EPM Jul/Aug 2016 by EPM Magazine

CALL IN THE EXPERTS – PCI PHARMA SERVICES OUTLINES POTENT DRUG IN CAPSULE CAPABILITIES PLUS: BIOLOGICS – POLYMER Vs GLASS FOR DRUG DELIVERY IS AN APP THE ANSWER TO COUNTERFEITING?

JULY / AUGUST 2016

Performing solutions.

All over the world.

Thanks to the Coating-Wise Program, IMA Active makes available to the pharma industry over 30 years of experience, results from latest studies and meticulous customer support, in order to develop increasingly effective solutions. Join our Coating Community and mark your calendar for Research. coating.ima-pharma.com

Contents July/August 2016 | Volume 16 Issue 5

Regulars

Features 19

THE GLASS CEILING

COMMENT

Global Biologics looks at the advantages of polymer containers over glass in biologic drug delivery

6 NEWS FOCUS

LAND OF OPPORTUNITY

REGULATORY AFFAIRS

NEWS ANALYSIS

SWITCHED ON

Medidata Solutions outlines how the pharma sector can make the most of the digital health opportunity

OPINION Source Global Research looks at management consultants in pharma and ALS Pharmaceutical examines how the gender bias can be redefined in STEM jobs

26 CHECK POINT How a smartphone app allows manufacturers and consumers to verify the authenticity of drugs

16 COVER STORY PCI Pharma – pharmaceutical development and clinical trial service using Xcelodose technology

34 PHARMA AT THE FLICKS

Lu Rahman eyes up the opportunities for the European pharmaceutical sector

29 SUPER DRY SPX Flow, discusses high yield spray drying of monoclonal antibodies in the production of fine biopharmaceutical powders

33 MEASURE FOR MEASURE Cobalt outlines a new technique for fast low-level polymorph API quantification

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 group editor lu rahman, lu.rahman@rapidnews.com deputy group editor dave gray david.g@rapidnews.com publishers mark blezard, duncan wood

production art robert wood

advertising robert anderton tel: +44 (0) 1244 680222, rob@rapidnews.com

subscriptions subscriptions@rapidnews.com qualifying readers Europe - Free, ROW - £115 outside qualifying criteria UK - £80, ROW - £115 please subscribe online at www.epmmagazine.com

Address changes should be emailed to subscriptions@rapidnews.com. European Pharmaceutical Manufacturer is published by Rapid Life Sciences Ltd. European Pharmaceutical Manufacturer is distributed in electronic and print formats to a combined readership of 14,000 pharmaceutical manufacturing professionals. Volume 16 Issue 5 © July / August 2016 While every attempt has been made to ensure that the information contained within European Pharmaceutical Manufacturer is accurate, the publisher accepts no liability for information published in error, or for views expressed. All rights for European Pharmaceutical Manufacturer are reserved and reproduction in part or whole without written permission is strictly prohibited.

BPA Worldwide Membership ISSN No - 2052-4811

from the editor THE GREAT DEBATE T he debate around Brexit and its impact on the European economy isn’t showing any signs of dying down. As might be expected, from one day to the next we have conflicting output about the on-going effect of the UK’s decision to leave the EU – and the pharmaceutical sector is an integral part of this conversation.

The size of the UK pharmaceutical market is considerable. According to the ABPI, over the last decade the sector has generated a trade surplus - £1.1 billion year, which is greater than any other industrial sector in the UK. From R&D to developing a pipeline of drugs, the UK market contributes significant exports to the EU and beyond. The UK’s Brexit decision has created many questions – going forward will it have enough skills to maintain the sectors’ excellence? What will happen to the 6,000 or so life science researchers from EU countries? How are the major pharmaceutical companies that have made the UK their base, viewing their future in this country? The recent news that pharma giant GSK is planning to invest £275 million in three of its manufacturing sites in the UK, has been viewed as good post-Brexit news and evidence that the country is open for business. The investment will boost production and support the delivery of the company’s respiratory and large molecule medicines. With the majority of these products being for global export, the investment has been seen as a positive step with GSK highlighting the UK as an “attractive location for investment in advanced manufacturing due to the number of factors including the skilled workforce, technological and scientific capabilities & infrastructure and a competitive corporate tax system”. Not everyone is so optimistic however. The Guardian newspaper in the UK recently claimed that the UK economy was beginning to show signs of a post-Brexit decline. And not surprisingly, a global eye is watching. Peter Gough from the US public health and safety

organisation, NSF International, discusses a range of issues that may potentially affect the pharmaceutical sector going ahead. He examines pharmaceutical legislation: “Until recently most EU pharmaceutical legislation has been issued as directives, which means that these directives have already been transposed into UK legislation; mostly in The Human Medicines Regulation 2012 (Statutory Instrument 2012-1916). However, this statutory instrument (SI) will almost certainly have to be revised as it has been issued under the authority of the European Communities Act 1972, which will have to be repealed, and contains numerous references to EU directives. The replacement legislation could revert to the Medicines Act 1968, which was the governing legislation in the UK prior to 2012, but hopefully will be substantively unchanged.” Hough says the future of legislation will depend “on the outcome of the negotiations between the UK and the EU. The most logical outcome for medicinal products would be for the UK to adopt the Swiss model. This would require the minimum re-writing of the existing UK legislation and could be applied to future EU changes whether they are issued as directives or regulations.” Of course no one knows yet how the UK’s relationship with the rest of Europe and the world will pan out. Hopefully clinical research and the development of drugs to benefit the global community remain strong as pharmaceutical companies, both here and Europe, continue to see the benefit of doing business in as well as with, the UK.

Lu Rahman

WWW.EPMMAGAZINE.COM

NEWS FOCUS

IBM lab-on-a chip helps detect cancer at nanoscale I

BM scientists have developed a new lab-on-a-chip technology that can, for the first time, separate biological particles at the nanoscale and could help enable physicians to detect diseases such as cancer before symptoms appear. Reported in the journal Nature Nanotechnology, the IBM team’s results show size-based separation of bioparticles down to 20 nanometers (nm) in diameter, a scale that gives access to important particles such as DNA, viruses and exosomes. Once separated, these particles can be analysed to potentially reveal signs of disease even before patients experience any physical symptoms and when the outcome from treatment is most positive. Until now, the smallest bioparticle that could be separated by size with on-chip technologies was about 50 times or larger, for example, separation of circulating tumour cells from other biological components. IBM is collaborating with a team from the Icahn School of Medicine at Mount Sinai to develop this lab-on-a-chip technology and plans to test it on prostate cancer, the most common cancer in men in the US. In the era of precision medicine, exosomes are increasingly being viewed as useful biomarkers for the diagnosis and prognosis of malignant tumours. Exosomes are released in easily accessible bodily fluids such as blood, saliva or urine. They represent a precious biomedical tool as they can be used in the context of less invasive liquid biopsies to reveal the origin and nature of a cancer. The IBM team targeted exosomes with its lab-on-chip technology as existing scientific techniques face challenges for separating and purifying exosomes in liquid biopsies. Exosomes range in size from 20-140nm and contain information about the health of the originating cell that they are shed from. A determination of the size, surface proteins and nucleic acid cargo carried by exosomes can give essential information about the presence and state of developing cancer and other diseases. IBM’s results show they could separate and detect particles as small as 20 nm from smaller particles, that exosomes of size 100 nm and larger

could be separated from smaller exosomes, and that separation can take place in spite of diffusion, a hallmark of particle dynamics at these small scales. With Mount Sinai, IBM plans to confirm their technology is able to pick up exosomes with cancer-specific biomarkers from patient liquid biopsies. “The ability to sort and enrich biomarkers at the nanoscale in chip-based technologies opens the door to understanding diseases such as cancer as well as viruses like the flu or Zika,” said Gustavo Stolovitzky, program director of translational systems biology and nanobiotechnology at IBM Research. “This extra amount of time could allow physicians to make more informed decisions and when the prognosis for treatment options is most positive.” With the ability to sort bioparticles at the nanoscale, Mount Sinai hopes that IBM’s technology can provide a new method to eavesdrop on the messages carried by exosomes for cell-to-cell communications. This can elucidate important questions about the biology of diseases as well as pave the way to noninvasive and eventually affordable pointof-care diagnostic tools. Monitoring this intercellular conversation more regularly could allow medical experts to track an individual’s state of health or progression of a disease. “When we are ahead of the disease we usually can address it well; but if the disease is ahead of us, the journey is usually much more difficult. One of the important developments that we are attempting in this collaboration is to have the basic grounds to identify exosome signatures that can be there very early on before symptoms appear or before a disease becomes worse,” said Carlos Cordon-Cardo, chair of the department of pathology at the Mount Sinai Health System and professor of pathology, genetics and genomic sciences, and oncological sciences at the Icahn School of Medicine. “By bringing together Mount Sinai’s domain expertise in cancer and pathology with IBM’s systems biology experience and its latest nanoscale separation technology, the hope is to look for specific, sensitive biomarkers in exosomes that represent a new frontier to offering clues that might hold the answer to whether a person has cancer or how to treat it.”

WWW.EPMMAGAZINE.COM

NEW FOCUS

Holography trade body welcomes UN anti-counterfeiting report The trade body for the global hologram industry has welcomed a new United Nations report that reaffirms the technology’s important role in anti-counterfeiting

“More needs to be done – and quickly – to begin to deal with the problem and this might include increased integration of holograms as part of brand protection strategies.”

he UN Interregional Crime and Justice Research Institute (UNICRI) research report ‘Ensuring Supply Chain Security: The Role of Anti-Counterfeiting Technologies’* reflects the agency’s ‘first effort’ in analysing the impact of anti-counterfeiting technologies on government initiatives to secure legitimate product supply chains. It clearly acknowledges how technologies such as holograms remain important weapons in tackling counterfeiting and securing product authentication in global supply chains.

Increasing adoption of holography reinforces the technology’s position as a pre-eminent security feature in the global anti-counterfeiting fight. Real deal: The IHMA’s Dr Mark Deakes welcomes UN report reaffirming roles holograms play in tackling counterfeiting

The International Hologram Manufacturers Association (IHMA) says the report is a sobering reminder that the war on counterfeiting remains far from won and is another ‘timely’ wake-up call for those desperate to protect brands and profits around the world. Welcoming the report, IHMA general secretary Dr Mark Deakes, said: “This is important and timely insight, which throws the spotlight on the massive issue of counterfeiting. “It reminds us of the need for continued investment in technologies and added value track and trace solutions if counterfeiting in global hotspots such as China, India, and Eastern Europe are ever to be checked, let alone stopped. “Brand owners and those authorities responsible for legislation will also welcome this report.

Security holograms on items like liquor bottles, tobacco and luxury merchandise will confirm quality and lead to illicit items being seized and destroyed.

“Holography has a key role as a highly effective, highly flexible weapon in the ongoing battle to thwart counterfeiters and fraudsters,” Deakes said. “All involved in the supply chain – manufacturers, distributors, consumers, tax authorities - will be reassured by the presence of holograms on products and recognise the benefits they provide.” The use of well-designed and properly deployed authentication solutions, as advocated in ISO’s 12931 standard, on authentication solutions, enables examiners to verify the authenticity of a legitimate product, differentiating it from the counterfeits coming out of China. Even those that carry a ‘fake’ authentication feature can be distinguished from the genuine item if that item carries a carefully thought-out authentication solution.

