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Contents June 2015 | Volume 15 Issue 4

Regulars

5

6

Features

20

COMMENT

JOINING FORCES

Lu Rahman looks at the developments in immuno-therapy

Mergers & acquistions in focus from Patheon and Achieve Breakthrough

6 NEWS ANALYSIS

25

10 OPINION

22 SMART THINKING Freeze drying expertise from SP Scientific and Telstar

27

Good to Talk gets political and innovation is in the spotlight

IN THE MIX

11

Catalent looks at formulation

REGULATORY AFFAIRS

29

34

MOVING STORY GS1 UK offers insight into logisitics

CHEMICAL REACTION Featuring AMCo this month

30

30

WATER WORLD Purification & filtration from Water Purification Systems UK

31 LIQUID ASSET Blow Fill Seal knowledge from Rommelag

head office Carlton House, Sandpiper Way, Chester Business Park, Chester, CH4 9QE. Tel. +44 (0) 1244 680222 Fax. +44 (0) 1244 671074 Web: www.epmmagazine.com

editorial editor ellie valero, ellie@rapidnews.com group editor lu rahman, lu.rahman@rapidnews.com associate editor dave gray david.g@rapidnews.com contributing editor aleksandra jones, ola@rapidnews.com publishers mark blezard, duncan wood

production art robert wood

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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 15 Issue 4 © June 2015 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.

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Better medicines through science and engineering.

from the editor Forward thinking Advances in the treatment of disease have taken another step forward with the discovery that a genetically engineered version of the virus that causes cold sores could be used in the treatment of skin cancer.

While the treatment – which works by injecting the modified herpes virus into tumours where it replicates substances which help to fight cancer – isn’t licensed yet, it is thought it could increase survival rates for cancers such as melanoma. Interestingly, similar immunotherapy treatment for this disease is already available in the US and Europe and it is hoped that T-Vec would be able to add to this therapy.

A study was carried out – the largest randomised trial of an anti-cancer virus involving 436 patients from the UK, US, Canada and South Africa with inoperable malignant melanoma.

Prof Kevin Harrington, from the Institute of Cancer Research, led the UK trial on this development. He told the BBC: “There is increasing excitement over the use of viral treatments like T-Vec for cancer, because they can launch a two-pronged attack on tumours - both killing cancer cells directly and marshalling the immune system against them.

“And because viral treatment can target cancer cells specifically, it tends to have fewer side effects than traditional chemotherapy or some of the other new immunotherapies.”

Pursuing the benefits of immunotherapies is an important goal for many drug companies at the moment. The recent American Society of Clinical Oncology (ASCO) conference contained a strong focus on this topic highlighting the excitement surrounding this area of expertise at the moment.

AstraZeneca is one company developing treatment in this area. It is currently working on drug combinations in immuno-oncology and has made this area of development a key priority for the business at the moment. Along with Pfizer and Merck KGaA, the company presented data on trials and studies carried out in this field, showing the importance these breakthroughs are becoming for the pharmaceutical sector. Also, Roche subsidiary Genentech highlighted its excitement in this field regarding data in different types of advanced lung cancer including investigational immunotherapy.

The pharmaceutical sector breaks boundaries on a regular basis. With advances being made in immunotherapy and the work that drug companies are pushing forward, a very exciting time lies ahead as we increase our ability to tackle and conquer a range of illnesses and disease.

Lu Rahman

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5

NEWS ANALYSIS

UK lags in access to new medicines, says report

T

he government’s Life Science Competitiveness Indicators – the publication which shows how well the UK performs internationally compared with other countries in the life sciences sector – shows that the UK continues to lag internationally in providing patients with access to new, innovative medicines. The report also highlights the relevance of the uptake of new medicines, alongside other indicators, to the UK’s global competitiveness underpinning the crucial role the industry has in shaping how the UK’s Life Science industry is perceived on the global stage.

pharmaceuticals fell slightly in 2013 after rising in the previous four years but there has been a rise in foreign direct investment in the UK life science sector.

At the request of the ABPI the report, published by the Department of Business, Innovation and Skills, includes an indicator which highlights the low and slow uptake of new, NICE-approved medicines launched over five years in the UK compared with Australia, Austria, Belgium, Canada, Finland, France, Germany, Ireland, Italy, Japan, Netherlands, New Zealand, Spain, Sweden, Switzerland, and USA. This indicator features alongside 25 other indicators of performance and competitiveness in order to provide an overall picture of how well the UK is performing in life sciences.

“However, the fact that uptake of new medicines is only 11% of the average of other developed countries after one year, less than a third of the average after two years, and still only half the average after four years highlights that this remains a major issue. We know that these low and slow levels of uptake are even worse for non-NICE approved medicines after five years from launch. Not only is this a disadvantage for patients in the UK who are not able to access the newest, most innovative medicines when they need them, but we can now see that this is a disadvantage to the country as a whole impacting our global competitiveness. Publication of this report annually will provide us with the ability to track how well we are performing and enable us to work with government to ensure the UK improves its position versus other countries.

Other statistics in the report show that the number of science graduates in the UK and employment in the manufacture of pharmaceutical products are rising gradually. However, it also showed that the gross value added by the pharmaceutical manufacturing industry has declined and then flat-lined since 2010, and that government spending on research and development has fallen slightly. Exports of

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Commenting on the publication of the Life Science Competitiveness Indicators ABPI’s executive director, commercial UK, Alison Clough said: “We are delighted that government has responded to our request and included the use of medicines in the NHS as an important indicator of the UK’s competitiveness in the life sciences sector.

“The ABPI is committed to contributing to the Accelerated Access to Medicines Review in order to support improvement in this area for the benefit of patients and the wider economy.”

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NEWS ANALYSIS

How cancer tricks the lymphatic system into spreading tumours

S

wollen lymph nodes are often the earliest sign of metastatic spread of cancer cells. Now cancer researchers and immunologists at Sweden’s Karolinska Institutet have discovered how cancer cells can infiltrate the lymphatic system by ‘disguising’ themselves as immune cells (white blood cells). The researchers hope that this finding, which is published in the scientific journal Oncogene, will inform the development of new drugs.

lymph nodes, just like immune cells.

According to the researchers, their results link inflammation and cancer in a novel way and make possible the development of new treatment models.

“With this discovery in our hands,

The main reason why people die of cancer is that the cancer cells spread to form daughter tumours, or metastases, in vital organs, such as the lungs and liver. A route frequently used by cancer cells for dissemination is the lymphatic system. Upon entering lymphatic vessels, they migrate to nearby lymph nodes, which then swell up, and from there, to other organs via the blood. The details of how and why cancer cells use the lymphatic system for spread are, however, relatively unknown.

we’d now like to try to find out which additional immune-cell properties cancer cells have and study how they affect the metastatic process,” says Dr Fuxe. “The possibility of preventing or slowing down the spread of cancer cells

via the lymphatic system is an attractive one, as it could reduce the risk of metastasis to other organs.”

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“It’s not clear whether there are signals controlling this or whether it’s just random,” says principal investigator Jonas Fuxe, cancer researcher and associate professor at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics. “However, in recent years it has become evident that inflammation is a factor that can promote metastasis and that anti-inflammatory drugs may have a certain inhibitory effect on the spread of cancer.”

The study is based on an interdisciplinary collaboration between cancer researchers and immunologists, which the researchers point out has has contributed to the new, exciting results. What they discovered was that an inflammatory factor known as TGF-beta (transforming growth factor-beta) can give cancer cells properties of immune cells by supplying the surface of the cancer cell with a receptor that normally only exists on the white blood cells that travel through the lymphatic system.

Equipped with this receptor, the cancer cells are able to recognise and migrate towards a gradient of a substance that is secreted from the lymphatic vessels and binds to the receptor. In this way, the cancer cells can effectively target lymphatic vessels and migrate on to

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7

NEWS ANALYSIS

Law society Benjamin J Lehberger, St Onge Steward Johnston & Reens LLC, looks at patent challenges in the pharmaceutical industry and a recent trend of investment companies challenging the patents of foreign pharmaceutical manufacturers

T

he 2011 America Invents Act brought several new options for challenging the validity of patents in the United States. The most widely used option to date has been Inter Partes Review (IPR), which is a trial-like proceeding for challenging a patent on prior art grounds before the Patent Trial and Appeal Board (PTAB) in the US Patent Office. The new mechanism has drawn unexpected (and likely unintended) parties into patent challenges: speculators seeking to invalidate patents in order to affect the patent-holder’s stock price. Publicly traded companies in industries that rely heavily on patents to protect their markets are particularly vulnerable to this new challenge.

The Coalition for Affordable Drugs, backed

by Hayman Capital Management LP, recently filed an IPR petition challenging US Patent No. 7,895,059 owned by Jazz Pharmaceuticals. The ‘059 patent is listed in the FDA’s Orange Book as one of the patents protecting Jazz’s successful narcolepsy drug, Xyrem. According to reports, Hayman Capital seeks to profit from the challenge by shorting the patent owner’s stock, ie, betting on the stock going down as a result of a patent protecting the Xyrem market being put at risk or ultimately invalidated.

