process modules, which help manufacturers simplify, verify and re-use designs. This flexibility means additional functionalities can be added or replaced in a seamless fashion. Delivering cost-effective treatments places pressure on manufacturing to get the most out of its people and equipment. Improving agility and effective use of equipment, tries to balance biopharma’s long process duration times and expensive raw materials. Where possible, pushing down manufacturing costs can be achieved through optimisation, reduced material usage and energy consumption.

When the physical processes within a biopharma manufacturing facility are modular, their agile nature is enhanced by the software component facilitating the modular connections. Software is the umbrella that allows change within the process, moving each validated module into place, according to the process demands. Industrial automation plays a key role in making manufacturing lines suitable for several products. However, hardware is of little use without a communication system and software package that offers a holistic view and coordinates different stages, from research and development to the shop floor production systems, storage and transport. Industrial automation software needs to be intuitive and easily configurable. This eliminates the lengthy and complex process of writing and validating programmed code. By using parameterisation, automation software becomes easy to implement in pharmaceutical manufacturing environments, therefore increasing process flexibility.

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Biopharmaceutical companies are already experiencing a gentle transition from ‘oneline one-product’ setups to agile, multiproduct facilities to manage current and future manufacturing. The transition might not be a straightforward or rapid one, but it is a journey that is made easy by the next generation of industrial automation software that improves process knowledge, demonstrates regulatory compliance and Delivering reduces risks associated with cost-effective process changes.

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treatments places pressure on manufacturing to get the most out of its people and equipment

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ADVANCES IN SINGLE USE TECHNOLOGY

Bio hazard Dr. Andreas Nixdorf, business development manager, extractables and leachables testing at SGS - Life Sciences, examines new developments in safety, toxicity and E&L standards for single use manufacturing

he single use system (SUS) market will grow rapidly as the technology is adopted for commercial manufacturing of pipeline products, having been estimated in 2015 to be about $1.2 billion, with an upstream market of more than $750 million growing at a CAGR of 14% and a downstream market of more than $270 growing at a CAGR of 8%. According to BioPlan Associates Inc.’s 2015 Annual Report, 49.1% of biopharmaceutical manufacturers surveyed, said at least 50% of their commercial/clinical operations will be single-use by 2020.

Supply chain control With the industry shift to SUS, it is important to recognise that safety qualification determines suitability for use and initial selection of materials in a biopharmaceutical manufacturing process, but does not constitute process validation itself. The most significant factors to be assessed for safety validation include physico-chemical material compatibility with the biopharmaceutical manufacturing process and the toxicity profiles of these materials to ensure there are no possible adverse effects on patients’ health. General toxicity, biological reactivity/ cytotoxicity, systemic toxicity (sensitivity) and genotoxicity of SUS materials all need to be assessed. Single-use systems offer numerous advantages, but also introduce a new set of materials into the production process and consequently expose biomanufacturers to a new set of risks related to those materials. There are several publications reporting that polymer films have negatively impacted culture growth by the introduction of leaching substances into biopharmaceutical processes.1-3 The compound bis(2,4-di-tertbutylphenyl)phosphate, which leaches at trace levels from bag films, was shown to be highly detrimental to cell growth. The toxic compound is derived from the breakdown of tris(2,4-di-tertbutylphenyl) phosphite, a common antioxidant additive present in many polyolefin formulations. Cell growth experiments with multiple recombinant protein-expressing CHO cell lines show a 50% reduction in culture growth. Furthermore, an unexpected impurity can be introduced at any point along the supply chain. The supplier of the raw polymer material master batch used in construction of a SUS cannot support all the regulatory expectations of the end user for different reasons. The SUS supplier wants to deliver high-quality materials to meet the expectations of different clients, ranging from companies operating in the food industry to medical/pharmaceutical sectors. Consequently, the SUS becomes a

critical part of the qualification system at the end-user side. The role of the supplier is therefore now more critical, and regulators expect drug and medical device manufacturers to mitigate any risk with close partnerships and thorough knowledge of their suppliers’ quality systems and supply chains. The regulatory requirements of the end user are more or less satisfied by the quality standards of these suppliers. The pharmaceutical end user demands a sustainable SUS product, fit and ready for its intended use, and expects the support of suppliers when changing systems or operating procedures. The end user also expects to receive all valid and sustainable data from suppliers for prequalification of materials prior to selection. It is also necessary for the end user to confirm the security of the supply chain, the compatibility of the SUS with the pharmaceutical manufacturing process, and that no leachables accumulate in the finished drug product. Qualification is, in fact, the critical criteria that must be achieved at the end users side. Finally, official bodies expect drug products to meet, and over and above, all their regulatory requirements. Regulatory bodies normally request that the end user carries out an extractable and leachables (E&L) risk assessment also for the SUS being employed in the manufacture of the drug product.