WWW.EPMMAGAZINE.COM

s low F n

I re

e Wh

o ati v no

Single-Use Pumps for

Biopharma Processes

Quattroflow™ quaternary diaphragm

pumps deliver high-value solutions for your applications. Depending on your requirements, Multiple-Use and Single-Use models are available. • Ideal for critical processes such as filtration (TFF), chromatography, and many more • Single-Use Pumps offer faster speed to market at lower costs • No risk of product contamination

EPM-July-quarter pg advert.indd 1

22/07/2016 17:07

Unrivalled quality and expertise from the UK’s leading Inflatable Rubber Seals Specialist

• No identifiable particle release (verified by third-party test) • Self-priming and risk-free dry running • Ensures product safety, efficiency and reliability • High turn-down ratio

NS TIO UA

16-QTRO-0163 Quattroflow - European Pharmaceutical Manufacturer - July/August 2016.indd 1

URNARO

DISCOVER THE ISO-FLATE® DIFFERENCE

ALMATEC Maschinenbau GmbH Carl-Friedrich-Gauß-Str. 5 47475 Kamp-Lintfort, Germany P: +49/2842/961-0 info@almatec.de quattroflow.com

WN TIME SIT O D

ISO-FLATE® delivers exceptional customer service, rapid turnaround and over 100 varieties of stock profiles & material configurations. It’s easy to see why we’re fast becoming the trusted name in the pharmaceutical industry.

REDUC E

• Seal-less technology with constant, lowpulsing flow

For further information contact our dedicated sales team on: ✆ 01942 604 107 or online at: www.iso-flate.com

WWW.EPMMAGAZINE.COM 6/30/16 2:44 PM

OPINION

Balancing act Sharon Hanly, ALS Pharmaceutical, examines how the gender bias can be redefined in STEM jobs

“The trouble with girls in the lab: you fall in love with them, they fall in love with you, and when you criticise them, they cry.”

sciences tends to be a part of the STEM spectrum that is less likely to show such a distinct gender bias.

A year ago, this comment by a Nobel prize winning scientist hit the headlines of newspapers around the world. It kicked off vast column inches of comment accompanied by such negative reaction in the social media and beyond that the speaker, Sir Tim Hunt, resigned as honorary professor in the life sciences department, University College London.

However, if you add into the mix the number of women in senior posts in pharma companies, it becomes more complex. Firstly, it is not always easy to discover the numbers, and secondly, data that is available tends to indicate senior or Board level posts filled by women hover around 10% to 17%. Again, I am in the unusual position of working for a company whose parent – ALS Limited – has a female chairman, Nerolie Withnall. This perhaps is where I can contribute to the debate. First and foremost, I am fiercely focused on meeting our clients’ needs – having also experienced being a client in this sector myself. I believe in creating a close-knit team of women and men that share a passion for the scientific analysis and services we provide. Our laboratory is like a second family underpinned by a deep sense of loyalty and commitment. Also, I think I have created an atmosphere where women in science do not feel out of place – if anything, it has seemed perfectly natural for women to thrive here and develop their careers both managerially and technically.

Last month my laboratory, ALS Pharmaceutical in Ely, Cambridgeshire, was cited in the news twice regarding gender issues – firstly when it came to light that we had an 80-20 ratio in favour of women in senior positions in the facility and then came an announcement that I had been shortlisted for a First Women Award in Science and Technology. Consequently, EPM asked me to write about gender bias in STEM jobs – Science, Technology, Engineering and Maths – and on how ALS has bucked the trend.

More senior roles in the pharma industries will be filled by women, creating an opportunity for female mentors to keep that momentum growing. It is clear from the differences between the ‘in post’ stats and the higher education data, that boosting the talent pool in science from classroom to laboratory - is critical not just for closing the gender gap, but for future economic and business growth in STEM.

Firstly, though, I needed to analyse and define the gender bias – if there is indeed a bias in the first place. The data on the issue needs unpicking. For example, the most recent numbers from the UK’s Office of National Statistics’ Labour Force Survey, does indicate that just under 15% of STEM posts in the UK are filled by women; with women making up approximately 50% of the workforce, that is a considerable gender gap. However, STEM comprises a spectrum of jobs and if you unpick each sector then the gender bias turns out to be similarly broad. There are more women in ‘associate health professionals’ and ‘health professionals’ roles than men, for example, at 63% and 54% respectively. The next band, science professionals, is almost even but from then on there is a steep decline in the ratio from women to men, with the far end of the scale indicating that in skilled trades less than 1% are filled by females. When it comes to higher education, there is even a wider range. At one end of the spectrum, last year over 80% of graduates gaining qualifications in ‘subjects allied to medicine’ were in fact women. At the other end of the data charts, just 14% of the engineering and technology graduates were female. These ranges may make the second part of the request from EPM – for me to explain how ALS has bucked the trend – a little weaker, as life

I have been inspired by science and would seek to forge stronger links with the education community to bridge the gap between the perceptions of science careers with the reality. After all, what other career could you have where every day is different, you’re with a bunch of like-minded committed and passionate co-workers, and you are doing vital work, helping people and making a positive difference to the world around you.

WWW.EPMMAGAZINE.COM

OPINION

Consulting has an in increasing role to play in the pharma sector. BJ Richards, Source Global Research offers, a pharma executive’s guide to the service

You don’t need us to tell you that Europe’s pharma & biotech industry has a lot on its plate. The demand to develop innovative drugs and devices, maximising the profitability of R&D investments, improving efficiency and slashing costs, plus the endless crush of regulatory demands. It’s an agenda that keeps pharma executives and their teams scrambling. Now more than ever, it’s driving work for Europe’s management consultants. Indeed, in markets across Europe, consulting to the pharma & biotech industry is not only on the rise but growing a good deal faster than consulting as a whole, a trend we expect will continue for the foreseeable future. In Germany, for example, consulting to the pharma & biotech industry grew an impressive 10.7% last year while consulting overall grew just 6.5%. Likewise, in the Benelux region, consulting to the pharma industry grew 7.7% while the larger market’s growth sat just below 5%. Even in France, where the pharma market continues to be constrained by an environment of uncertainty, consulting in the sector still grew 4.1% to the overall market’s 3.6%. Pharma and consulting haven’t always enjoyed such a cosy relationship. In fact, the industry has long been among the most reluctant to engage with consultants, largely out of fear that management consultants didn’t have the high level of specialised industry knowledge necessary to make engagements successful. But as the pressures have mounted, and as the questions have become bigger and more complex, pharma leaders have had little choice but to turn to consultants for help. And it would seem the industry likes what it’s found, as it now depends on consultants more and more each year. We can’t say we’re surprised. After all, the world’s leading consulting firms are already well known for having the scale and breadth of capability to deal with complex projects that cut across business functions and geographies - qualities of importance to Europe’s big and ambitious pharma companies. Add in the fact that consultants have been going hard after this reluctant but attractive market, spending the last few years making big investments in their pharma capabilities, and clients here are finding that they’re now able to get that widely admired scale and scope from like-minded pros who wear the t-shirt and speak the lingo. So it’s little wonder that consulting is at last proving so popular.

With the pharma industry investing in consulting like never before, it’s inevitable that there will be a lot of companies and executives shopping for consultants for the first time. Maybe they know they need help but are unsure of what consulting can do for them, how they should go about picking potential partners, or how to get the most out of their consulting engagement once it’s started. Here are our top three tips for making it work:

KNOW WHAT YOU’RE LOOKING FOR

KNOW WHO CAN HELP YOU GET THERE

KEEP THE LINES OF COMMUNICATION OPEN

Before making the first exploratory phone call to a consulting firm, you need to have a clear idea of what you want consulting to do for you. Whether you already have a well-defined project in mind or you’re looking for someone with the expertise needed to help you flesh out a solution to a pressing problem, being able to articulate where you are and where you’d like to be, will make the consulting process easier from first conversations to project’s end.

When people look for a consultant, they’re usually looking for an expert. But what sort of expert would suit you best? In broadest terms, consulting skills are of two varieties. There are issue-specific skills, for instance, expertise in regulatory compliance. Then there are industry-specific skills, where the consultant speaks your language and knows your industry (and your competition) insideout. Ideally, you’ll want someone who offers a healthy mix of both, but getting the balance right means thinking hard about the nature of your project, its complexity, and how important it is that someone ‘gets’ you before they can help you achieve your objective.

The most effective consulting projects are those where the client and the consultant work together as a team throughout the life of the engagement. By making sure you give your consultants the information they need, promptly supply all promised resources, and check in early and often to identify and address stumbling blocks, you will go a long way towards ensuring a successful project and a solid return on your consulting investment.

WWW.EPMMAGAZINE.COM

TIME IS SHORT – SERIALIZE NOW !

More and more government regulations are demanding that drugs be serialized and accompanied by track & trace processes. Legislation to this effect will soon be coming into force in both the EU and the USA – serialization is already compulsory in China.

It’s time to discover

MedTracker

The modular and future-proof software solution for controlling and monitoring your serialization and track & trace processes – in any country.

Ask our team for more information:

+44 1264 324-222 mail@serialize-now.com

Benefit from our comprehensive one-stop solution! www.serialize-now.com

FEATURING 7 EXCHANGEABLE DRUMS 40 - 920 L VOLUME FLEXIBILITY

Scan the QR code to view a video of the Thomas Flex 500® high performance features!

WORLD’S MOST ADVANCED TABLET COATING SYSTEMS & TABLET PRESS TOOLING THOMAS ENGINEERING INC. - 575 West Central Rd. Hoffman Estates, IL, 60192 USA - sales@thomaseng.com - tel. +1 847-358-5800

WWW.THOMASENG.COM

WWW.EPMMAGAZINE.COM

OPINION

FOLIO

Making a difference BioNTech is a biotech company specialising in lab-to-market immunotherapies. Sean Marett, COO reveals the reasons for his love of biotech and the company’s quest to further advances in this field

How did you enter the pharmaceutical sector? My interest for pharma and biotech arose during my studies at university where I became fascinated in particular in how the immune system reacted to disease. I started my first job in the pharma business in 1987 at Pfizer. Since then I have been working for large pharmaceutical companies such as GSK and Pfizer for over 30 years in different positions such as the management of operations, sales and marketing and licensing, M&A and new product development and I am still fascinated by the dynamics and innovative power of this sector. What do you think is the greatest discovery in medicine? There are many important discoveries that each played a pivotal role in human health from Jenner’s first use of the cowpox vaccine to protect against smallpox to Fleming’s discovery of penicillin. However, one of the overarching discoveries that will continue to shape medicine for decades to come is the discovery of DNA in 1953. How do you see pharmaceuticals evolving? We see medicine for chronic disease evolving rapidly to tailored solutions for the individual patient. This is being enabled by swift leaps in technology that allow us to investigate disease at a molecular level and determine treatment options on an individual patient basis. Probably the most advanced application of such an approach today is in cancer. Just like you and I are unique, so our tumours are too and based upon the information we can obtain from the tumour, we can develop a treatment just for you. That´s what we are doing at BioNTech: we provide a personalised cancer vaccine treatment for each patient . What do you think is the biggest threat to health at the moment? There are a number of threats to health, ranging from the threat of multiple resistance to antibiotics to increasing obesity in industrialised nations to emerging or mutating viruses. In the cancer area, access to affordable medicines will increasing become a challenge, given that treatment will continue to move to combination products containing higher priced immunotherapies. Can you name one goal to achieve today that could have a positive impact against that threat? At BioNTech, we are very focused at reducing the cost of manufacture of our individualised cancer vaccines to allow broad access to these medicines. In this regard, we partnered in 2015 with Siemens to help us to build a fully automated, digitalised and paperless manufacturing facility to help us to achieve this aim. We are also looking at lower cost ways to deliver our vaccines, as described in the scientific journal Nature in June of this year.