Hayman Capital has indicated that it plans to target a number of companies in the pharmaceutical industry with IPR challenges.

Since February, it has filed at least thirteen other IPR’s challenging patents protecting Acorda Therapeutics’ Ampyra, Shire’s Lialda, NPS Pharmaceuticals’ Gattex, Pharmacyclics’ Imbruvica, and Biogen’s Tecfidera, Celgene’s Revlimid, Pomalyst, and Thalomid. The strategy has seemed to work, at least in the short term, as Acorda’s stock fell nearly 10% immediately after their IPR challenge.

Hayman Capital is not the only investment firm filing IPR’s. Ferrum Ferro Capital, a New York based hedge fund, recently filed an IPR petition challenging an Allergan patent

8

relating to its glaucoma drug, Combigan.

This challenge comes after Sandoz was unsuccessful in invaliding the same patent in court leaving it blocked from entering the generic market. While the focus has so far been on the pharmaceutical industry, where the critical patents can be easily identified from the FDA’s Orange Book and the stakes are high, we could start to see similar challenges leveraged against publicly traded companies in other industries.

The number of IPR petitions filed in the US Patent Office has been on the increase since the procedure first became available at the end of 2012. 701 IPR petitions were filed in 2013 followed by 1501 in 2014.

Unlike challenging a patent in a U.S. district court, there need not be any accusation or threat of patent infringement to initiate an IPR proceeding. This eases the requirements for potential infringers to challenge patents before any actual infringement occurs. Thus, in the pharmaceutical field, IPR’s can be an effective tool for generic drug companies to use not only after filing an Abbreviated New Drug Application (ANDA), but even before the ANDA filing or when there is otherwise no jurisdiction to bring the challenge in the district court. However, it opens the door for nearly anyone to attack the validity of a patent.

Challenging a patent with an IPR is generally cheaper and faster than in a district court, and may offer the challenger a greater chance of success. The cost of an IPR proceeding is generally in the hundreds of thousands (USD) rather than the millions (USD) which could be incurred in a district court litigation and, where a district court litigation may take several years, an IPR is generally resolved 12 months after being instituted. The PTAB only institutes a proceeding when it finds that there is a reasonable likelihood that at least one of the challenged claims is unpatentable, however the standard is met in approximately 75% of the petitions filed. In the IPR’s that have been instituted and decided thus far, 62%

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have resulted in all of the instituted claims being found unpatentable and another 21% resulted in a partial finding of unpatentability.

Increasing the chances of a patent being invalidated in an IPR is the fact that the PTAB gives the claims a broader interpretation than in district court, which potentially allows more prior art to read on the claims, and applies a lower standard in evaluating the evidence of unpatentability. One advantage for the patentee in an IPR is that, unlike in district court, there is an opportunity to amend the claims to avoid the prior art. However, the requirements to do so are stringent and, to date, only one motion to amend the claims has ever been granted by the PTAB. What can a publicly traded company do to protect itself from losing its patent protection and stock value to an IPR attack? While you cannot prevent a third party from filing an IPR petition, it may be possible to lessen the impact on your business. The first line of defence is during the early stages of obtaining patent protection. As is typically done, obtaining a comprehensive patentability search of US and foreign patent documents and literature before filing helps to identify and address any prior art that could be used to challenge the validity in the future.

Next, consider filing multiple patents (either at the time of initial filing or later as continuation or divisional applications), particularly when the product or process embodies more than one invention. An IPR challenge by a speculator can be most detrimental when a high grossing product is protected by a single vulnerable patent. The more patents and diverse claims you have covering the product and processes for manufacture and use, the less likely you are to lose all protection. For example, in the case of Jazz Pharmaceuticals, there are numerous other patents listed in the FDA’s Orange Book that would need to be overcome before a generic competitor could enter the market. During the life of the

product, evaluate any improvements for the possibility of filing for additional patent protection.

If your company’s patent is the subject of an IPR petition, it is important to get started on a defence as soon as possible after receiving notice. The patentee has the option to file a preliminary response before the PTAB decides whether there is sufficient evidence for the proceeding to go forward. Once the proceeding is instituted, the patentee then has only three months to seek limited discovery from the petitioner and submit a full response to the petition including any arguments, evidence, and expert declarations to be used in defence of the patent. Thus, while the Board is considering whether to institute the IPR, time would be went spent by developing your defence, gathering evidence and retaining experts given the high probability (statistically) of the IPR proceeding being instituted.

Also consider early on whether there are any amendments that can be made to the claims to avoid the prior art cited in the petition. The patentee is only permitted one motion to amend as of right, and it must be filed no later than the filing of the patentee’s response (three months after institution).

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5/26/2015 1:55:19 PM

9

OPINION

It’s good to talk Following the general election we asked your opinion on what the result means for pharma Professor Colin Garner, Antibiotic Research UK David Cameron stated in the last parliament that medicine would go back to the dark ages if we did not tackle the problem of antibiotic resistance. He set up the O’Neill Antimicrobial Review to report back to him in 2016 on how to revive the development of new antibiotics. Our charity would like to see the O’Neill’s recommendations of a global fund for antibiotic development implemented with the UK government taking a significant financial lead. We also want to see the charity sector playing a much bigger role in tackling antibiotic resistance at a national and international level.

Dr. Chris Watkins, Translational Research & Industry at the MRC (Medical Research Centre) The UK has undoubtedly benefitted from having a UK Life Sciences Strategy, demonstrating nationally and internationally the significance of the life sciences sector to the British economy – and the government’s commitment to it. It’s the only sector to have its own industry strategy. The UK is a global leader in life sciences research and long-term investment in infrastructure and skills is vital to maintain this position. Collaborative investments are driving the research agenda. The UK Dementias Platform, for example, brings together existing resources, capabilities and expertise to help crack one of the major health challenges of the 21st century.

James Christie, ABPI (Association of the British Pharmaceutical Industry) The MMIP (Medicines Manufacturing Industry Partnership) has been established to bring the UK’s medicines manufacturing industry together to create an attractive and innovation-rich environment to drive UK competitiveness, and build international recognition, in medicines manufacturing. The UK’s medicines industry is one of our leading manufacturing sectors, with exports worth £24bn and generating a trade surplus of £5bn in 2013. We want to ensure that the UK continues to be an attractive place for this high-value industry. The MMIP, which is supported by the ABPI, BIA (BioIndustry Association) and the KTN (Knowledge Transfer Network), wishes to reemphasise the need for science and skills funding not only in R&D but also in the area of manufacturing technology and manufacturing skills.

Steve May-Russell, Smallfry Regardless of who’s running the country, the facts remain — we will see further cutbacks for the NHS and social services, further pressure on hospitals and a significant increase in people being cared for at home. Before we all rush off to be really clever, we should stop being stupid. There are plenty of opportunities to get more from less, particularly if we aim to make the most of new technology and its prolific rate of development. However, in order to be truly innovative, something drastic needs to be done to get trusts to collaborate and share best practice. Stop solving the same problems in multiple ways and figure out how to share the learnings better.

Gareth Davies, UDG Healthcare plc Gregory Stoloff, SEEK We are seeing that with the advent of personal devices that can measure and record health status, and with the search capacity available as a result of the internet, people will want to be able to access safe, effective and affordable medicines to treat basic conditions themselves rather than going to doctors and specialists. The government needs to encourage and assist drug developers to improve and enhance existing medicines, and to use these in new indications to satisfy this demand in a timely and cost efficient way. This will not only reduce the pressures but also have significant cost saving consequences for the NHS.

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This is a very exciting time for the healthcare industry. Innovations have led to new drugs being developed and there has been a significant increase in product approvals. It is important to communicate the benefits of these drugs to ensure high patient adherence. We know that educating and helping patients understand how these drugs work can lead to significantly higher adherence. Today, patients are looking increasingly to social media for information. The UK, and companies like UDG Healthcare plc, are leading the way in developing innovative solutions to help communicate to patients to achieve this. The government has been very supportive of the industry and we hope the next five years will build on this success.

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REGULATORY AFFAIRS

Picking a clinical solutions partner Dr Siddharth Chachad selects the criteria when choosing a clinical research organisation (CRO)

I

n the process of drug development a difficult task is to ensure appropriate clinical development. Choosing the right CRO partner for your clinical project can seem stressful.

CROs catering to clinical and preclinical development services range from large, multinational organisations to small and medium-sized companies with specialised services.

Identifying the right CRO considering several factors:

5. Time – you may have a great CRO with the right resources, infrastructure and experience in a particular type of preclinical or clinical project. But if they do not have a time slot that can match your project Gantt chart for regulatory submission, all is in vain.