Reality check Based on pharmaceutical companies’ feedback, the reality is often very different from these ideals. SUS components have sometimes been changed without adequate information being given to the end user. It is often the case that important data are missing. Chemical and physical resistance is important information to assure that materials can resist process conditions, such as high and low temperatures or corrosive chemicals. For example, sodium hydroxide is widely accepted for cleaning, sanitising and storing chromatography media and systems for removing proteins. As with any sanitising agent, certain precautions should be taken and compatibility with both chromatography media and systems determined. In bio-pharmaceutical processes, silicone tubing is used for passing the cleaning in place (CIP) solution through the system. In a failure mode study it has been observed that some silicones can be easily attacked by sodium hydroxide at high pH, and delamination and loss of polymeric mass occurred. The damage mechanism of polymeric materials is an important factor to understand in materials use compatibility, and failure mode studies should be conducted separately from E&L studies.

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The pharmaceutical end user demands a sustainable SUS product, fit and ready for its intended use, and expects the support of suppliers when changing systems or operating procedures.

Other quality issues that can occur include inadequate quality procedures for incoming chemicals or raw materials; agreements in respect of changes to the quality control system are lacking; or measures for cleaning production equipment between production campaigns have been assessed as insufficient. As a company, we have analysed hundreds of disposable materials over the past decade. Any change on materials chemical constituents could put the qualified status in question. From our point of view it is a serious disadvantage that there are often no sufficient impurities controls for incoming starter materials established. In polymer processing, production equipment should be cleaned to avoid carryover. Even if the extent of carryover is not controlled by appropriate cleaning validation, environmental impurities could end up in the polymers, and therefore could also be accumulate in the finished products. Our conclusion is that many substances of toxicological concerns are sourced from uncontrolled side reaction from plastic processing. These impurities are already present in the raw materials, and so all suppliers must ensure that their quality systems are robust, and their supply chains are well controlled. Product quality must be the responsibility of all parties involved that make up the clinical or commercial finished drug product supply chain. The end user should ensure that there is a clear and proper legal framework in place that provides confidence that supplier delivers equal quality regarding chemical profile from lot to lot.

Work in progress There are numerous organisations4 engaged in most of the relevant activity areas. The American Society of Mechanical Engineers BioProcessing Equipment Extractables Task Group, having made several updates to its 2016 standard. The U.S. Pharmacopeial Convention (USP), has developed a range of standards for plastic materials, packaging systems and components used in the manufacture and distribution of pharmaceutical products.

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It is also crucial that the risks associated with employing only standard extraction protocols in assessing SUS are addressed. There are misconceptions about the applicability of these methods, which may increase the risk of the end user making inappropriate manufacturing decisions. In some cases, standard extraction protocol procedures may be too harsh, causing decomposition of the SUS polymer network. The overall effect of this is that material qualification would no longer be valid, and it could be the case that under real-use conditions there may be no risk of material leaching into the drug product. Therefore, the best practice to assess risk from SUS such as bags, tubes, connectors and filters would be to perform a simulated migration or customised use study under real process conditions.

Recommended practice A legal, established definition of what ‘medical-grade plastic’ exactly means is needed. End users must ask suppliers to give them all the information that is relevant to SUS materials, including resistance to chemicals, pH, temperature, radiation, moisture etc., and the exact significance of test results assessed. Such approaches will result in design of the most appropriate E&L strategies for customised manufacturing processes. Moreover, it is essential to distinguish between chemical resistance testing and E&L testing: suppliers should test for unintentional added impurities in critical raw materials. Increased co-operation between polymer raw materials companies, SUS suppliers, biopharmaceutical manufacturers and regulatory agencies is the key to ensuring the safety and quality of the biopharmaceutical products of the future.

References

The next decade will see the field of extractables within the growing area of SUS evolve and it is crucial all stakeholders within the supply chain work together to ensure the guidelines and standards being developed can be applied through an appropriate risk assessment, to evaluate the suitability of single-use components in production processes. Assessments need to consider the overall risk of the components and their use, including their suitability for the process and any potential E&Ls. It is vital that support is given from suppliers in providing documentation and evidence of supply chain security.

Hammond, M. et al.; “A cytotoxic leachable compound from single-use bioprocess equipment that causes poor cell growth performance”; Biotechnology in Progress Vol., 30 Issue 2, March/ April 2014, pp 332-337.

Hammond, M. et al. (2013) Identiﬁcation of a Leachable Compound Detrimental to Cell Growth in Single-Use Bioprocess Containers, PDA J. Pharm. Sci. Technol. 67, 123-134

Eibl, et al. “Recommendation for Leachables Studies: Standardized Cell Culture Test for Early Identiﬁcation of Critical Films for CHO Cell Lines in Chemical deﬁned Culture Media”; Dechema Jan. 2014.

James D. Vogel; Maureen Eustis; The Single-Use Watering Hole: Where Innovation Needs Harmonization, Collaboration, and Standardization”; BioProcess International Jan. 2015

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French connection Pharmapack Europe, organised by UBM EMEA, is a two-day exhibition and conference dedicated to pharmaceutical packaging, drug delivery and affiliated industries. Next year’s event is on 1 & 2 February 2017 at Paris Expo Porte de Versailles (Hall 4), Paris.