WWW.EPMMAGAZINE.COM

secure, hygienic and simple communication

melaphone

visaudio

Clean Rooms Food Industry Hospitals Certified to ISO 14644-1 Level 5 needs:

& Environmental Control

Call us now on

UK 01359 233191 Int +44 1359 233191 info@melaphone.co.uk melaphone.co.uk

WWW.EPMMAGAZINE.COM

OPINION

Controlling factor Steve Alley, Reading Scientific Services, offers advice on finished product testing within the drug development life-cycle

he quality control testing of pharmaceutical finished products is an essential role of the pharmaceutical industry and is pivotal in delivering drugs that are not only efficacious but do not pose significant safety risks to patients. Formulations must be marketed as therapeutically active and safe, with consistent and predictable performance. As time progresses, newer and better medicinal compounds are emerging which tend to require the development of more challenging analytical methods for their determination (be that qualitative or quantitative).

Suitability criteria The suitability of a drug product for its intended use is determined by (i) efficacy versus safety and (ii) conformity to specifications regarding identity, purity and other physical and chemical characteristics. In terms of the latter, it is vital that appropriate specifications are set, which should be based upon an extensive body of data collected over the drug-development life-cycle. This would not only cover the drug product but also the raw materials (API and excipients), intermediates and packaging materials.

Specification A specification is defined as ‘a list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described’. It sets out a set of criteria to which a drug substance or drug product should conform to be deemed acceptable for its intended use. The quality aspects of a product that could be covered by the specification include (but are not limited to) the following: • General characteristics of the dosage form (physical characteristics) • Assay of the active substance • Identification of the active substance • Identification and assay of excipients (if required) • Identification and assay of antimicrobial/antioxidant agents • Purity tests (related substances, residual solvents or other known process impurities) • Pharmaceutical tests (e.g. dissolution, disintegration)

Safe and sound: The quality control testing of finished products is pivotal in delivering drugs that are efficacious and do not pose significant safety risks to patients

In determining the specifications of the finished product, the quality characteristics relating to the manufacturing process should be considered. The specification for each of the quality aspects studied during the development and validation of the manufacturing process should be established. As a minimum, those attributes considered to be critical to the drug product should be routinely verified. It is also important to consider the difference between ‘release specification’ and ‘shelf-life specification’. The former of these would be applicable to a product that has been newly manufactured; the quality required at the end of the shelf-life would be taken into account in determining the specification at the time of manufacture, which could, for example, include the need for an overage to account for product stability.

Different dosage forms A variety of different pharmaceutical dosage forms exist, depending upon the nature of the condition being treated. These range from oral dosage forms (tablets/capsules), topicals (creams, gels, transdermal patches) to injectables. Each of these different types will require assessment of different product characteristics. Many of the tests are shared across different formulation types, such as description, identification, assay, and related substances. However, when looking at say, an injectable product, there would be an array of formulation-specific tests to be included, such as clarity of solution, pH, osmolality, fill volume, viscosity etc. Tablets on the other hand, would generally require tests such as dissolution, disintegration, hardness/ friability; the latter of these may only be required if they have a significant impact upon the quality of the drug product (such as for chewable tablets). The tests selected would pertain to all of those characteristics that are considered key to the efficacy and safety of the product.

Outsourcing finished product testing In light of the large body of specification testing that can be required, if testing is to be outsourced, it is key to make an informed decision when selecting a CRO to support the analytical activities for batch release. It is very advantageous to select a CRO that can facilitate all of the necessary testing and adopt a seamless, flexible approach to project management; from a logistic perspective, this aids control of the overall process, and will serve to minimise any delays in batch release and hence supply of the product to the market place.

WWW.EPMMAGAZINE.COM

COVER STORY

Call in the experts Following the acquisition of Penn Pharma, PCI Pharma Services’ pharmaceutical development and clinical trial service includes the production of drug in capsule (DIC) using Xcelodose technology. David O’Connell, PCI Pharma Services explains

Team work: David O’Connell, PCI Pharma Services says that early expert involvement in the development of a client’s product can optimise the process

he pharmaceutical industry’s on-going demand to shorten drug development times, making significant cost savings, is driving forward technological advances. At at the same time there are major changes happening in the research and development of high value, often potent speciality medicines. Currently more than half of research projects from pre-clinical to late clinical development fall into this category. In the past, pharmaceutical companies have competed on the grounds of product innovation. Taking into account the high cost of R&D coupled with the economic and political pressures for better end product pricing, finding ways to reduce overall costs becomes critical. But it is not just cost which is at the forefront of development – the size, timescales and complexity of clinical trials are all putting pressure on the industry to shorten the drug development process. Research and development within the industry has the potential to transform patient care across a range of diseases through the use of an ever increasing range of new chemical entities (NCEs). Since the supply and cost of these new chemical entities are of high value, the importance of accelerating the supply of drug product into the clinic for initial Phase I, first-in-man clinical trials becomes crucial. But the traditional product development route of a formulated solid oral drug for Phase I clinical trials involves a range of complex activities. These include the initial compatibility studies; analytical method development; prototype development; short-term stability; process/formulation refinement; Phase I method validation; stability manufacture; and finally clinical manufacture. This process can take in excess of nine months to complete, with significant cost for product development alone – and such costs do not take into account the cost of delivering the actual clinical trial. The ability of pharmaceutical companies to remain commercially competitive depends on transforming new chemical entities into clinical

products and onto commercial launch. Filling an active pharmaceutical ingredient (API) directly into a capsule is potentially the quickest and preferred option for entering early phase clinical trials. Manufacturing drug in capsules (DIC) can reduce time and financial investment at the early stage of the drug development process. It can minimise the use of costly API and reduce the amount of formulation and analytical development necessary to support an investigation new drug (IND) application or investigational medicinal product dossier (IMPD). As such the timeframe for completion to early phase clinical manufacture can be reduced to approximately four to six months – potentially halving the time taken by the traditional product development route. The associated cost savings can be as much as 70%, though once again this is dependent on the cost of the API and does not include the cost of the actual clinic trial. However, as the biological activity and the specificity of the API increases, the dosage strengths are decreasing, making the APIs more potent in terms of occupational handling for drug product manufacture. Therefore it is not suitable to use methods of manufacture such as hand filing, semi-automatic filling and traditional automatic encapsulation for the accelerated development pathway of drug in capsule (DIC) for low dosage strengths. Such processes may also lead to inconsistent capsule filling, and are often time consuming and inefficient in terms of cost. Automated powder precision dosing at very low powder fill weights (less than 50mg) was until recently not possible. Manual hand filling using human operators was very time consuming, requiring an enormous amount of concentration to accurately weigh such low fill weights. Following the acquisition of Penn Pharma, PCI Pharma Services’ comprehensive pharmaceutical development service offering includes the production of drug in capsule/vial using Xcelodose technology.

WWW.EPMMAGAZINE.COM

This technology was first introduced at PCI’s Tredegar facility in 2010 with the installation of the Xcelodose 120S – a semi-automated process. This required capsules to be manually separated and capsules loaded into the dial plate, filling was automatic and acceptable capsules would be manually capped and closed.

All new project enquiries handled by PCI’s business development team will be based on the principles of lean manufacture and will follow the SDQC process, which examines Safety, Quality, Delivery and Cost. An initial questionnaire is issued to potential clients to assist with this process. Only when all elements of this process are fulfilled will a proposal be prepared and sent to the client.

In December 2015, PCI’s Tredegar site invested in the very latest Xcelodose 600S microdosing system. This new technology has the If a project is subsequently awarded, a second questionnaire is capability to fill amounts as low as 100 µg at speeds of more than 600 completed to further inform the process following which, each molecule is awarded a ‘potent passport’. During the capsules an hour – approximately 10 times production cycle, all information is constantly faster than filling the capsules by hand. The reviewed and updated during the product Xcelodose 600S achieves a 50% increase development and clinical trial lifecycle. in through-put over previous models, is By involving our experts early fully automated, and is controlled by a in the strategic development Health and safety is a primary driver for the programmable logic control (PLC) system of a client’s new product, we can company during the process; great attention that is 21 CFR Part 11 compliant. assist in optimising the process, is given to on-site security and safety with four levels of secure access to the containment The system does away with the need for ensuring that regulatory hurdles facility and only qualified staff being allowed initial formulation screening and associated are minimised and that the most within the production unit. stability testing enabling PCI to achieve faster efficient routes to clinic times to first-in-man on behalf of its clients Through the investment in the latest and inform the key go/no-go decision point are delivered. technology, PCI is able to ensure that of Phase I clinical studies for the development products reach the patient faster, cost-effectively and with no loss of new molecules. in quality. Capsules are loaded into the feed hopper and a dispense head is selected and fitted on to the system. Drug powder is placed into the With the pharmaceutical industry targeting more specialist niche dispense head or the operator can use the integral high through-put unit medicines with ever increasing potency, PCI is able to offer clients a modern facility and the latest contained technology adhering to industry for longer runs and greater fill weights. guidelines for the processing of potent molecules, delivering contained Once product batch data is entered into the control PC, the system auto- manufacturing which offers speed-to-market of the highest quality. handles and fills the capsules, separating and then realigning the base and cap before closure. The capsules are then checked for length and sorted automatically. The fully programmable system provides PCI with exceptional levels of accuracy and precision. There is very little waste First class: The Xcelodose of expensive drug product and batch production is recorded allowing microdosing unit enables traceability of samples that meet GMP requirements. PCI to offer a premium

“

”

service to clients

As the industry continues to focus on products to treat more specialist disease areas, the trend will be towards the development of more potent, expensive molecules, putting even greater pressure on the need for greater cost effectiveness and shorter development and production timescales. The development of these potent compounds, which include drugs aimed at oncology, immunosuppresants, antivirals and opiod-based analgesics, coupled with the distinct lack of early toxicity data available when initiating the drug in capsule (DIC) process, requires a focus on safety through the use of contained processing. The Xcelodose technology ensures safety and prevents operator exposure to potent products by the installation of the Xceloprotect isolator. The high levels of containment afforded by this equipment ensures an occupational exposure limit (OEL) down to 0.1µg/m3 over an eight-hour time weighted average meeting the intended regulations for Safebridge 3 and 4 applications. Housed within PCI’s new containment facility at Tredegar, South Wales, the Xcelodose microdosing unit enables us to offer a premium service to our clients. PCI is continually investigating and investing in ways in which we can accelerate the manufacture of our clients’ products, while maintaining our uncompromising commitment to safety and quality. By involving our experts early in the strategic development of a client’s new product, we can assist in optimising the process, ensuring that regulatory hurdles are minimised and that the most efficient routes to clinic are delivered.