6. Cost – Although most multinational innovator companies don’t mind beefing up their submission dossiers with multiple clinical studies, including unnecessary ones, you may want to work smarter by waiving extraneous preclinical and clinical

requirements while keeping the regulators happy. Work with a medium-sized, experienced CRO rather than a CRO giant and discuss the minimum required clinical development programme with regulators in a scientific advice forum.

requires

1. Intended service and its regulatory implication – clinical CROs may claim they conduct multinational trials but is this investment necessary? Except for certain countries, where local study sites are mandatory, major markets such as the EU and US accept foreign sites that offer significant cost benefit. So if the CRO knows how to conduct clinical operations but not regulations behind the clinical registration strategy, this CRO may not be a good choice. While most CROs have operations capabilities, few have a clear understanding of nonclinical requirements. This is crucial since worldwide, different regulators have different preclinical requirements.

Eg, while toxicity studies may be good enough for registration of some drug products in semi-regulated markets such as India; advanced regulated markets such as EMA or FDA have much more complex non-clinical requirements, such as pharmacokinetic studies, pharmacodynamic studies or even tissue distribution studies. Also keep in mind the type of drug product (pharmaceutical product, device, biologic or vaccine) since preclinical programme may vary.

2. Capability and past experience – investigate the expertise of the CRO for the conduct of a particular study. A CRO may have experience of clinical development for ASEAN submission but this does not mean it would be the best option for a study meant for marketing authorisation in the EU region.

3. Financial stability – ensure that the CRO partner can withstand business downturns while providing required attention to your project.

4. Infrastructure – good facility infrastructure and a qualified and welltrained team with independent quality assurance are important for any clinical project. The CRO may have conducted bioequivalence studies in healthy volunteers for FDA and EMA submissions but may not have the facility infrastructure to run complex biostudies in special populations such as cancer patients.

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11

OPINION

Cutting edge Reinhold van Ackeren, Mettler-Toledo PCE discusses driving innovation in the pharmaceutical sector

Trend setter: Reinhold van Ackeren, Mettler-Toledo PCE says innovative technology solutions are available now to help pharmaceutical manufacturers to meet current trends

W

hether talking about the development of supply chain traceability or the implementation of stringent regulations, the pharmaceutical industry has long been at the leading edge.

Companies are increasingly seeking innovative ways to standardise both their own production processes internationally and those of their contract manufacturers to uphold quality while at the same time optimising line efficiency. Advanced data monitoring technologies are increasingly being used to achieve this in combination with enterprise resource planning (ERP) software. These technologies are helping to boost transparency in the value and supply chain, ensuring consistent product quality and limiting unofficial “grey market� activities, while also cutting operating costs to keep up with competitors.

At the same time, there has been growing concern among lawmakers and manufacturers alike about product counterfeiting and its effect on consumer safety and brand reputation. This has led to calls for improved product traceability throughout the pharmaceutical supply chain to prevent false or counterfeit medicines reaching end consumers and to minimise the risk of product recalls or mix-ups.

New legislation, such as the European Union (EU) Directive on Falsified Medicines or the US’ newly introduced Drug Supply Chain Security Act (DSCSA), has been created to enforce this. Under the DSCSA, for example, companies will have to introduce serialization at package level by 2017, as well as ensure comprehensive reporting of the history of the batch both from their own lines and those of their contract manufacturers.

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There are innovative technology solutions available now to help pharmaceutical manufacturers to meet these trends. Manufacturers can make use of cutting-edge serialization systems, that not only provide comprehensive product traceability, but also offer advanced network connectivity to enable both track-and-trace data and production status information from all global operations to be stored in a single location. Such technology will help manufacturers comply with the strictest regulatory requirements, uphold brand integrity, plus it can also standardise their global operations to maximise efficiency, reduce bottom-line costs and protect profit margins.

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Mitsubishi Electric’s range of SCARA, articulated-arm robots and controller components fulfilled MAQUET’s Perfusion Systems division requirements exactly, especially as all the Mitsubishi Electric robot arms are clean room ready and can, therefore, (almost) be used straight out of the box.

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OPINION

Time zone MHRA guidelines on trial master files – where are we one year later?

Asks Jennifer Goldsmith, Veeva Systems

I

globally. Lacking any significant form of configurable n April 2014, the UK’s Medicines and Healthcare security, these systems made all trial documentation Products Regulatory Agency (MHRA) updated its visible without restriction, forcing sponsors to create definition of a critical GCP inspection finding to mirror files containing just the relevant documents for include trial master files (TMFs) that were “not readily Annual pass: Jen Goldsmith, Veeva, asks where are we inspectors. Even with this mirroring, inspectors often still available or accessible.” The Agency asserted that this with MHRA guidelines on trial had to wade through unrelated trial data. change was partly driven by the fact that more than onemaster files a year later third of TMF inspections are delayed due to incomplete or inaccessible files. In response, the global life sciences The next evolution industry heightened its focus on managing TMF content compliantly as part of a larger movement away from paper to fully electronic trial To improve the inspection process, sponsors and CROs have begun master files (eTMFs). This drive is bolstered by the increased use of moving to purpose-built, cloud eTMF solutions. In fact, five of the service providers such as contract research organizations (CROs) to world’s largest drug makers and half of the leading CROs now rely on next-generation systems to meet four key requirements: support the clinical development process.

Although the motivation driving the move towards eTMFs was undisputable, the technology landscape at the time this transition began was not structured to support increased regulatory and changing business models. Since then, some technology providers have addressed these challenges by evolving the eTMF from a static, end-of-lifecycle archive repository into an active, in-process, accessible solution. A year after the MHRA update, the industry is starting to make progress. More and more sponsor organizations and CROs are leveraging purposebuilt eTMF applications to increase the scope and functionality of their TMFs, providing unfettered accessibility and inspection readiness while improving the overall efficiency of clinical operations.

Twelve months of transition While companies start to make the move to next-generation eTMF solutions, variances in the design and sophistication of early systems help explain the MHRA’s assertion that many TMFs failed to meet inspectors’ expectations for accessibility and completeness, when Veeva Systems surveyed more than 250 TMF owners in 2014 in the largest eTMF survey to date, over half of the organizations reported working with either local file-share systems (26%) or cloud file share such as an FTP site or Dropbox.com (18%). More than one-third of respondents reported using generic content management systems such as EMC Documentum or Microsoft SharePoint to store and share clinical trial documents, whereas only 13% had implemented life sciences-specific eTMFs. Sponsors that replaced paper TMF files with such local network file shares did not foresee the resulting reporting and quality-control challenges. For example, one of the biggest challenges is that these systems often served as a company’s central repository for all clinical trial documents and data

1. Continual inspection readiness and unlimited accessibility.

2. Comprehensive trial documentation, with no incomplete or missing documents.

3. Easy navigation with intuitive user interfaces.

4. Rich insight to improve operational efficiency.

Specifically for the global life sciences industry, the updated MHRA definition meant next-generation eTMF systems became a business must-have practically overnight. Nigel Jones, vice president of global clinical development at TFS, a global full-service CRO headquartered in the UK, believes the simplicity and accessibility of cloud-based eTMF systems have become a prerequisite for doing business with global drug makers. “The vast majority of proposals CROs submit today include some form of modern eTMF support,” he said.

Unexpected advantages Many first-generation eTMFs were built around functionally simplistic “electronic filing cabinets” that retained paper-based processes, such as printing and scanning documents. But sponsors, CROs, and inspectors found these early systems did not deliver the benefits of truly paperless TMFs. “The entire trial process is rapidly moving away from paper,” Jones observed. “Today the majority of clinical trials are done with electronic data capture to save the data-entry step and enable the collection of important trial performance data.”

To support the paperless model, next-generation eTMF systems offer electronic processes for information sharing and storage. Individuals no longer send paper to central records management teams. Rather, the responsibility for filing documents into the eTMF is distributed across the clinical ecosystem, making it critical to assign and communicate

continued overleaf >

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OPINION ownership of TMF documents. When all parties have defined roles in the study SOPs, sending files electronically and ensuring task completion are quick and efficient.

Renee Fate is a senior manager responsible for document management at Kythera Biopharmaceuticals, a clinical-stage biopharmaceutical company that develops therapies for the aesthetic medicine market.

Fate said that Kythera’s new eTMF system provided the rapidly growing company with a single platform on which to collaborate with partners efficiently and ensure inspection readiness at all times. “Since adopting a cloud eTMF, we’ve been able to shave at least 40% off the time needed to reconcile TMF documents at the conclusion of a trial. Now we have full visibility and can track the status of the TMF in real-time for the duration of the study.”

Even before the MHRA issued its guidance to simplify eTMF navigation, one of the biggest challenges that sponsors and CROs faced when implementing eTMFs was getting people to use them.

Typically, eTMF and content management systems proved overly complex and cumbersome to navigate. Over the last year, more sponsors have started implementing improved eTMF systems with simplified operations to satisfy inspectors’ ease-of-use requirements.

Technology providers are adopting best practices from consumer e-commerce, developing familiar, Amazon-style user interfaces that allow all parties – including regulators – to share, review, and access trial documents without extensive training or understanding of the system architecture.

Some forward-thinking organizations are already unlocking the benefits of TMF metrics. In the Veeva 2014 eTMF survey, the companies that

reported extensive use of performance data saw markedly more benefits from their eTMF systems than those that did not collect metrics. For example, these organizations noted improved document quality (63% versus 29%), greater audit and inspection readiness (56% versus 25%), easier collaboration with sites (54% versus 32%), and increased SOP compliance (49% versus 16%).