017 marks the event’s 20th year, and over its lifetime the organiser says it has grown in size, profile and popularity from a bi-annual event to a major annual show that attracts 5,100+ visitors and over 380 exhibitors from more than 70 countries around the world. Attendees and delegates range from CEOs and CMCs to pharmacists and business execs, and work in every area from R&D and drug development to purchasing, engineering, marketing, logistics and business development. Innovation is at the very heart of Pharmapack. An innovation gallery showcases selected industry innovations from exhibitors, while Innovation Tours guided by industry experts take visitors on a tour to innovating exhibitors’ stands. The newest addition for 2017, the Pharmapack Start-up Hub, is designed to let innovative young pharma firms benefit from valuable networking and learning opportunities at a price that suits their budget. This dedicated area on the show floor gives them a unique platform to showcase their ideas, meet potential customers, partners and investors and forge new relationships that will help them develop for years to come.

category. This latter category distinguishes the packaging of new health products introduced to the market, or the improvement of the packaging of an existing health product (for human or veterinary use). Both awards recognise products that have significantly contributed to the proper use of medication, increased patient/user safety and compliance or represent a significant step towards sustainable packaging. Pharmapack is an opportunity to sharpen up technical and industry knowledge. The extensive content programme comprises two days of conferences, a one-day Serialisation, track and trace symposium, a day of workshops and a learning lab that hosts short, sharp presentations on key topics from exhibitors throughout the two show days. Dedicated networking areas and a special drinks reception mean there’s never a shortage of new faces to meet. It’s a unique opportunity for companies to boost their networks and kick-start their growth.

The Pharmapack Awards recognise new products that are set to shape the future of the industry, in two categories. The Exhibitor Innovations category is dedicated to Pharmapack exhibitors who have developed a new product. For those who are not exhibiting, there is the Health Product

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Ralph Fienne s stars in this adaptation of the John Le Carre no vel (image credit: Denis Makarenko / Shutterstock .com)

A M R PHA THE AT CKS FLI

Reviewed: The Facility EPM’s Reece Armstrong reviews 2012’s The Facility, a movie which seeks to give clinical trials the Hollywood treatment The Facility features a group of people participating in a drug trial for an experimental drug called Pro9. For a two-week period and a payment of £2000 the seven participants have a seemingly easy way of earning some cash. As this is a horror film however things soon turn sour. What follows is a claustrophobic thriller, placed in a setting that feels like it could be all too real. The film takes place at Linebrook Clinic, a facility conveniently placed in the middle of nowhere. The seven participants are a collection of familiar stereotypes but are nevertheless convincing in their performances. Looking For Eric’s Steve Evets gives a particularly The interest in pharma tremendous performance as an unemployed man willing and drug trials is a to inject himself with any welcome one but it concoction of drugs.

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could have been better developed.

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The group are told to refrain from sex, drugs, alcohol and physical activity but besides that there is no other information given about Pro9, least of all that it could result in a deadly aggressive side-effect. And the mentioned side effect? A gruesome bodily swelling that looks plausible. It’s one of the film’s better judgements; to gauge the side-effect to look as effectively real as possible The Facility succeeds in presenting a horrifying vision of unexpected reactions to drugs. When the side-effects eventually start to manifest, characters begin to turn violent and a real threat begins to emerge. The close confines of the facility make for a thriller that is engaging and tense, if not terribly inventive. A twist revealing that some of the participants were given a placebo instead of the real drug is meant to provide a smart diversion but it can be seen coming from the beginning of the film. It’s an enjoyable watch though and the tonal style of the film fits perfectly with the sterilised setting of the Linebrook Clinic. In places The Facility almost looks like a documentary, shot

to expose the shady dealings of pharma companies and the unfortunate side effects of the drugs they market. The film does successfully manage to raise questions into the involvement of pharma companies and drug trials. ProSyntrex – the company behind Pro9 – attempts to detach itself from the trials as things begin to go bad. Whilst the plot’s involvement with ProSyntrex is minimal, it does portray the company as an organisation solely out to benefit itself. The underlying threat beneath the violence is contained within the drug the participants willingly put into their bodies. In an age where there is an abundance of health products marketed to benefit our bodies, shouldn’t we understand what it is exactly we’re taking. The film aims to ask this but gets lost along the way. The interest in pharma and drug trials is a welcome one but it could have been better developed. Instead we’re treat to a thriller that is both original and entirely predictable. Its setting is the thing that makes it stand out but the film abandons the premise for a tirade of violence. Indeed, perhaps the most horrifying aspect of The Facility is its relation to real life stories. In 2006, a trial now known as ‘The Elephant Trial’ had six men admitted to hospital for organ failure after taking part in a trial for the drug TGN1412. Certain men in the trial were reported as having their heads swell up, thus the trials name ‘The Elephant Trial’. The six men fortunately survived but were told they could face a lifetime risk of cancer and arthritis. More recently a man became brain dead after taking part in a drug trial in France earlier this year. The trial had 90 people test a drug to treat mood disorders such as anxiety developed by Portuguese pharmaceutical company Bial. Six men were admitted to hospital after taking the experimental drug. Alongside the brain dead man, three other men could suffer irreversible neurological damage. A judicial investigation was opened by the French state prosecutor alongside two state-run inquiries. Trials on the drug were suspended and volunteers who took part in the drug trials were called back.

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