WWW.EPMMAGAZINE.COM

www.lbbohle.com

BOHLE TECHNOLOGY CENTER

Continuous Manufacturing Starts Here • Standard of excellence from Bohle and eight partners • Pharma systems and expertise from one source • Complete hardware and software integration • Measuring, monitoring and controlling continuous production under excellent conditions • Comprehensive process support and service

ur success

as for yo Smart ide

Our partners:

Expert Pharmaceutical Analytical Services RSSL provides analytical testing, consultancy and training for the global pharmaceutical, biopharmaceutical and healthcare industries. RSSL is GMP approved and is inspected by both the MHRA and FDA. Our services include: • Analytical Services for Drug Formulation

• Method Development and Validation

• Biopharmaceutical Product Analysis

• Microbiological Analysis

• Contamination – Chemical and Physical

• Pharmaceutical Training

• Cleaning Validation

• Pharmacopoeial Testing to USP, EP, JP and CP

• Extractables and Leachables

• Physical and Structural Properties

• Impurity Isolation and Sample Purification

• Stability Storage, Management and Testing

• Medical Devices

Customer Focused, Science Driven, Results Led For further details contact Customer Services on: +44 (0) 118 918 4076 or email: enquiries@rssl.com or visit Web: www.rssl.com 18

WWW.EPMMAGAZINE.COM

DIGITAL HEALTH

Switched on Christian Hebenstreit, Medidata Solutions says there is a huge interest in digital health in Europe and outlines how the pharma sector can make the most of this opportunity

here is a huge opportunity for pharma companies to capitalise on the digital health movement and we see significant interest for this technology throughout Europe.

For starters, this interest in new technology reflects Europe’s demographics. In its developed markets, the populations are ageing quickly leading to increased healthcare costs. There’s a real need for technology that can bring down those costs as well as improve our understanding of disease. Wearable sensors and apps can dramatically improve our ability to gather real-time, real-world data from patients. Bayer’s Barbara Voith, who heads the German pharmaceutical company’s clinical sciences operations group, recently summed it up: “Right now patients, investigators, physicians, health authorities and payers are scrutinising the value of new medicines. We really need to think about how we can optimise drug development in a way that provides meaningful outcomes for patients.” Pharma companies are exploring new technologies to push the traditional measurements used in clinical trials. Companies like Boehringer Ingelheim are using an end-to-end digital approach in clinical development, from study design optimisation to risk-based monitoring technology. In a similar approach, Sanofi attaches a digital health strategy to each molecule in the company’s R&D pipeline. Clearly, Europe’s leading pharma companies are embracing the adoption of digital health, and often they are the most progressive in this pursuit. Within this push towards digital health, mobile health (mHealth) technology is becoming a new focus for innovative life science companies. We recently helped Nestle’s life science team launch a twoyear, mHealth-enabled clinical study to assess the impact of nutrition and physical activity in adults with joint discomfort. Patients are equipped with Garmin activity trackers and asked to fill out diary data in Medidata’s Patient Cloud electronic patient-reported outcome (ePRO) app.

Similarly, GlaxoSmithKline teamed with McLaren Group – known for its Formula 1 racing team – to incorporate biotelemetry into its clinical studies. As with most of Europe’s leading pharma companies, GSK anticipates sensor technology, which can collect real-time, continuous patient data, will enable collection of more meaningful, real-world data. Companies need to go the extra step with strong feasibility studies to promote adoption by patients, healthcare providers and government payers in each country and prove that these sensors and apps are not only safe but effective tools for understanding disease and treatment. Of course, data privacy is paramount in all this, and the EU has taken a very strong stance on protecting patient data. The EU is adopting regulation meant to thoroughly protect data generated by wearable devices, including activity trackers. The easiest way to have a comprehensive global data privacy policy is to promote the harmonisation of privacy and security measures around the world. When it comes to data privacy, earn the trust of patients, regulators and partners by being better than required. We opened a data centre in Europe specifically to meet our customers’ data requirements in the region; this was a substantial investment on our part, but we recognize our clients in Europe have specific data requirements that can differ from our US customers. Despite the challenges that accompany adoption of any new innovation, the promise of mHealth in clinical trials is starting to be realised. The European Commission is launching initiatives to encourage digital health startups and working with organisations to establish mHealth assessment guidelines. The regulators see the value that digital health can bring to address the inefficiencies and cost pressures of clinical development, and they see the promise of new insights that these tools offer. As an industry, we are only limited by our own inertia. As long as we all push forward, Europe’s digital health future is bright.

WWW.EPMMAGAZINE.COM

BIOLOGICS

The glass ceiling Graham Reynolds, Global Biologics, looks at the advantages of polymer containers over glass in biologic drug delivery

or drug manufacturers one of the early considerations for any container system is likely to be the interaction between the drug and the container closure system. Many companies evaluate both a glass and plastic option at an early stage of the development process to ensure that they have an appropriate solution that may help to optimise time to market and ultimate effectiveness and quality of the product. As part of compatibility testing, interaction with any materials that might be present in the system are examined.

a mechanical delivery device, such as an auto-injector) there needs to be a consideration of the tolerances of the various elements and the impact on functionality. Plastic offers significantly higher dimensional precision compared with glass and has benefits when considering these types of combination systems. In addition, glass can be more prone to breakage, resulting in potentially dangerous particulates in the drug or loss of sterility. Breakage can also occur during secondary operations, including labelling, auto-injector assembly and even during usage. Polymer components, on the other hand, are more resistant to breakage during shipping, handling, manufacturing and throughout the overall supply chain, drastically reducing patient risk.

Traditionally, glass has been used to store and deliver a range of injectable drugs. However, the rising popularity of biologic therapies— used for a number of conditions such as cancer, autoimmune diseases, cardiovascular issues and diabetes—has changed glass’ position as the Delivering biologics comfortably and effectively via glass containers default system in drug containment. Glass is not always compatible with can be difficult due to the large dose volumes typically required. For biologics and other complex or high-viscosity drug products, and that example, the traditional volume limit for a conventional glass syringe incompatibility can result in costly recalls and, worse, compromise patient and auto-injector is 1mL, but the high concentrations necessary of a safety. As a result, greater consideration novel biologic often exceed that limitation. In has been given to alternative containment addition, a higher dose volume may enable systems, such as plastic, in recent years. In less-frequent dosing and the improvement some cases, incompatibility with glass (or of patient adherence and outcomes. Plastic related processing materials such as silicone The rising popularity of biologic components, however, can incorporate oil lubricants for prefillable syringes) can inhibit therapies has changed glass’ design flexibility, allowing for complex progress through the drug development and shapes, configurations, custom sizes and position as the default system commercialisation process. unique solutions not possible with glass.

“

in drug containment

Plastic’s pace of adoption has been different in various markets due to local regulatory and cultural forces. In Japan, for example, presentation of products in a plastic format is common due to an emphasis on visual product quality and disposability. In the United States and Europe, this trend has been slower, but examination of plastic materials as part of stability studies is rapidly expanding as part of product lifecycle management and risk mitigation, especially with the launch of new biologics. The utilisation of the wrong container and container closure system can put patients in jeopardy. In general terms, glass will not disappear; however, while glass certainly has its place in drug containment and delivery, plastic alternatives, such as cyclic olefin polymers have a number of very tangible advantages.

Preventing risks associated with breakages Large molecule drugs require a level of stability that must be considered at every step of the manufacturing and packaging process. In cases of a combination product (eg when a drug container is incorporated into

”

Another cause for breakage of glass containers is related to the low temperatures at which biologics must be stored to avoid compromising the drugs. Conversely, plastic containers offer a more robust containment system at low temperatures and cells can be stored for months at a time and still exhibit rapid recovery two hours after thawing.

Elimination dangerous chemical reactions Glass is not an inert material. Its chemistry can and does interact with certain medications in ways that can alter a drug’s safety, stability, purity and effectiveness. Certain additives applied to the inner walls of glass syringes, may also interact with medications. Plastic components comprised of cyclic olefin polymers can reduce or eliminate the risks associated with glass-based chemical interaction. When a drug’s chemistry interacts with the chemistry of a glass vial, a process called delamination may occur, causing the glass to corrode and flake. Glass vials are particularly susceptible to delamination in areas that have been flamed during manufacturing, such as the vial’s

WWW.EPMMAGAZINE.COM

base or shoulder. This interaction is especially prevalent with high pH medications, including many biologics, biopharmaceuticals and other new and advanced therapies. Unlike glass, polymers used for plastic components will not delaminate. The increasing use of proteins as therapeutics has also created a concern related to the potency and safety of drugs contained in glass pre-filled syringes. Silicone oils, which are used as lubricants to aid the movement of the plunger, can degrade proteins. Protein aggregation can induce an immune response that could neutralise the effect of the drug. Plastic pre-filled syringes, when used in conjunction with plungers fully coated with fluoropolymer barrier films, don’t require silicone oils, thus removing the potential interaction. Fixing a needle into a glass syringe can also result in potentially dangerous chemical reactions. The process involves the use of adhesives or the needles can be moulded into the glass with the aid of a tungsten or nylon pin. These processes have also posed risk for leachables, particulates or protein aggregation. Organic solvent from a partially dried epoxy used to attach a needle to the syringe barrel can leach into a product and cause an increase in protein oxidation followed by aggregation. With plastic syringes with insert moulded needles, no such process is necessary.

Reducing recalls From a patient safety standpoint alone, the advantages plastic containers can have over glass make a compelling argument. Over the last several years, biologics recalls have increased due to quality issues, including fundamental weaknesses in primary glass containers. Earlier in the decade, drug recalls related to glass particles were rising to very concerning levels: In 2008 and 2009 there were a total of nine FDA recalls related to glass issues; between 2010 and 2012, that number jumped to a total of 47 recalls.

Manufacturers should also consider the final method of drug delivery at an early stage in the development process. For instance, the determination of dose volume can drive selection of container closure and delivery systems. In addition, if the drug container has to be integrated into a delivery system as part of a combination product, early understanding is essential to ensure that the necessary work is done to support regulatory submissions. Many drug manufacturers are choosing to evaluate both a glass and plastic option at an early stage of the development process to ensure that they have an appropriate solution that may help to optimize time to market. As part of compatibility testing, interaction with any materials that might be present in the system, such as silicone oil, adhesives and elastomer components should be considered.

Conclusion As more attention is paid to the interaction between biologic therapies and primary drug containers, finding solutions to these challenges has taken on an increased urgency in order to protect patients, enhance therapeutic outcomes and to prevent costly recalls. While glass is suitable for many drug products, the advantages plastics have in certain areas cannot be ignored. By closely collaborating early in the drug development process, pharmaceutical manufacturing companies and their packaging and delivery system partners can identify the specific needs around containment and delivery of both the drug product and the patients who will be using it. The result is an opportunity to effectively develop and optimise the manufacturing process accordingly to ensure a container closure system that facilitates quality, effectiveness and patient safety.

From investigations, to loss of market share, to replacement costs and impact on reputation in the marketplace, a recall affects a pharmaceutical manufacturer’s bottom line significantly. The more important consequence, though, is when a patient’s health and wellbeing is compromised. Utilising plastic containment systems can eliminate the potential for many of the issues leading to drug recalls.