Kythera’s eTMF solution allows the internal auditor to regularly run a full range of standard and ad hoc reports, giving a more accurate view of trial progress. According to Fate, “when everyone has visibility into the reports, it removes a lot of questions at team meetings and on the phone with our CRO. We are all spending less time meeting and more time working.”

Automated filing and accessible data-sharing systems mean that internal auditors have the opportunity to redefine their roles and do more with less. Cloud eTMF solutions allow auditors to manage the quality of TMFs remotely and in real-time, ensuring compliance without the need to visit multiple sites and spend weeks at a time on the road.

Driving life sciences Sponsors, CROs, and health authority inspectors all have similar goals: to be able to access the TMF easily, whenever and from wherever they are. Cloud technology provides this type of ubiquitous access, but when also linked innately to clinical processes, the TMF becomes more than just an electronic record. Fully unlocked, next-generation eTMF solutions can be strategic assets that not only dramatically improve the inspection process, but also offer sponsors the type of insight within and across trials that drives long-term improvement for clinical programs.

Percent rating improvements in inspection area as good or major after implementing an eTMF Benefits attributed to am eTMF system

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COVER STORY

Perfect fit Schott Pharmaceutical Packaging and GEA on boosting lyophilisation efficiency

L

yophilisation vials are normally washed and sterilised prior to processing and filling, which requires the use of cleanrooms, washing machines and sterilisation tunnels — depending on the level of containment needed — to perform these tasks.

However, to improve efficiency and to reduce both time and costs, prewashed and sterilised ready-to-use packaging materials may offer a solution and improve the overall process.

Owing to newly developed products, increasingly smaller batches, more highly potent products and the need for flexible and efficient vial and syringe filling solutions, there are constant demands by the pharmaceutical and biotechnology industry to make the freeze drying process faster, safer and more cost-effective, particularly during changeovers.

One such product, which has been developed by Schott, is the adaptiQ nested vial system. It can be used with existing nest filling systems and allows pharmaceutical companies to freeze dry and handle filled vials inside the nest. In collaboration with GEA, the system has been tested to ascertain its suitability for the freeze drying process in both a standard pilot plant and a production-scale lyophiliser, specifically to assess its handling capabilities with a standard loading and unloading system.

Johannes Selch, product manager, automatic loading and unloading systems (ALUS) at GEA, discussed the results. “Our focus, together with Schott, was to find out how the nested vial product influences the freeze drying process, particularly in terms of handling (loading and unloading), in a production environment. The obvious advantage is that there’s no need to use a washing machine or a sterile tunnel in front of the filling line. The vials are supplied clean, sterile and ready to use in a sealed, nest/tub configuration. The user can then bring the nest/tub into their containment area — be it an open/closed RABS system or an isolator — where it can be manually or automatically opened.”

In essence, all process steps can take place within the nest, and there’s no glass-to-glass contact. Container production, depyrogenation and

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washing are done prior to nesting after which the package is sterilised by gaseous ethylene oxide. For in-process-control and crimping, the vials have to be removed from the nest and reinserted for further processing.

He added: “Normally when you operate a freeze drying process, the user has to wash and sterilise the vial frames or trays. And, after the process, the washing/sterilisation step has to be repeated. With nested vials, this is no longer the case; it’s a single-use, disposable technology and the post-lyophilisation washing step is not required.”

Configuration and structure of the nest The nest uses a rigid honeycomb structure that provides both stability and separates the individual vials from each other. Each vial is resting on three clips that vertically support it by the collar. The bottom of the vials is easily accessible, which allows the vials to remain nested during most of the processing steps (including lyophilisation). If the vial has to be removed (e.g. for traditional crimping) it can pushed out of the nest from below for de-nesting. Using the same principle, the vials can be re-inserted (renested) by placing them on a piston that spreads the clips from below and receives the vial to be securely lowered back into the nest.

Thanks to this design, the vials are unable to come into contact with one another, a feature which prevents scratches and breakage, consequently lowering the reject rate. The nests also have walls for freeze dryer handling, finger cut-outs for manual removal and an alignment guide for precise positioning. Individual nests can be linked together and a wide variety of sizes are available, from 2/4R (100 vials) and 6/8/10/15R (48 vials) to 20/25/30R (25 vials) in an industry standard tub format.

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Under Test Conditions Selch explained: “Having tested the nested vials using a standard tray loading system, they performed perfectly well, irrespective of whether the nests were fixed together or left unattached. Unloading using a standard system was also problem-free.”

He added that the interconnectivity most likely plays a greater role in manual handling, but, for automated systems, the nests can be used as individual units. “In development and when processing very expensive product in small batches, the connectivity would also be an advantage, as it facilitates manual loading and unloading. Key advantages here are simplified and stable loading/unloading, and less downtime as a result of higher loading/unloading speeds.”

Capacity Restriction

Processing Tests

On the topic of capacity, Selch said: “We have calculated how many vials can be processed, with and without nesting, using a standard loading/unloading procedure without frames or trays. Using a freeze dryer with standard shelf dimensions, a process capacity reduction of up to 40% was recorded using nested vials compared with nonnested ones.

In a comparative drying test at pilot-plant scale, a 3% mannitol solution was processed in a standard freeze dryer. Nested and non-nested (hexagonal format) vials were used. The test showed that placing the vials in nests resulted in a 10% faster drying cycle. It could be concluded that the surrounding plastic had no detrimental insulating effect, and that the less dense arrangement of the vials in the nest lead to a positive influence on the total drying time.

“We can process 200–300 nested vials a minute to improve the overall efficiency (100 vials/nest means 2–3 nests per minute), but the 40% capacity loss is significant. To fully utilise nested vials and to compensate for this loss in the future, it will be necessary to address the issue at the design stage and produce tailor made freeze dryers.”

It is presumed that nested vials will, initially, be used to process very expensive products. The real benefit comes for high value or highly potent compounds.

Scaling up to a production-level freeze dryer, a comparable test was done with 3% mannitol, with a similar result obtained.

In addition, stoppering was also examined and the result was nearly identical for both sets of vials. Fixing the vials in the nest prevented the stoppers from sticking to the freeze dryer shelves, and no nested vials fell over during the procedure.

When looking at residual moisture values, it was noted that the nested vial results were slightly better than the non-nested vials at the edges of the containers. The additional space between the vials enhances the sublimation flow and reduces the total level of residual moisture.

“

Our focus, together with Schott, was to find out how the nested vial product influences the freeze drying process, particularly in terms of handling (loading and unloading), in a production environment

”

Schott adaptiQ vials allow nested freeze drying and the nests can be used in existing automatic loading and unloading systems. The nestand-tub configuration, as used for pre-fillable syringes, offers a lower packaging density that allows for equivalent or faster drying cycles.

The higher price for ready-to-fill sterile vials compared with conventional vials will be more than compensated at a total cost of ownership (TCO) level. Investment, energy use and utility consumption can all be reduced by eliminating washing machines, water for injection (WFI) systems and sterilisation tunnels. And, despite Big Pharma being a very conservative industry, there are clear applications for this technology in both R&D and full-scale production. A system is already in operation, at start-up phase, in Asia. Comprising a GEA freeze dryer with a back-pusher unloading system, full-scale production is expected to commence in 2015.

Conclusion It is unlikely that nested vials will replace non-nested ones in standard freeze drying and vial handling production cycles. However, this innovative development does open up new possibilities for future production. Nested vial handling can easily be implemented into existing and proven lyophilisation equipment and, as such, both the nests and the technology are “ready to use.”

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MERGERS & ACQUISITIONS

Pole position

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Patheon explains the importance of mergers and acquisitions as the company strengthens its position in the sector

Mergers and acquisitions are an important component of Patheon’s strategy

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We have posted organic and inorganic growth, thanks in part to successful M&A transactions

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nder the leadership of CEO James Mullen, Patheon has transformed into a leading global provider of high-quality drug development and delivery solutions to the pharmaceuticals and biopharma sectors. This transformation was based on a four-pronged business strategy: strengthen the core operations, sell the business differently, enter logical adjacencies and drive industry consolidation.

Mergers and acquisitions are an important component of Patheon’s strategy to bolster our leadership position. During the transformation we have posted both organic and inorganic growth, thanks in part to five successful M&A transactions, all aimed at helping us expand our strategic capabilities around the globe to address growing customer needs.

While assessing strategy and developing long-term objectives in 2014, Patheon’s active pharmaceutical ingredient (API) business team learned that many small to mid-size pharma companies are based in the US and prefer to have development work (Clinical Phase I-III) completed geographically closer to home. This led to the company’s most recent acquisition – in March 2015 - of Florence, SC-based IRIX Pharmaceuticals, a recognised leader in API development and manufacturing services for drugs in all phases of pharmaceutical development and commercialization. IRIX provides North American API process development and manufacturing services, helping to address customers’ interests with manufacturing capabilities closer to their operations.