Considerations for drug manufacturers It is critical for drug companies to perform extensive risk assessments to determine how glass may impact each therapy before containment. Such assessments should be based on factors such as the physical, functional and chemical characteristics of the container closure system, as well as the interaction with the drug product to enable the selection of the most suitable container closure system.

WWW.EPMMAGAZINE.COM

“

The utilisation of the wrong container and container closure system can put patients in jeopardy

”

EMERGING MARKETS

Ahead of the game The pharmaceutical sector holds a prestige position in its contribution to the European economy. Lu Rahman looks at some the the global hotspots and conditions that offer significant opportunities to companies looking to expand their business

he European pharmaceutical industry plays a key role in the European economy. It is Europe’s fifth largest industrial sector, according to the European Federation of Pharmaceutical Industries and Association, which highlights the industry’s strengths as a trade surplus, investment in R&D and the creation of skilled employment across Europe. The European Commission says that in 2012 the market was worth €200bn, employing around 800,000 people.

Despite its established success, emerging markets are key to future success of the overall pharmaceutical sector. A report published by Booz & Company in 2013, discusses the way on which the significance of emerging markets will increase – 52% of those interviewed for the survey’s report expected more than 30% of their global sales to originate in emerging markets by 2018. While Brazil, Russia, India, China, Mexico and Turkey (BRICMT) were highlighted as the dominant areas, secondtier markets such as those in Indonesia is the largest Southeast Asia, would also be pharmaceuticals market in the increasingly relevant.

“

growing Southeast Asia/Asia Pacific region

”

In its 2015 Life Sciences Outlook Southeast Asia, Deloitte outlines the potential of this region: “Indonesia is the largest pharmaceuticals market in the growing Southeast Asia/Asia Pacific (SEA/AP) region, followed by Thailand, the Philippines, Vietnam, Malaysia and Singapore. SEA/AP is generally viewed by life sciences companies as secondary to traditional mainstay markets due to lower purchasing power and overall health care system maturity. Yet, the region is developing rapidly and holds considerable future potential.” Reasons for the region’s potential include a population growth and society’s move away from infectious diseases to chronic diseases. Picking out individual regions, Deloitte says that pharmaceutical sales in Singapore are forecast to grow an average of 9% a year to 2018; the pharmaceutical market in the Phillipines, which was worth $5.2bn in 2013, also looks likely to grow by 9% a year until 2018.

Growth factor: According to Deloitte, the pharmaceutical market in the Phillipines, looks likely to grow by 9% a year until 2018

There are opportunities to be had in this region. According to Deloitte: “Generics account for around 40% of the Philippine drug market by value and 60% by volume. Most of the biggest pharmaceutical companies with operations in the country are foreign but the market share of local companies has been rising slowly.” Where exactly do opportunities exist? Deloitte highlights innovation as a key factor for businesses looking for long term success. It adds: “While most manufacturers do not consider the region to be an R&D or clinical centre of excellence, some are using facilities there to modify products for emerging/low-cost markets. Moving forward, infrastructure improvements and foreign investment is expected to jumpstart local innovation in numerous forms, including locally based R&D and clinical trials to improve market access, shorten licensing approval periods, or produce a genuine pioneering product developed.” Deloitte adds that an increasing number of businesses are looking at “SEA/AP as a promising region in which to make bold moves in business model innovation; for example, creating a second brand, forging longterm strategic partnerships, and upgrading supply chains to support near-sourcing of raw materials and finished products to nearby highgrowth markets”. The rise in certain conditions has also created opportunities for pharmaceutical businesses – one of these being obesity. The World Health Organization reports that around 13% of the global population suffered from obesity in 2014 and that the rate of increase in emerging countries is higher than developed regions. A range of products, including the FDA-approved Contrave, have been developed to service this market. A recent report from Persistence Market Research discusses areas of opportunity for this type of drug: “North America dominates the global market for anti-obesity prescription due to increasing prevalence of obesity and lifestyle associated diseases. Asia followed by Europe are expected to show high growth rates in the next five years in the global anti-obesity prescription market. China and India are expected to be the fastest growing anti-obesity prescription markets in Asia-Pacific region. Some of the key driving forces for anti-obesity

WWW.EPMMAGAZINE.COM

“

prescription market in emerging countries are a large pool of patients, increased government funding and improving healthcare infrastructure”.

China and India are expected to be the fastest growing antiobesity prescription markets in Asia-Pacific region

Linked to obesity, it's no surprise that diabetes is a growth area for pharmaceutical companies. This year a report by Visiongain predicted that the global market for diabetes medication would hit $55.3bn by 2017. It highlights that the anti-diabetic medicines industry generated $35.6bn in 2012 and revenues will continue to grow to 2023. Hemant Mistry, a pharmaceutical industry analyst, Visiongain, said: “The incidence of diabetes will surge owing to rising levels of obesity and sedentary lifestyles in the global population. Those trends are most evident in emerging countries, such as China and India, which are expected to account for much of the growth of the treatment market. Also, as companies set up operations and facilities in developing countries, to harness the growing patient pool, this increases market competition. That trend helps stimulate innovation and price reductions, an incentive for less-affluent patients in developing countries. “Furthermore, the diabetes drug market has a strong R&D pipeline. Also, there’s need for new anti-diabetic treatments with improved efficacy and safety. In addition, as obesity is closely related to type 2 diabetes, medications that target long-term weight reduction and other related conditions are in high demand. Indeed, owing to the multifactorial aspects of diabetes, drug manufacturers developing medications for associated complications – obesity, heart disease, kidney disease or stroke – are evaluating medicines in clinical trials for treating diabetes. That expanded use of anti-diabetics will offer drug manufacturers opportunities to tackle multiple aspects of metabolic disorders and to market drugs to a larger target population, increasing revenues and profits, as well as benefiting patients and healthcare providers. Worldwide, the diabetes drugs market retains great potential for increasing revenues, through technological and commercial progress.” Like diabetes, the Alzheimer’s market offers opportunities for pharmaceutical manufacturers. There are currently 46.8 million people across the world with the condition – this figure is set to rise to 131.5 million by 2050, according to the Alzheimer’s Society.

”

While there is currently no cure for the illness, treatments have been developed to aid its decline. One substance which recently received media attention, was LMTX which showed improvement cognitive function and delayed brain shrinkage in those that had a mild to moderate form of the illness. Much work has yet to be done on treatments for this condition but its development offers potential for the sector and those looking to produce similar products. Over recent years the biologics market has grown in significance. According to Visiongain there are a range of opportunities in this market that will benefit drug developers and producers – in 2014 seven of the ten top selling drugs were biologics. The market holds significant value – BCC Research says it is set to grow from $234bn in 2014 to $386.7bn by the end of 2019. Rheumatoid arthritis for example, has benefitted from the use of biologics. One company that has taken advantage of the biologics market is Bristol-Myers Squibb – in 2013 the company carried out a $280 million expansion of its biologics facility in Massachusetts. In the same year the company entered into an agreement with Samsung Biologics to manufacture antibody cancer drugs at Samsung’s South Korean plant. Opportunity for pharmaceutical companies is strong. Societal change and an increase in demand for certain types of drugs mean that new and expanded markets are open to pharmaceutical manufacturers. Thanks to a wealth of market research, future trends are well documented offering increased business for those looking to expand their portfolios.

Opportunity knocks: 13% of the global population suffered from obesity in 2014 with antiobesity drugs being developed

WWW.EPMMAGAZINE.COM

ADVERTORIAL

Donâ€™t neglect cleaning: A critical part of your bio-decontamination programme!

typical bio-decontamination programme in a pharmaceutical cleanroom can be broken down into three distinct phases, cleaning, disinfection or sanitisation and validation. Cleaning should be classed as a separate activity to disinfection as you are trying to achieve a different result. By definition, cleaning is the removable of non-viable contamination by physical means or a suitable agent from a surface to render it visibly clean. By comparison, disinfection or liquid sanitisation is the process of reducing the number of viable organisms on a surface, by the action of an agent on their structure or metabolism, to a pre-defined level.

Cleaning Even when using the most efficacious of disinfectants there are still benefits to be gained from introducing a regular cleaning regime into the bio-decontamination programme. The majority of disinfectants leave a residue on the surface, some as high as 20,000 ppm. A surface with a high level of soil or residue from a disinfectant is harder to subsequently disinfectant as the soil/residue will have a detrimental effect on the disinfectant used. Starting with a surface free of nonviable contamination may mean a less aggressive disinfectant can be employed. Unlike the cleaning of product contact containers and vessels the objective of cleaning cleanroom surface is to reduce the amount of non-viable contamination, such as dust, dirt, powder, light oils to a visibly clean state. The amount of gross soil even in the lowest grade of pharmaceutical cleanroom is minimal compared with other industries so cleaning may only need to be carried out on a regular but infrequent basis. Invariably, this will be weekly, monthly or quarterly dependent on the disinfectants used, products produced and levels of activity in the cleanroom. Cleaning can be the most important step to a successful sanitisation programme. The mechanical action of cleaning with wipes and mops also helps to dislodge any biofilm formation which can inhibit the efficacy of a disinfectant. In order to clean effectively it is worth considering how particles attached to a surface. Research has shown the predominant force between the particle and the surface is a capillary force caused by a thin layer of liquid between the particle and the surface. This capillary force is 3 times greater than the Van der Waals forces which are also acting on the particle. To remove particles this boundary layer needs to be broken down usually by the use of a low surface tension fluid such as alcohol

or a surfactant (detergent). This lowers the capillary adhesion forces allowing for easier removal of the particles.

Choice of cleanroom detergent There are many options of detergents available but are they all suitable for use in a cleanroom environment. Detergents are usually classified into enzymatic and non-enzymatic detergents. Where no organic soiling is present, which will be the case in most cleanrooms non enzymatic cleaners are preferred. If required in a hospital cleanroom environment, enzymatic cleaners are highly effective on protein soils. Detergents can be further sub divided into alkaline, neutral and acidic cleaners. Alkaline cleaners are especially suitable for the removal of fats and proteins. Acidic cleaners are more suitable for metal oxides and scale removal. However, the higher the pH of the fluid the more corrosive the cleaner could be. A general rule is to use the mildest cleaner which will be effective. The levels of soil in a cleanroom environment are by definition very low and a neutral pH cleaner is a very safe and effective choice. These detergents are especially suitable for the removal of light oils and small particles. Detergents are also classified as anionic, cationic or non-ionic. Nonionic detergents tend to be used for surface cleaning as they will not react with other agents, they also tend to be low foaming so are easyto-use. Examples of non-ionic surfactants are alcohol ethoxylates and ethylene oxide/propylene oxide block co polymers. Anionic surfactants are generally poor cleaners and cationic surfactants are more commonly used in immersion cleaning. Other considerations for a cleanroom detergent should be that it is low foaming and free rinsing. In the same way as a disinfectant can leave a residue, most if not all detergents leave a residue which also needs to be removed. A detergent with low levels of residue which are easily removed will help save time during the cleaning and disinfection cycle. Rinsing can be carried out with either water for injection, purified/ deionised water or alcohol. In a Grade A or B cleanroom, both the detergent and the method of residue removal will need to be sterile. A cleanroom detergent should also have its own validation file. Contec has recently launched a neutral detergent based on an amine oxide which is especially suitable for cleanroom environments. Contec NeutraKlean is available sterile and filtered, double bagged for ease of entry into a cleanroom or barrier system. Contec NeutraKlean is ideal for the removal of disinfectant residues, removal of light soil and dirt

WWW.EPMMAGAZINE.COM

after maintenance or a spill. It is available as a 1L trigger spray with a protected system for isolators and product contact areas and 5L readyto-use capped product for larger areas. Presaturated wipes with Contec NeutraKlean are also available in resealable pouches.

Cleaning methods and detergent application Various studies have shown that wiping is a very effective way to control contamination on a hard surface. Initial work carried out in 1978 looked at seven different surface cleaning techniques for removing contaminants from optical surfaces and concluded that wiping with a saturated lens tissue was the most effective particle removal process. Other methods of cleaning include dry wiping, compressed air blowing, vacuuming, tack rollers or irrigating with large volumes of solvent. Vacuuming may have a place for the removal of large visible contamination and cleanroom vacuum cleaners with HEPA filtered exhausts are available. The use of compressed gas to blow particles may remove some particles but are they being physically removed from the cleanroom?. The use of large volumes of fluid to irrigate surfaces is ineffective and produces liquid containment and disposal issues. Further studies of cleaning methods for larger areas came to the same conclusion that damp wiping is the most effective cleaning method. Work carried out using a Dryden Q3 Surface Analyser on pre-prepared plates with particles of known size showed the percentage reduction in particle contamination as shown in Figure 1.

removed from the surface to remain with the wipe. Once the wipe is removed from the environment, the particles go with it, resulting in the most effective method for removing particles from a cleanroom surface. The amount of fluid used to pre-wet the wipe is critical as if the wipe is over saturated then particles are re-deposited on the surface and simply moved around , not picked up into the wipe. However it must be remembered that a wipe can only remove the contamination if it comes into contact with it, so care must always be taken to ensure the wipe comes into consistent and intimate contact with all areas of the surface to be cleaned or disinfected. Unless carefully done hand wiping can be quite variable and wiping tools such as isolator cleaning tools and mops reduce surface contact variability. Mouldings, door and window frames, seams all pose a challenge to good surface contact. Ideal mopping systems for cleaning need to be able to apply suitable aqueous cleaner in a sufficient quantity to walls, floors and ceilings to ensure any potential soils and disinfectant residues are removed. Mop heads with a certain level of abrasion will help to remove any potential biofilms that have formed on the surface. For spill control a mop with outstanding absorption and fluid retention properties is required to prevent the contamination being spread across the surface. Contec can provide a wide range of cleanroom mop hardware and single use mopheads suitable for all grades of room and all types of facility. All parts of the decontamination process should be validated and documented. If it isn’t written down it didn’t happen! The cleaning process should be carried out to a documented procedure in the same way as the disinfection process. Trained personnel should undertake the cleaning process, this is regardless of whether the activity is carried out by the facilities own staff or sub-contracted. The validation of cleaning on hard surfaces in a cleanroom is quite straightforward and is usually a visual or black cloth test of the surface. Simply take a black or coloured wipe over the surface to see if any dust or dirt remains. There are black light or UV torches available which allow an operator to see non-visible dirt on a surface and which can be used to help validate the cleaning process. All cleaning agents should have a validation file.

Wiping is such an efficient method of particle removal as it has been estimated that a modest downward force of 0.5 kg on a cleanroom wipe translates into a 50 kg force at the surface where it is acting to remove particles. At a microscopic level it can be seen that only the outermost fibres of the wipe are in contact with the surface to be cleaned and these fibres act like “micro-squeegies” with all the downward force acting through these few fibres. This mechanical action overcomes the various forces holding fine particles (including sub-micron particles) to the surface. This coupled with the fact that the structure of the wipe itself allows for entrapment of the particles and the subsequent physical removal of them from the surface explains why wiping is so effective. The ability of a wipe to trap particles varies dependent on the structure of the wipe and size of the contaminant. Wetting a wipe further enhances its ability to trap particles. Not only can a surface-tension reducing fluid be used but a damp wipe allows better surface contact to be achieved. A dry wipe will capture and retain some of the particles from the surface, but the attraction to the dry wipe must be stronger than the attraction of the surface. If there is nothing to bias the particles to remain with the wipe, some particles are left behind with the surface. Using a wetted wipe provides an overpowering bias for the particles to remain with the wipe, since capillary hydroscopic forces from the moisture on the wipe provide the mechanism for the particles

Contec’s portfolio of contamination control products can help with your cleaning regime, with a wide range of mops, wringers and bucket systems, there is a suitable mop for all areas and surfaces available. Wipes are available sterile or non-sterile, presaturated or dry, knitted or nonwoven, in a variety of substrates, sizes and formats. Contec NeutraKlean is a cleanroom manufactured neutral pH detergent specifically formulated to be low foaming and easyrinsing whilst being highly effective on light soil.

WWW.EPMMAGAZINE.COM

COUNTERFEITING

Check point Thanks to a smartphone app from U-Nica both manufacturers and consumers can verify the authenticity of drugs anytime, anywhere

pproximately 2,000 people die every day from consuming counterfeit medicines. In 2019, an EU directive comes into force that requires safety labelling for prescription drugs to reduce the risk to consumers. To effectively prevent piracy, counterfeit products must not only be clearly identified but pharmaceutical manufacturers must also know where the counterfeits enter their supply chain and where grey market shifts occur. The Swiss security company U-Nica has developed a new method, which enables a continuous authentication of products, providing comprehensive anti-counterfeiting protection over the whole supply chain. The technology, Scryptotrace, is a reliable pattern recognition method, which detects certain codes on a label or packaging that are otherwise imperceptible to the eye. The app is simply installed on mobile devices such as smartphones or tablets. Manufacturers allow customers to verify the authenticity of their product using this app any time or at the point of sale.

“

In 2015, under Operation Pangea, Interpol seized a record number of 20.7 million counterfeit drugs with an estimated value of 81 million US dollars. Counterfeit medicines pose an enormous health risk for consumers and are also a major economic problem for the pharmaceutical industry: “They damage the reputation of the industry and can lead to sales and customer losses,” explains Alfred Rutz, CEO of U-Nica Group. “The end consumer loses confidence in the medicine or the manufacturer of the medicine and then replaces it with another,” he adds Rutz.

Approximately 2,000 people die every day from consuming counterfeit medicines.

An update to the EU Falsified Medicines Directive from February 2016 includes provisions for unique barcoding and anti-tampering features that can prove a pharmaceutical product’s authenticity. Since all pharmaceutical manufacturers must meet these requirements by 2019, forgery-proof marking methods are becoming worldwide increasingly important in the sector. In the USA and Asia, there are also already similar regulations either implemented or in planning.

”

Control over the entire supply chain ”To successfully combat counterfeiting, however, it is not only sufficient to identify plagiarism,” says Rutz. “Pharmaceutical companies should also know about how exactly the forgeries reach their distribution chain, where the grey market emerges, and how the goods are being moved.” U-Nica has developed a security solution that not only meets the requirements of the regulation, but unlike alternative technologies

Safe and secure: When using the Scryptotrace system, security elements are applied to packaging and can be easily read using special recognition

can also ensure a comprehensive and effective protection against counterfeiting: Scryptotrace fills a gap in the existing range of security solutions. It allows the authenticity of branded products – from manufacture to point of sale – to be checked at all critical points. The producers are made aware, both globally and in real-time, of the emergence of a counterfeit issue or grey market movements. Scryptotrace is based on dynamic digital markings, which are integrated by print into drug packaging. The codes are generated by the Scryptotrace server by the pharmaceutical manufacturers themselves. They are managed and used as flexibly as needed. Only the original print layout is needed to perform the encoding. The layout and the printing processes remain unchanged, without numerous printers being used, which may be a security vulnerability in certain countries. “The software-based security solution can be scaled very effectively. Therefore, expenses for conventional security solutions of a manufacturer can be drastically reduced,” explained Rutz.

Control via commercial smartphones For this purpose, samples at various checkpoints will be taken along the distribution chain with a standard smartphone or a tablet. Just photographing the coded imprint is sufficient, and the app responds within seconds, whether the product is genuine or counterfeit. The result will then be transmitted, along with important information such as date, time, location, and user identity via the mobile network or data connection to the corporate headquarters. The pharmaceutical company learns immediately where counterfeit or grey market products are in circulation. The producer can evaluate the collected data and efficiently identify the risk and quantify. By automatically synchronising with the Scryptotrace server (on which all information is stored), the company can accurately analyse its supply chain and the effectiveness of its brand protection measures, precisely optimise and use the resources effectively. The encoding can be matched to different print runs and is easily changed for criteria such as a validity period or sales channel. This effective method increases the reliability of the detection of counterfeits and grey market movements and additionally provides differentiated information about the distribution process and customer behaviour. As the technology uses conventional smartphones and tablets it can be used globally and offline, which makes it very user friendly. "A key advantage is that employees, inspectors, customs, police or other partners along the national or global distribution chain are able to select a product and test it, without special training or expensive readers," says Rutz. The process requires minimal investment or change in business processes. It can be introduced and scaled without long

WWW.EPMMAGAZINE.COM

lead times. Therefore, global companies with complex organisational structures and products with high risk potential reap maximum benefits. This solution fills a gap in the existing range of security solutions and offers combined with an existing logistics solution a powerful yet costeffective solution for serialisation and traceability of original products. It is significantly more economical than conventional methods.

End consumers verify in the future Moreover, scryptotrace offers brand owners the additional option to interact with end consumers, to build on trust: "Through the app, manufacturers can enable every smartphone or tablet user to verify the authenticity of a product at the point of sale," says Rutz. “An end consumer can perform verification with their own smartphone, rather than having to rely on someone else. This creates confidence in the brand and enhances customer loyalty.” There are no costs for the end consumer. Of great importance is that the app can be used anywhere in the world and at any time regardless of whether the user is connected to a wireless or mobile network. The direct verification by customers or consumers however could still have a more important side effect: “If the consumer can identify fakes at the point of sale, this places pressure on those involved in the distribution chain to ensure that fewer fakes enter the market. Sales points that deal with counterfeits may become publicly known,” explains Rutz. “Therefore, producers would no longer be alone in fighting the global counterfeiting problem. Costly inspections and detection methods would no longer be required. A potential global verification team of 1.9 billion consumers with smartphones will support future campaigns in deterring the trade in counterfeits significantly more than any previous actions."

System for different industries The security solution is suitable for almost any industry, such as the cosmetics or food industries. The security solutions provider U-Nica is active in various industries, promoting product protection solutions. For example, the company has entered into a distribution agreement with

the international pharmaceutical ingredients trader Fischer Chemicals, which also offers the solution to its customers. Furthermore, the method can be used in many other industries, for example in the aftermarket or electronics industry, in order to identify and control the distribution chain forgeries. Renowned multinational corporations, who would want to protect their valuable brands, are already using the solution worldwide, or are in the global rollout. The demand is growing steadily. "We can already count the top industry leaders among our clientele," explains Rutz.