The IRIX acquisition, based on our business strategy of entering logical adjacencies, supports Patheon’s effort to deliver an integrated solution to customers of all sizes. The deal supports Patheon OneSource integrated offering, and together the companies boast an array of cutting edge technologies, regulatory support and API sourcing services that address a broad range of supply chain issues for customers.

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Having brought five companies into the Patheon network in a short timeframe, the company has developed a robust and structured formula that allows for seamless transition among employees, customers and suppliers. Integrations are led by experienced teams that place strong emphasis on employee communications, transparency and alignment with the company’s unified global culture. Patheon’s global culture has five key aspects: 1) provide industry-leading customer experience; 2) be the highest quality, most efficient and flexible provider; 3) deliver the best technical and scientific solutions to enhance product value; 4) create a culture of engagement, accountability and a commitment to excellence in all that we do; and 5) operate our business in a compliant, safe, disciplined, responsible and ethical fashion.

This hands-on approach to culture has been well-received and adopted

by Patheon’s more than 8,000 global employees, a large number of whom came to the company through our M&A activity.

Patheon is focused on changing how development and manufacturing services are delivered to pharmaceutical companies, creating exceptional value for customers while also enhancing the company’s leadership position in the CDMO industry. Throughout the Patheon organization, there is a remarkable focus on providing value to customers, who increasingly demand simplified supply chains and a wider range of services.

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Joining forces Mergers & acquisitions – it’s all about collaboration, says Mike Straw, Achieve Breakthrough. He argues that deals are all about people as well as the numbers – and it’s the collaboration that will make a deal truly work

T

he amount of M&A and deal activity in the pharmaceutical and biotech sectors in recent months has been remarkable: more than $460bn of deals since the beginning of 2014, the highest amount in such a timeframe on record.

This is partly being driven by the fierce competition in the industry, the simple need to get ahead. So pharmas are looking to buy in R&D if they can’t do something in-house.

It is also, perhaps, being driven by today’s ‘cheap money’ environment.

This recently led Sir Andrew Witty, CEO of GSK, to query the wisdom of some deals. Speaking to the FT, he questioned “stretched” valuations and wondered whether some “poor choices” were being made.

Regardless of the wisdom or otherwise of some of the deals that are being hatched, the fact is that they are happening – and so the pressure to make them work will be all the greater.

But how can companies maximise the chances of their deal delivering all that it promises?

As with so many things in life, I believe that it all comes down to people.

Doing the DD Of course, no one goes into a deal lightly. Extensive due diligence will be performed, the financials will be scrutinised, balance sheets analysed, forecasts of efficiencies and synergies will be made. Promises will be made to the City, and these will then have to be met.

But what will really make the difference as to whether the deal will work and targets will be reached is not the cold numbers, but the people involved.

Bringing together two organisations, whether an acquisition or a merger or a JV, means that you are instantly setting up a complex people dynamic that needs very careful and skilful handling.

The aim of course in any deal is to increase value. You are looking for 1 + 1 to equal at least 3, hopefully more. The last thing you want is for value to be lost so that 1 + 1 equals 1.5.

The reason why, in some deals, value is lost is because all too often you have the scenario of one company or culture taking over, consuming, the other. One organisation wins and the other loses. But the reason for the deal in the first place was surely that both organisations were successful and winning. The last thing you want to do is remove the magic of winning from one side.

The denial trap A frequent danger is that you end up with what we call the ‘denial trap’.

The acquirer calls the deal an ‘acquisition’ while the acquired calls it a ‘merger’. They are coming at it from different perspectives, separately, and don’t have any kind of shared vision.

The paradigm for the deal becomes about ‘power and control’ – all driven by the need to create efficiencies in order to meet the targets that have been communicated to the City. And so, for the people involved, the mindset becomes not ‘how do we all do things better?’ but quite simply ‘how do I survive?’

People fear for their futures and focus on short term wins. There is no real sense of being part of a new and stronger whole.

Collaboration to make it come alive In my experience, the key to the most successful deals is collaboration.

This means both sides standing in each other’s shoes, seeing the other’s perspective. It means creating an environment where people can innovate, create and get the best out of each other.

Too often when deals happen the focus is simply on cooperation or coordination. But that is quite different from collaboration. Cooperation and coordination are about working with what you’ve already got, making things work operationally. But collaboration is about getting the best from yourselves so that you can increase what you have, reach new levels of output and productivity.

There are some great examples of collaboration and the innovation it can drive. Think of Apple and its network for example.

It’s much harder to do than it sounds. It requires management at every level to be fully bought in and in some cases upskilled to create the environment to allow it to happen.

But if pharmas doing deals can create that forum for collaboration they may just find that, like a great reaction in a petri dish, something remarkable happens in front of them and they can achieve and exceed the goals they were hoping for.

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FREEZE DRYING

Smart Thinking Using SMART freeze drying technology to understand the impact of controlled nucleation temperature on product resistance, by SP Scientific

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Because of the high resistance, primary freeze drying is relatively slow

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T

he ability to control nucleation in freeze drying is now possible by using ControLyo Nucleation on Demand Technology originally developed by Praxair1. Figure 1 shows the impact of controlled nucleation on the primary drying phase of freeze drying. A high degree of super-cooling leads to small ice crystals, which in turn results in product morphology of small pores during and after sublimation. These small pores create a high resistance (Rp) to mass flow (water vapor leaving product via sublimation).

Because of the high resistance, primary freeze drying is relatively slow2,3. When nucleation is forced at higher temperatures, larger ice crystals are formed, which result in larger pore structure. This morphology of larger pores allows for lower resistance to mass flow and faster primary drying time.

Figure 1. Illustration of the effect of the degree of supercooling

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In the first series of experiments, the impact of nucleation temperature on product resistance was explored using a 5% sucrose solution.

In two cycles, nucleation was not controlled and SMART cycles were run. Subsequently, we nucleated the same solution at -2°C, -3°C and -5°C and SMART was utilized to determine and complete the cycles.

Figure 2 shows product resistance (Rp) plotted against dry layer thickness (Ldry - also calculated by SMART) for each of the experimental runs.

Two points are worth noting in the graph: 1. The reproducibility of the data as evidenced by the overlap of the two separate runs nucleated at -3°C. 2. The ability to discern differences in resistance with only a 1°C change in nucleation temperature.

Figure 2. Product resistance vs dry layer thickness

As mentioned above, product resistance is one of the most important critical product parameters in freeze drying4. Cake shrinkage, collapse and cracking, even subtle changes in the cake inner morphology (micro-collapse) can be examined by the product resistance data5.

The complementary use of product interface temperature (Tp-mtm) and product resistance (Rp) provides a direct link between temperature during primary drying and product quality. This is clearly illustrated in the example in Figure 36.

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Once the pressure control was regained, the product temperature decreased to below the collapse temperature

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Figure 3. Illustration of relationship between product resistance measurement and cake morphology. Courtesy of Dr. Henning Gieseler, GiLyos

References: 1. Sever, R.R., (2010). ControLyo Nucleation On-Demand Technology. SP Scientific Lyolearn Webinar. http://www.spscientific.com/LyoTech-Center/LyoLearn-WebinarsArchive.aspx 2. Pikal, M. (2011). Quality by Design and Scale-Up Issues in Freeze Drying: The role of controlled ice nucleation. SP Scientific Lyolearn Webinar. http://www.spscientific. com/LyoTech-Center/LyoLearn-Webinars-Archive.aspx 3. Searls, J.A., Carpenter, T., Randolph, T.W. (2001). The Ice Nucleation Temperature Determines the Primary Drying Rate of Lyophilization for Samples Frozen on a Temperature Controlled Shelf. J. Pharm. Sci., 90:860-871.

4. Gieseler, M. (2011). The Relevance of Product Resistance on Primary Drying. SP Scientific Technical Briefs. http://www.spscientific.com/Lyotech-Center/Lyolearn-TechBrief.aspx 5. Gieseler, H., Kramer, T., and Pikal, M.J. (2007). Use of Manometric Temperature Measurement (MTM) and SMART Freeze Dryer Technology for the development of an optimized Freeze-Drying cycle. J. Pharm. Sci., 96:3402-3418.

6. Gieseler, H. (2011). Unpublished Results.

In this example, three (3) separate runs were performed in the Lyostar 3 freeze dryer, without controlling nucleation. At the end of the runs, Rp was plotted against Ldry. The run with the green triangles ( ) and the run with the open blue squares ( ) are classic resistance plots that one would expect to see. The run with the open red circles ( ) reveals an anomaly that occurs about half way through the primary drying.

The resistance of the product drops significantly for a short time period and then continues its normal course, similar to the others. During this short time interval, the pressure in the chamber increased. As a result, product temperature at the ice-sublimation interface increased, as well, and resulted in structural loss (collapse) in this particular region of the cake. Once the pressure control was regained, the product temperature decreased to below the collapse temperature and the cycle was completed. When the freeze dried cake was examined, the increase in temperature and subsequent collapse that occurred during the pressure loss can be seen as a layer of decreased structural integrity in the cake.