High-tech company introduces further innovation to the market Also in the medical sector, U-Nica has tested successfully its digital security solutions under the brand name Scryptotrace as a ‘fingerprint’ solution. The system was developed and tested with a leading manufacturer of surgical equipment as part of a Swiss nationally-funded technology project to identify original parts by their surface structure. “The partner company discovered counterfeit consumables in the market and received eyewitness accounts reporting that single-use parts were being used repeatedly,” says Rutz. “In one case, the same supposedly sterile product was used for several different patients.” The Scryptotrace fingerprint solution, which reliably detects existing random patterns of material surfaces, rather than added encodings, was used to identify unused original products and consumables in real time. It alerts medical personnel during surgical procedures to contact with potentially contaminated materials. It also warns that the product has been in use or does not come from the original manufacturer. The use of consumables that may have been produced in a non-sterile environment can be excluded from surgery. The technology can also be used in such a way that equipment can only function if original consumables are being used, which in turn allows other applications. U-Nica will bring this solution as a world’s first on the market by the end of 2016. The solution provider specifically focuses on quality and system-critical products with high liability risks such as medical equipment and supplies in the health sector.

Picture this: Samples at various checkpoints will be taken along the distribution chain with a standard smartphone or a tablet. Just photographing the coded imprint is sufficient

WWW.EPMMAGAZINE.COM

2 & 3 November 2016 Discovering innovation at the heart of the laboratory industries

Lab Innovations is THE industry event to network, generate new business leads and develop industry knowledge. Join Professional Scientists and Laboratory Managers from the Food & Drink, Research & Development, Medical, Chemical, Biotechnology and Manufacturing industries who are all looking to looking to meet and compare suppliers and discover new products and services.

FREE

registration now open!

Seminar sessions on the show floor by

Find out more gg www.lab-innovations.com

2016

NEC, Birmingham

CONTAINMENT

Keeping it contained The containment industry is evolving – are you? Asks the Dec Group Realising the desired levels of containment to minimise operator exposure while protecting sterile products is a complex process in which nothing can be left to chance. Aseptic high-potency API processing calls for specialised facility design to help pharma improve and maintain the sterility of its drug products.

Both visors are then closed and the isolator environment started. Before production an automated pressure decay test is performed. The operator then removes the outer foil bag from which each bag which is disposed via a non-sterile endless liner in the airlock. Each one is hung in a specific validated position using Dec’s automated bag rack system.

It is essential to partner with vendors that understand both containment and the requirements for sterile potent-compound handling. Equipment should be purpose built and provide the necessary flexibility to deal with process changes, especially for multipurpose facilities. Many technologies help improve the safety and efficiency of aseptic drug manufacturing. These include mobile cleanrooms and restricted access barriers (RABs), laminar flow cabinets or glove boxes and increasingly isolators – this article presents a recent application in the field of animal health.

Both isolator chambers are biologically decontaminated using Vaporised Hydrogen Peroxide (VHP). This achieves a 6-log reduction using a validated decontamination cycle and an integrated open loop VHP generator.

The customer faced the challenge of how to charge a reactor with sterile high potent ingredients assuring operator and product protection.

The weight of each bag of powder is then manually verified on an internal scale prior to manually opening the bag and manually charging the sterile APIs into a pre-sterilised (with clean steam) powder transfer hopper. The APIs are then conveyed into a sterile process reactor using Dec’s patented powder transfer system, which is installed directly on the process reactor in an adjacent vessel room.

The isolator had to meet the following requirements: • OEL (Occupational Exposure Limit) of < 1 µg/m3 time weighted average over 8 hrs (TWA) • Provide a safe barrier between the operator and the active drug substance to ensure both operator and product protection • Achieving and maintaining an ISO 14644-1 class 5 environment for particles and viable micro organisms • Plant designed to operate in both positive and negative pressure modes and in sterile and non-sterile conditions • Multi-product use of OEB 5 category (sterile potent compounds) • CIP / SIP / temperature mapping Dec’s process containment experts designed this high level environment isolator as an L-shape twin chamber isolator consisting of a fast gassing airlock and a main charging chamber which are connected via an internal transfer door. The system is designed for the charging of either sterile or high potent compounds supplied in various number of bags of different sizes and weights max 15 bags x 10 kg into a process reactor by means of a powder transfer system (PTS). For cleanliness the isolator features a through-the-wall design creating a dedicated technical area for maintenance and services at the rear which is accessed separately to the process area. The process operation mode is selectable either in positive or negative pressure via the HMI. Sterile mode operation - both chambers are initially loaded with bags of sterile APIs in various weights and sizes through the front visors.

The bags are then removed from the rack and those from the airlock are transferred into the main charging chamber. The internal transfer door is then interlocked closed.

Due to the campaign requirements the process is continued by using the airlock as a fast gassing airlock and the internal transfer door between both chambers interlocked until the next VHP cycle has been completed. This enables the charging chamber to remain sterile at all times. Potent mode operation – The isolator operates in the same principle as the sterile product but the isolator operates in negative pressure. There is no requirement for biological decontamination of the incoming product. Due to containment in this mode the main charging chamber operates at a lower negative pressure to the airlock and the airlock is operated as a conventional transfer airlock chamber. The PTS conveys and doses dry and wet powders and granules. To convey powder, the system operates with vacuum and pressure. It is composed of a cylindrical body which is alternately filled by vacuum and discharged by pressure. A flat filter membrane in the upper part prevents fine dust particles from entering the vacuum line. The membrane is cleaned by each discharging cycle by means of sterile compressed air or inert gas. The system including charging hopper and transfer hose to the process reactor is sterilised in place (SIP) with clean steam with full thermal mapping. Sterility is assured throughout the whole dispensing and charging process.

WWW.EPMMAGAZINE.COM

BIOPHARMACEUTICALS

Super dry Robert Turok, SPX Flow, discusses high yield spray drying of monoclonal antibodies and its use in the production of fine biopharmaceutical powders.

ests on spray dryers have revealed they can offer high yields in the manufacturing of monoclonal antibodies (mAb); producing powders that offer advantages in storage and transportation compared with liquid or frozen alternatives. The process has been shown to produce good stability and potency; offer practical reconstitution times, and proven scalability â€“ giving manufacturers a viable and beneficial alternative to conventional ultrafiltration (UF) and freeze drying (lyophilisation) processes. The resulting spray-dried powders give no process limitation to solution viscosity in the preparation of high concentration mAb formulations.

What are monoclonal antibodies? Antibodies are proteins produced by the body's immune system when it detects harmful substances such as bacteria and viruses that might cause an infection. Monoclonal antibodies are clones of a single type of antibody that recognise and attach to specific proteins produced by cells in the body. They work in different ways to help with the treatment of cancer. These include triggering the immune system to attack cancer cells; stopping checkpoint inhibitors in the body so the immune system can work effectively; blocking signals that tell cancer cells to divide, and acting as carriers to transport cancer drugs or radiation to cancer cells. They are also used in diagnostic tests, including pregnancy tests; to help stop organ rejection after a transplant, treatment of other diseases such as multiple sclerosis, and by researchers to identify and trace specific cells or organisms.

Conventional mAb production process

â€œ

As with many other biological drug substances, mAb tend to be produced over periods and may be stored for long intervals until needed to produce the final drug product in line with market demands. Traditionally they are produced using a single UF/diafiltration (DF) process which produces a drug substance that is in liquid form. This is then shipped and stored in a frozen state to reduce instability and prolong its shelf life. When needed at the drug production plant, it is thawed and filtered ready for use.

The problem with handling frozen drug substances is the equipment needed to store them. They can be kept in large volume cryogenic tanks, small volume

The problem with handling frozen drug substances is the equipment needed to store them. They can be kept in large volume cryogenic tanks, small volume plastic bottles or small volume disposable bags. Maintaining this cold storage, however, is costly and troublesome. Large stainless steel or Hastelloy storage tanks are expensive; regular maintenance and cleaning are required, and systems require validation. Furthermore, bulk storage creates long freeze-thaw cycles, requires a lot of space and careful control of temperature and temperature change rates. Small volume storage options use a lot of bags or bottles per production batch and produce more challenging conditions for sampling and maintaining quality.

â€?

If higher concentration levels of mAb are required, the drug substance production plant may introduce a second UF stage. This can, however, present additional challenges as gelation can occur at the filter membrane as viscosity increases and permeate flux (flow rate through the membrane) reduces. An increase in process temperature will lessen the solution viscosity and alleviate this problem, but the higher temperature may cause problems in sensitive proteins and degrade product stability.

Use in the production of fine biopharmaceutical powders Spray drying using a cyclone to collect powder is a well-established process and is widely used in pharmaceutical applications including areas such as encapsulation, microencapsulation and agglomeration. It is also gaining in popularity in biopharmaceutical applications and offers producers the capability to control particle characteristics with consistent precision and performance. The dryers use heated gas that mixes with an atomised feed in a chamber to create a dry powder. The thermal energy of the hot gas is consumed in evaporation so there is reduced heat exposure to the product being treated, making spray drying ideal for the processing of heat sensitive compounds. Historically spray dryers have not been used for larger production capacities with particles less than 10 microns. This is because cyclones were designed for lower pressure drops therefore imparting reduced forces to the particles collected. Higher efficiency cyclones with increased pressure drops have been successfully applied to large molecule bio-pharm applications. Pharmaceutical particles have been found to be physically robust and have not experienced attrition or smearing within the cyclone. Multiple high efficiency cyclones may also be used, smaller cyclones will generally have greater small particle collection efficiency. This means that high yield, predictable and consistent performance can now be achieved using spray drying in such applications. The clear benefit of using spray dryers is that the drug substance is in powder form. This alleviates the difficulties and cost of cryogenic storage of the liquid product, enables easy handling and transport as required and, although reconstitution is required, removes the need for long freeze / thaw cycles. Tests on spray drying mAb formulations have given very positive results that make this an interesting alternative to traditional methods of producing this important drug substance.

WWW.EPMMAGAZINE.COM

Tests using multiple mAb formulations Carbohydrate sugars can be used to stabilise mAb in a dehydrated state. Too much sugar in the formulation, however, can reduce yields as the resulting powder can have a reduced glass transition temperature and stickier properties resulting in particles sticking to the sides of the drying chamber. Organic or inorganic salts can be used to reduce viscosity to aid processing. Tests on the effectiveness of spray drying were carried out using multiple mAb formulations with sugar (trehalose) and/or salt (arginine succinate). With a limit of 220:1 molar ratio of sugar to mAb, spray drying produced powders with approximately 5% moisture and yields typically greater than 95%. Formulations were tested on a lab-scale Anhydro MicraSpray35 (38 kg/h drying gas rate) and pilot scale Anhydro MicraSpray150 (154 kg/h drying gas rate). Under similar drying conditions both dryers produced powders of similar moisture content, particle size and powder yield; showing the scalability of the process. As a result of the spray drying process, mAb powder samples were stored at 40 Â°C for up to three months and at 25 Â°C for up to six months. When liquid formulations from the reconstituted powder were compared with liquid formulations prior to spray drying, the results were similar. Both aggregation and fragmentation were comparable, suggesting that the high temperature spray drying had a negligible effect on the stability or quality of the spray-dried mAb stored over long periods. The reconstitution properties of the mAb formulation powders are obviously a critical factor in using spray dryers. The reconstitution time may depend upon factors such as protein concentration, particle

size, solubility and agitation intensity. The spray dried powder showed reasonable reconstitution time; generally less than three minutes to typical bulk drug substance concentration levels. It also showed good reconstituted solution turbidity, with similar characteristics to the original liquid after the subsequent filtration stage that both liquid and reconstituted powder formulations would require.