This example offers opportunity to use product resistance as a process analytical technology (PAT) tool to perform “In-Process” analytical analysis. If Rp vs. Ldry was reported and visible in real time, the anomaly that occurred would have been seen during the run, and would have predicted that the cake would likely have morphological anomalies.

Credit: Mark Shon

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FREEZE DRYING Small wonder: One of the advantages of microparticles freeze drying is that they are porous and have good solubility

Freeze frame Robert Bullich, Telstar, discusses the generation and freeze drying of microparticles

F

reeze drying (Lyophilization) is a drying process whereby a product solution is first frozen and subsequently dried by solvent sublimation in primary drying and by desorption in secondary drying. Sublimation is the change of phase of the solvent from solid to gas without passing through an intermediate liquid phase.

In freeze drying applications, product is typically dosed in containers, vials or ampoules or in trays for bulk production. Conventionally, the product undergoes initial freezing inside the freeze dryer with product loaded onto a series of shelves inside a vacuum chamber. A heat transfer circuit cools down the shelves, freezes the product and removes the freezing latent heat. The same circuit can provide energy to the product to promote sublimation during primary drying and desorption during secondary drying.

Limitations of conventional FD Freezing is a non-homogenous process. Product in containers freezes at different temperatures and at different points in time; the result is a crystalline structure which differs from one container to the next.

During sublimation heat must be transferred through the ice and littleby-little the solvent is sublimated.

Generating and drying microparticles avoids these problems and provides frozen product as microspheres that have been generated by a homogenous process. Microparticles have an enormous surface area compared to the block of ice present in conventional FD. When heat is transferred to the microspheres, sublimation takes place over the entire surface and thereby sublimation speed is increased.

Cryogenic generation of microparticles Microparticles can be generated using various methods: Spraying into liquid nitrogen: The microparticles are formed by atomization of an aqueous feed solution containing the API beneath the surface of a cryogenic liquid (eg, liquid nitrogen). The aqueous solution is sprayed directly into liquid nitrogen through a capillary nozzle under high pressure to form frozen microparticles.

Dual-fluid nozzle: Product is atomized via a dual-fluid nozzle in a chamber. Atomizing N2 gas and liquid are pressure-driven to the nozzle assembly. Liquid is fed to the nozzle cap and external atomization is achieved by the exiting N2 gas. Liquid droplets are frozen with liquid N2 that is sprayed by pressure through nozzles.

Ultrasonic nozzle: The spray freezing is performed by atomization of liquid solution into a separation funnel filled with liquid nitrogen using an ultrasonic nozzle.

Spraying into a cooling gas stream: Frozen microspheres are generated by dispersing the substrate liquid using high precision nozzles into single droplets, which by gravity pass through a cooling zone with a current of N2 gas at low temperature, producing frozen particles.

Vacuum freezing: Liquid solution is sprayed as droplets into the top of a column under vacuum. As water evaporates from the particles the latent heat is removed and the droplets freezes to form particles.

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Freeze drying process

Challenges

After generation, frozen microparticles can be loaded into a freeze dryer in appropriate containers; vials or trays. Water is sublimated in the primary drying and desorbed in secondary drying as in conventional freeze drying processes.

One problem is to increase the sublimation rate as much as possible while minimizing product loss. At high sublimation rate sublimating vapor exits the particle surface at high velocity in all directions, resulting in particle floatation. As a consequence of this mechanism, microparticles can be transported from the drying chamber to the condenser, where they are readily retained in the ice surface and lost upon defrosting.

Freeze drying conditions can be more aggressive than in the conventional process; due to the enormous surface area of the particles the sublimation rate is much higher and the duration of the drying process is substantially reduced. The reduction in drying time depends on the product, its concentration and particle size.

Advantages of microparticle freeze drying The main advantages of this process compared to the conventional process are:

To properly control the microparticle size is another challenge.

Size depends on the nozzle diameter and the spray pressure. The various generation methods affect the size and uniformity.

Particle generation and freeze drying must be carried out under sterile conditions for aseptic parenteral products. All fluids and components of the system must be clean and sterile and sterility must be maintained during the process and during unloading of the dry product.

In all cases containment will be required to eliminate the risk of aerosols causing environmental contamination.

• Microparticles are frozen in an ultra-rapid process; • Particles are spherical with a uniform size distribution; • Droplets are frozen instantaneously into a homogeneously structure so there is no dispersion of concentrations. Crystal structure is homogenous from particle to particle. In conventional freeze drying the product undergoes concentration of components and the resulting dry product is not homogenous; • Microparticles are dried very rapidly because the high surface area and cycle duration is consequently reduced; • The dried product is in a convenient powder form and it doesn’t require a crushing process in order to be readily manipulated;

Conclusions Microparticles have new and exciting properties and lend themselves to a broad range of process applications. In the shorter term the main opportunities are in non-sterile production: tablets, APIs, ingredients for inhalation, etc. Outside of medical products, there are also applications for food and general fine powder materials.

• Microparticles are porous and have good solubility.

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FORMULATION

In the mix Dr Julien Meissonnier, Pharmaceutical Softgel Europe, Catalent looks at lipid-based formulations to increase the bioavailability of poorly soluble drugs

Solutions solutions: Poor solubility remains an ongoing challenge in formulation development says Dr Julien Meissonnier

P

oor solubility remains an ongoing challenge in formulation development. The number of poorly soluble compounds is estimated to be 40% of molecules on the market, however, more than 70% of drugs in development are classified as poorly soluble.1,2 There are a number of existing technologies and approaches available to overcome this challenge, as well as several emerging solutions.

One of the most established approaches is to create a crystalline formulation of the drug, however, the size of a drug particle is critical to its bioavailability. Particle size engineering, and increasing surface area by creating micro-crystals and nano-crystals using techniques such as jet or ball milling crystalline drugs along with a surfactant, is one method used to increase solubility, and therefore bioavailability.

Crystalline drugs that are poorly soluble in water may dissolve in lipids.

Adding emulsifiers creates a semi-solid oil or paste that then selfemulsifies into a micro-emulsion or nano-emulsion when taken orally (self-emulsifying drug delivery systems or SEDDS). These formulations can be readily made into softgels or capsules, which have numerous patient experience benefits, as well as formulation benefits of ensuring dose uniformity and offering an established scale-up route.

A successful lipid formulation must first resist its dispersion in the gastrointestinal (GI) fluids by maintaining the drug in solution. Upon dispersion, the formulation could be present in different states, ranging from coarse emulsions to thermodynamically stable microemulsions, which present different features. After the lipid components of the formulation are subjected to the action of enzymes, which act specifically at the oil/water interface, the lipids undergo de-esterification into fatty acids and partial glycerides. Upon digestion, it is important to ensure that the poorly soluble drug remains in solution form before facing the enterocytes within the GI tract.

SEDDS and self-microemulsifying drug-delivery systems (SMEDDS) are categorised on an effective classification system for lipid-based formulations3 based upon their qualitative and quantitative composition.

Each of the four categories within the system exhibit different behaviours upon dispersion and digestion based upon their hydrophobichydrophilic excipient composition.

As with any formulation development project, once a lipid-based delivery approach has been selected, working towards a target product profile (TPP) defines the parameters which any drug candidate must meet. Formulation-specific analytical techniques must be developed and refined to enable access to a more complete and accurate dataset from as early as possible in the process.

Pre-formulation studies must be based upon the kinetic evaluation of drug solubility in various classes of ingredients, in parallel with chemical compatibility screens. Catalent operates proprietary in-vitro and in-

silico models, including a computerised database of digestion profiles, and also pseudo-ternary diagrams based upon its experience in lipidbased system development. This simulation and modelling approach minimises the amount of potentially valuable API that needs to be used, and improves the efficiency of formulation determination as well as predictability to progress in further clinical studies.

The excipient selection process is also based upon careful selection of the ingredients in light of their global approvability and existing safety status. A wide variety of lipid ingredients are generally recognised as safe and several studies are underway on novel functional lipids to broaden their existing safety data to increase the number of options open in formulation.

A notable success of applying SMEDDS to an existing therapy is with oral cyclosporine where a lipid-based formulation has revolutionised organ transplant therapies. After overcoming challenges in development, the microemulsion delivery is perfectly suited to enhancing exposure to the API, while resolving variability issues and food effects. Being thermodynamically stable by definition, SEDDS and SMEDDS are much less sensitive to change in physiological conditions such as food intake, bile salts, and pH, and are particularly suitable for drugs with narrow therapeutic windows. These requisites, however, do not apply to all TPPs where simpler, fast-to-develop lipid systems would be suitable.

There are many benefits of using lipid-based drug-delivery systems to assist in the delivery of poorly soluble drugs and bringing better treatments to the market, especially that the technology addresses both physiochemical and biological bioavailability barriers. Lipid-based formulations do not have the associated challenges of some of the current solubility enhancing technologies, which can lead to longer development timelines because of increased incompatibilities, complex scale-up, and clinical acceptability. Using a rational approach in preformulation operations with liquid systems not only enables accelerated predictability of drug/ingredient interactions but also, with the use of in-vitro and insilico development tools, assists in tailoring the optimum lipid formulation system and increasing predictability of in-vivo performance.

References: 1 Patel ND, Patel KV, Panchal LA, Shukla AK, Shelat PK. An emerging technique for poorly soluble drugs: self emulsifying drug delivery system. Int J Pharmaceut Biolog Arch. 2011;2(2) 621-629 2 Benet et al. Bulletin Technique Gattefosse. 2006;9:9-16.

3 C.W. Pouton et al., Eur J Pharm Sci 29 (3â&#x20AC;&#x201C;4) 278â&#x20AC;&#x201C;287 (2006)

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LOGISTICS

Moving story David Weatherby, business consultant, GS1 UK, looks at pharma logistics and distribution and discusses the challenge of transformational change The pharmaceutical supply chain faces significant challenges when it comes to distribution, transport and logistics. The need to put the patient back at the heart of the healthcare system and guarantee quality and safety of care, while achieving savings and efficiencies, will drive transformational changes for all players in the healthcare industry.

• Emergency orders due to poor inventory management

Manufacturers will need to focus on how to improve efficiency in their logistics operations and give certainty of authentication of the products entering the healthcare supply chain.

This can only be achieved by providing transparent and consistent product information through the use of global identification standards.

• Failure to consolidate many small orders into a few larger orders

Continuous pressure on costs is leading to stock reductions at every part of the supply chain from producers to wholesalers and distributors through to providers. To manage this successfully, while still providing the level of service required by patients, requires visibility of stock levels and clarity of orders and deliveries – any errors will incur emergency deliveries with associated additional costs.

At the same time, there is a wide choice of logistic and distribution methods available from 4PL, 3PLs and direct delivery. Different products are likely to require different approaches.

But the foundation remains the same. All this involves clear identification of products and the locations where they are stored. It also requires clear accurate detailed orders in machine form so that they can be processed directly by computer systems avoiding rekeying of information and the associated inevitable errors.

Sources of cost within the supply chain, which can be cut through the use of global industry standards, include: • Obsolescence due to out of date stock or bad management of new/replacement products • Invoice queries dues to discrepancies of price or between order quantity and delivery quantity, or possible replacement products

• Manual picking by suppliers and receiving and checking by pharmacies/providers • Rekeying of information taking staff time and introducing errors • Transcription errors for manual orders

What is needed?

• Unambiguous product identification via the Global Trade Identification Number (GTIN) of the GS1 system.

• Unique identification of suppliers, customers and delivery locations via the Global Location Number (GLN).

• Automated data capture through standards barcodes.

• The integration of Electronic Data Interchange (EDI) standards in the supply chain and its administrative operation to achieve greater efficiency to processes thanks to their automation and streamlining.

• Accurate price and other product information via catalogues.

• Category management - i.e. match the systems/processes to the type of product.

The technology required to boost pharma supply chain standardisation is available today.

The widespread adoption of global standards will have an incredibly positive impact on improving patient safety, reducing the scourge of counterfeit drugs and improving efficiency within industry.

According to the McKinsey report - Strength in unity: The promise of global standards in healthcare - implementing global standards across the entire healthcare supply chain could save 22-43,000 lives, avert 700,000 to 1.4 million patient disabilities and save $9-58 billion in healthcare costs on an annual basis.

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The impact of new regulations Compliance with local and Europe-wide regulatory system represents more challenges for the pharmaceutical industry. The Falsified Medicines Directive (FMD) is requiring standardised product identifiers and barcodes to prevent the entry of falsified medicines into the legal supply chain.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) have a vision of GS1 standards being used on pharmaceutical products in Europe and beyond to enable the look up of product details, as well as any national numbers as required.

In the US, the eventual requirement is to provide a complete chain of custody record, or ‘pedigree’, for each and every product in the healthcare supply chain.

In Europe, we are currently adopting a pointof-entry/point-of-exit system which does not trace individual items through each stage of distribution through the supply chain – only at the point of packaging/production (entry) and the point of dispensing (exit). However, Europe is insisting that all the pieces are in place if it decides to move towards a US style Pedigree system at some point in the future.

Locally, the NHS eProcurement strategy mandates the use of GS1 standards to uniquely identify at item and case level and the need to place master data about all products and services supplied to the NHS into a single national Product Information Management (PIM) system.

Considering all this regulations coming into effect, it is certain that in the next three to five years the UK healthcare industry must move forward to create a more secure, cost- effective and flexible supply chain. Industry standards are essential element in achieving this.

Photo caption: Money matters: Continuous pressure on costs is leading to stock reductions at every part of the supply chain, says David Weatherby

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WATER PURIFICATION

Water world Mark Bosley, Water Purification Systems UK, explains how purified water systems can support growing pharmaceutical firms

Clean bill: A correctly chosen water purification partner will be able to guide customers to the system that is good for the present and the future

Making a splash: Purified water is a key component in many pharmaceutical applications, says Mark Bosley, Water Purification Systems UK

E

ven the most global of pharmaceutical companies were once small, manufacturing from modest premises before increasing the size of operation as demand grew. These established manufacturers are still likely to implement upscaling processes when working on new products, using smallscale laboratory testing processes ahead of launch. From a ‘benchtop’ or laboratory operation, the speed and success at which a pharmaceutical enterprise transitions from a pre-production pilot plant to high volume production depends on a number of factors.

Purified water is a key component in many pharmaceutical applications – from drug formulations to rinsing glassware.

Considering specific applications within pharmaceutical development, such as cell culture, media preparation, DNA sequencing and genome research, the efficacy of purified water must be of the highest order.

So that these processes can be carried out effectively and be fully validated any water involved must be purified to approved standards, eliminating all types of contamination. Therefore, the output of a water purification system needs to grow at the same rate as the business.

When considering water purification, making the step up from low volume

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laboratory trials through to batch or full production should not be complex process but does require a clear understanding of the critical phases involved. The key consideration is that the final product remains unchanged while the same applies to the quality of purified water required to produce it and the verification procedures used to ensure compliance.

The initial step is to draft up a User Requirements Specification (URS) document. This specifies the requirements of the water purification system and should provide sufficient detail for a prospective water purification system provider to suggest a solution that will provide purified water of required quality, quantity and consistency.

The initial audit involves sending samples of the existing feedwater supply for detailed mineral and microbiological analysis. While the water supplier should supply relevant information, it is necessary to clarify this if water comes from a mains supply. If a surface water or borehole source is being used, a detailed evaluation of water characteristics is critical. The pre-treatment system can therefore be appraised and a specification drawn up.

If water conditions are changeable then the design of raw water treatment systems and the provision of pre-treatment will need to cover every eventuality.

The next step is to calculate the size of the water purification units. Working out the maximum demand and also establishing the volume required on a regular basis ensures that any immediate and forthcoming needs can be met while avoiding any subsequent costs that may be incurred by changing the design, which means revalidating the system.

How the pure water is drawn into the process also needs to be considered.

For example, if supplies are required at different manufacturing locations, a centralised system feeding a ring-main may be the better option, offering a space-saving solution that can deliver high volumes and at verified quality.

Providing the right capacity can also mean that storage has to be part of the solution.

Higher volume production operations typically use scaled up versions of the smaller water purification systems, perhaps supplemented by systems such as sand and multi-media filters for eliminating particulates; activated carbon adsorption systems for the removal of organic contaminants and chlorine compounds that can affect colour, taste and odour; cartridge filtration for pretreatment; and reverse osmosis for the removal of ionic contaminants. All of which must of course be fully validated to the appropriate standards.

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Ion exchange technology is commonly used to soften and deionise water, with UV irradiation and membrane filtration often being specified to maintain microbiological integrity. Reverse osmosis (RO) is one of the most commonly used technologies and incorporates specialised semi-permeable membranes through which pressurised feed water is passed to remove inorganic ions and dissolved organic contaminants.

It’s also important to consider what the equipment will be used for. Within the URS document, a section relating to ‘System Definition’ may include details on the preferred functionality and operating schedule. Once this has been taken into account, the operator will be in a good position to create a scaleddown model which will represent the resulting larger system.

In order to transition to a pharmaceutical manufacturer that is ready to roll out high volume products, it is advisable that the manufacturer partners with a water purification provider with a track record of developing, installing and supporting high quality technology, validated specifically for the pharmaceutical sector. A correctly chosen water purification partner will be able to guide customers to the system that is not just good for the present, but can handle the potential production capacity of the future.

BLOW FILL SEAL

Liquid asset Blow-Fill-Seal technology ensures the highest aseptic assurance level possible for liquid products, says Rommelag

B

ottelpack machines can perform the primary packaging for a variety of products including nebulized inhalation drugs, ophthalmic OTC products and drugs and small volume injectable products.

A current challenge today is to produce an aseptic liquid product with the highest aseptic assurance level possible. A primary package is the final step in an aseptic productâ&#x20AC;&#x2122;s manufacture. This final step provides the product with a hermetically sealed environment, shelf stability and protection from the outside environment.

critical area is relatively small compared with other advanced aseptic techniques (eg. fillers in isolators or closed RABS). The point of fill as with all aseptic filling is very important.

Therefore clean in place (CIP) and steam in place (SIP) systems are fully automated and do not require manual or outside systems to complete their function. After sterilisation the system continuously monitors the aseptically filtered air shower that protects the point of fill through over-pressurization. Furthermore the BFS extrusion system kills spores and the plastic encapsulates any endotoxin found on the supplied plastic resin. Tests have shown that particles present in the environment do not find their way into a BFS container during the filling process.

Product compatibility

Bottelpack machines can perform the primary packaging for a variety of products including nebulized inhalation drugs, ophthalmic OTC products and drugs and small volume injectable products

Blow-Fill-Seal technology Blow-Fill-Seal (BFS) is an advanced aseptic process that performs the primary packaging for a variety of applications such as nebulized inhalation drugs, ophthalmic OTC products and drugs and small volume injectable products. BFS is an automated process where plastic resin is extruded and formed into a container. The container is then filled and hermetically sealed. The entire process is performed in a controlled environment and completed within 4 to 15 seconds. The

Plastic containers are not compatible with all products. The typical resins used in the BFS process are low density polyethylene (LDPE) and polypropylene (PP). Both materials have good water vapour barriers but poor gas barrier characteristics. In pharma applications the typical resin has minimized additives giving it a relatively clean extractable profile. Initial compatibility can be tested in a lab setting by filling the product into empty sterile BFS containers. This cost effective method can indicate basic compatibility with the plastic resin produced with the BFS process. Once basic compatibility is confirmed the next step is to test the product with BFS technology. Within the Contract Manufacturing Organization (CMO) community there are capabilities to test a wide pharma and biotech product range including injectable, inhalation, ophthalmic, vaccine, SVP, LVP, gels, creams, suspensions, and emulsions. BFS containers are well suited to be considered when glass containers are not product compatible. As the BFS container

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is fully sealed by a mono-layer polymer that has consistent expansion and contraction characteristics, this allows the product to be refrigerated or frozen without damage to the container. With proper container design the containers can even withstand submersion in liquid nitrogen.

Unique container design The BFS container is formed inside the Bottelpack aseptic system. This gives the advantage that there is no upstream container handling (empty container transport, storage prior to filling, depalletizing, descrambling, accumulation, washing, or depyrogenation). The BFS process enables for a unique container design including a positive handoff to downstream secondary packaging systems. Existing container designs include fills from 50 microlitres to more than 1000ml. A growing area in pharmaceutical packaging development is aseptic liquids supplied to medical devices. Here the BFS container is designed to fit into a device and supply an aseptic liquid. The BFS container can work as an aseptic cartridge that is disposable or be permanently intergraded into a single use device. It is also possible to insert a device into a container.

The BFS process enables container design with positive handoff to downstream secondary packaging systems

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EXCIPIENTS & APIS

Taking perpsective Denise Bowser, Onyx Scientific, looks at the challenges of a development project – from both sides of the coin

P

lanning a small-scale research or GMP API manufacturing project comes many challenges. For drug developers, it can be a daunting and confusing process. We explore key considerations when planning such a campaign. Alongside the CRO perspective, I’ve enlisted the assistance of Chris Wallis, who runs a consultancy firm that represents the ‘client side’ of the equation.

Firstly, client side...

The CRO side...

When you need drug substance for an upcoming activity, there is much that needs to be done. Whether it’s your first project or your twentieth, it will never be smooth. I’ve outlined three important elements to consider.

Now let’s look at the challenges from a CRO perspective.

1. Your choice of CRO Any development or GMP manufacturing project is likely to succeed or fail based on your choice of CRO. This is not a decision to take lightly. Do your research, seek recommendations and references.

The challenges you will face will be less stressful if you choose one with the relevant competence. If you’ve dealt with numerous CROs, you can spot a great one from a satisfactory one. If you have not dealt with CROs, do your homework, use your network of contacts for advice, carry out site visits and pick one based on scientific/ technical capabilities. Getting this right first time will save you in the long run.

2. Utilise your CRO’s expertise Having selected our CRO, it’s now time to utilise their experience and technical expertise. A good CRO will evaluate your chemistry and provide comprehensive feedback on its scalability. They will identify potential obstacles and provide alternative strategies to get around these problems. Most importantly they will provide realistic timelines for the project. A good CRO partner will have worked on many similar projects so will have a good feel for potential challenges and how these can be overcome.

3. Establish your key driver It goes without saying that quality is of paramount importance and should not be compromised, especially in GMP manufacture. The other two are time and cost. It’s unrealistic to expect your CRO to turnaround complex chemistry very quickly and very cheaply.

Make it clear from the outset what your key drivers are. Some CROs are better equipped to deal with rapid delivery so if that’s what you need, make sure they can deal with your requirements.

In reality, clients will have a combination of needs so whatever these are and however prioritised, ensure your CRO has the capability and flexibility to deal with the speed and economy you need.

1. A juggling act When the project is underway, it will require a serious amount of coordination. Alongside core work on the API, you also have to take into account support services like solid state chemistry, validation and analytical method development, which all need to be planned and managed. So it’s important to communicate closely and regularly with your CRO to keep everything on track and ensure nothing is missed.

2. Prepare to change course With so much going on at once, deviations are likely to occur.

Common issues clients face are delays with toxicity results or obtaining raw materials as you are reliant on third party suppliers. In such a situation, the project team needs to adapt quickly. Whatever comes up, you need to plan in advance and it’s wise to build in contingency. Not doing so gives you zero flexibility and no time to deal with unforeseen challenges. One aspect not going to plan can have a knock on affect to everything else, a major challenge when dealing with a tight timeline.

3. Start early If timelines are tight, development and ordering of long-lead raw materials and production of common intermediates can start ahead of final product selection. However, as final yields are likely to be unknown at this early stage the manufacture carries some risk and it is wise to build in contingency. Facilities and resources can be allocated ahead of time if the full program requirements are communicated to the CRO, including an indication of likely scale up quantities of both non-GMP API and GMP API material. Bulk intermediates can be manufactured from one campaign and split for non-GMP and GMP scale up, giving cost efficiency, especially if GMP API requirements are small.

This will hopefully provide food for thought for companies planning research work and/or GMP manufacturing campaigns. Ultimately, it’s all about planning, choosing the right partner and being aware things don’t always go to plan. Working closely with your CRO in an open way is likely to lead to a successful outcome. Chemistry is never guaranteed to work but give it the best chance by ensuing you pre-empt challenges and have a plan to overcome them in a collaborative manner.

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CHEMICAL REACTION It’s important to keep on top of the latest services, companies and innovation.

EPM’s Chemical Reaction highlights a technology, service or business we think would be worth keeping an eye on...

Supply and demand John Beighton, AMCo, outlines its role in the wider pharmaceutical sector offering medicines that are no longer supplied

EPM: Who are you and what do you do?

JB: We, at AMCo, supply medicines that the big pharma companies no longer want to supply and we continue to produce them for groups of patients who are unable to get them anywhere else. These medicines are often hard to make from a technical point of view and are often only required by small groups of patients. By ensuring they continue to be produced we provide a vital service for those who need them most.

Q & A

We are a multi-national company and our biggest market is in the UK with the NHS. However we operate in 112 countries and are continuing to expand. We have recently opened an office in Dubai to look after and grow our client base in the Middle East and North Africa.

EPM: What have you focused on recently?

JB: We have some very important therapeutic areas that we are focussing on. That means our service is vital for the ongoing health of small groups of patients who can’t get these niche medicines elsewhere. We have a strong presence in ophthalmology, endocrinology and urology.

We continue to be interested in developing and acquiring medicines in these areas and our recent acquisitions are a good example of this. For example we recently acquired the global rights to Fucithalmic, which is a treatment for bacterial conjunctivitis that cuts in half the number of times a medicine has to be applied Whilst we sell our medicines in 112 countries worldwide our direct geographical presence continues to grow from our homeland in Europe through to the Middle East and Africa. We expect that trend of growing our own staff numbers in markets in which we sell to continue in the coming months and years.

EPM: What is your latest service or innovation?

JB: The ongoing thread of AMCo’s strategy is to acquire and develop medicines which are at the heart of our vision ie, hard to make niche medicines, which are vital to our patients who would be unable to get them elsewhere.

We are working on streamlining and re-versioning these medicines so they absolutely suit our patients’ needs. This involves changing formulations or even strengths of medicines that were often developed decades ago to make them much more suited to the modern patient. This often leads to reducing the pill-burden on patients and therefore to greater compliance and improved efficacy.

EPM: Future plans?

EPM: How can you benefit the pharmaceutical sector?

JB: We are seen as partners by the pharmaceutical industry as we take care of the medicines that they originally developed but no longer focus on. They can ensure that groups of patients that they once served are well looked after into the future

34

JB: We intend to grow both organically and via acquisitions and are always looking out for opportunities for expansion both geographically and by adding new medicines to our portfolio. We hope to be announcing, in the coming weeks, some significant acquisitions.

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