Summary Spray dryers offer highly efficient drying capability with the potential to significantly reduce production time and cost. Their high inlet temperature has been shown to have negligible detrimental effects on the quality of mAb, which showed good stability and potency after processing. The use of high efficiency cyclone technology has enabled very high yields for fine powders in larger scale spray dryers; offering pharmaceutical and biotechnology producers a viable and more compact alternative to expensive freeze-drying processes. Spray drying is a continuous process facilitating validation in FDA regulated applications. The ability to achieve powder moisture levels of around 5% further offers manufacturers significantly simplified storage and transportation of drug substances. Tests on mAB showed that powders can reconstitute in a reasonable time and the reconstituted liquids give comparable viscosity and osmolality (concentration) to the liquid formulation prior to spray drying. Alongside high yield, high efficiency and scalability; spray drying offers the significant advantage in the production of mAb of enabling the creation of high concentration, high viscosity formulations without the concentration limitations of conventional UF processes.

WWW.EPMMAGAZINE.COM

FOLIO ADVERTORIAL

Successful presentation of new products Designs in multiple colours, serialisation with process safety • Innovative products for serialisation and late stage customisation meet with great interest from pharma-oriented packaging and label printers. • For the first time worldwide, the DIGILINE Versa combines serialisation and late stage customisation in multiple colors. • The DIGILINE Label Offline system allows serialised labels to be pre-produced – fast, in abrasion-resistant quality, and with optimum process safety. The drupa 2016 exhibition marks a turning point for track & trace expert Atlantic Zeiser: “We clearly noted strongly increasing interest in finalizing pharmaceutical packaging and labels at the latest possible moment”, says Manfred Minich, CEO of Atlantic Zeiser, summarising the exhibition. “More and more countries require serialisation, and late stage customisation of packaged pharmaceuticals is becoming increasingly urgent in view of continuously decreasing lot sizes. A large number of visitors therefore sought contact with us – many of them with specific project enquiries and investment plans.” Presentations with the topic “Serialisation meets Late Stage Customisation” done by Atlantic Zeiser experts at the “drupa touchpoint packaging” that were part of the Innovationsparks were very well attended. Visitors were also particularly interested in a world debut at drupa exhibition. Atlantic Zeiser premiered a solution that allows users to print all information that varies by market, language, or product on flat or already-bonded cartons immediately in front of the packaging process in multiple colours, while simultaneously serialising the cartons during the same process step. Thanks to the new OMEGA Pro DoD UV inkjet generation, the new DIGILINE Versa system is able to digitally print graphic and text elements as well as serialisation codes in four or six colours to verify the complete layout by means of a A high-resolution camera system, and to reject it products if required. A high-resolution camera system verifies the complete layout and triggers ejection if required. Based on UV-curable inks, the resulting printing quality features high contrasts and is resistant to water, light, and wear. “The huge number of visitors throughout the exhibition and their questions, some of which were very in-depth, showed us that we premiered the DIGILINE Versa at exactly the right time.

Many visitors confirmed that this solution may very well be unique”, said Helmut Schneider, product group manager packaging at Atlantic Zeiser. The professional visitors also focused on the new DIGILINE Label Offline, which allows users to pre-produce and serialise (pharmaceutical) labels – fast, in abrasion-resistant quality, and with optimum process safety. This means that the serialisation and the label dispensing processes can be separated both physically and in time. Pre-serialized labels can be produced in one centralized location for several packaging lines, or be outsourced to external label printers. Those who operate several packaging lines that do not consume more than 60m per minute label material can concentrate label printing with DIGILINE Label Offline system in an efficient and space saving way within the production process”, explains Michael Urso, product manager pharma & packaging solutions at Atlantic Zeiser. Both systems – DIGILINE Versa and DIGILINE Label Offline – feature the powerful Unique Code Software which ensures that codes are successfully generated, printed and stored with optimal process safety after camera verification, while related reports can be produced for downstream processes.

One-stop integrated solutions for serialisation, track & trace, and late-stage processes The Pharmaceutical and Packaging Solutions division of Atlantic Zeiser ranks among the leading suppliers of sophisticated individualisation, serialisation and track & trace solutions that efficiently and seamlessly monitor product movements, securely verify authenticity, and reliably protect against counterfeiters. Innovative digital printing uses drop-ondemand technology to create superior-quality labelling, coding and marking solutions – from primary packaging to late-stage customising in the pack printing segment. Specifically for the pharmaceutical and cosmetic sectors, the division develops tailored systems to facilitate the reliable, legally compliant, cost-efficient and fast application of unique security features to individual and mass products. Atlantic Zeiser’s track & trace systems bring together the latest machine and printing technologies with intelligent and fully compatible software architecture. The company addresses the particular needs of the pharmaceutical industry with its MEDTRACKER serialization software, and offers BRANDTRACKER to support the sophisticated brand protection endeavours of the cosmetic segment. Elements of these database solutions are also available to packaging manufacturers and other suppliers to the pharmaceutical and cosmetic industries in the form of unique code software.

WWW.EPMMAGAZINE.COM

SPECTROSCOPY

Plus points: TRS offers speed of measurement, robustness to sample presentation and cost savings per batch test, says Cobalt

Measure for measure Cobalt outlines a new technique for fast low-level polymorph API quantification using non-destructive transmission Raman spectroscopy

new technique for measuring low-levels of crystalline polymorphic materials is said to offer a range of advantages over industry standard techniques. Two recent papers describe the use of Cobalt’s TRS100 instrument for fast, low level quantification of API polymorphs (and excipients) in tablets. The latest paper shows sub-second measurements of intact tablets, which contrasts with the hours required using competing X-ray or NMR techniques. This makes transmission Raman spectroscopy (TRS) a suitable technology for both formulation development and final dosage form testing in pharmaceutical manufacturing. Published in the Journal of Pharmaceutical and Biomedical Analysis, the latest paper describes quantification of exceptionally low levels (0.621.32% w/w) of an API’s polymorphic forms in a typical pharmaceutical formulation. Measurement times <0.2 seconds were achievable using Cobalt’s Beam Enhancer technology.

This work comes soon after another recent publication, published by Genentech and Cobalt Light Systems in American Pharmaceutical Review, which describes the use of TRS for fast, non-destructive detection of low level crystalline forms in amorphous spray dispersion. Cobalt says pharmaceutical manufacturers are increasingly using its TRS100 system for polymorph quantification and content uniformity testing of tablets and capsules in R&D and production environments. TRS is attractive because of the benefits it offers in speed of measurement, robustness to sample presentation, lack of preparation time, avoidance of solvents/consumables and the significant cost that can be saved per batch test.

Accurate quantification of polymorphic forms is essential for pharmaceutical companies looking to protect their novel drugs – different polymorphs may have different patent protection. Increasingly, new APIs are formulated to have no polymorphic form – known as an amorphous API – to increase the drug’s solubility and therefore patient efficacy. Having a means to detect small amounts of polymorphs in intact tablets is extremely useful for final dosage form quality testing, stability testing and in monitoring intellectual property rights. Existing technologies for polymorph quantification include powder X-ray diffraction (pXRD) and solid-state nuclear magnetic resonance (ssNMR). Compared to transmission Raman, both XRD and ssNMR require destructive sample preparation, which can mechanically change the polymorph content, have significantly longer data acquisition times and the costs per test are much higher. Powder XRD has a significantly poorer limit of detection and ssNMR, which can require a full day of measurement time, is comparable in sensitivity but significantly more expensive.

Get the measure of: A technique for measuring low-levels of crystalline polymorphic materials is said to offer advantages over industry standard techniques

WWW.EPMMAGAZINE.COM

A M R PHA THE AT CKS FLI

FOLIO

LUCY

Reviewed: Lucy

In the life sciences, we strive to push the limits of our brain power. Lucy is a story about a drug that does just that.

The film: Lucy The year: 2014 The budget: $40 million Box office takings: $463.4 million Rating: 6.4/10 IMDB / 67% Rotten Tomatoes Leading lights: Scarlett Johansson, Morgan Freeman, Choi Min-sik, Amr Waked Written by: Luc Besson Directed by: Luc Besson

Scarlett Johansson stars in this mindbending science fiction thriller. Image: CarlaVanWagoner / Shutterstock.com

Synopsis Lucy, an American studying in Taiwan, finds herself in hot water when she is tricked into becoming a drug mule for a Korean mob. In a gruesome twist, the drug she must transport (a large quantity of something called ‘CPH4’) is sewn into her abdomen. She doesn’t get far into her delivery however: whilst being held captive, one of her abusers lands a kick which explodes the bag – and thus, the CPH4 enters her system in a massive dose. Lucy manages to escape, and heads for the hospital to have the bag removed. She’s told that CPH4 is a substance produced by expectant mothers, which gives the foetus the necessary energy to develop – but it’s only usually found in minute quantities. From here on out, the film operates on the popular urban legend that as humans we use only 10% of our brain capacity. The drug takes effect on an unprecedented scale, with Lucy developing astonishing psychological and physical capabilities far beyond the ‘normal’ 10%. She exacts revenge on her kidnappers, and then sets off on a journey to get help with her new condition – sensing that her

growing skillset will eventually lead to her own destruction. Finally, having learned all there is to know about everything, she morphs into a supercomputer and then, naturally, disappears into the spacetime continuum. Wow!

Pharmaceuticals There’s only really one drug to focus on in Lucy: the aforementioned CPH4. As ludicrous as this film may sound if you’re reading about it for the first time, CPH4 does apparently have basis in reality. According to writer/director Luc Besson, in an interview with Crave magazine: “It’s totally real. It’s not a real name. CPH4 is a name that I invented, but it’s a molecule that the pregnant woman is making it after six weeks of pregnancy in very, very tiny quantities. But it’s totally real, and it’s true that the power of this product for a baby is the power of an atomic bomb. It’s real. It’s totally real. So it’s not a drug in fact, it’s a natural molecule that pregnant women produce.” Besson also explained that he wanted to embrace the science before sitting down to

WWW.EPMMAGAZINE.COM

write the movie: “I worked on the scientific part for a couple of years first before I go to even think about the script. I want to have a knowledge first. I want to know what I was talking about first. And then after that I don’t want to do a documentary about the brain capacity. I wanted to do something entertaining, a thriller. And then I start to think, can we do a thriller with a philosophical content? Is it possible? Let’s try. Let’s try to do both. You can see one or you can see the other, but what about making a film where you have both? That was my goal.” And of course, though the 10% myth is just that – a myth – drugs and supplements do exist that allow the user to tap into more of their cognitive abilities. Racetams, choline, vitamin B derivatives, peptides and ampakines are all categories of nootropics. The use of these drugs and supplements amongst healthy individuals raises considerable ethical questions, which is one of the most interesting subtexts in Lucy.

Why you should see this film The special effects, like Lucy’s brain power, get better and better as the film goes on, culminating in one of the most memorable finales in sci-fi history.

RIGHT Idea. WRONG Tool. Just like dad always said, “the right tool for the job.” He was right (ok, maybe not about everything). You don’t butter bread with a shovel. You don’t set punches with a sledgehammer. What you do need is a customized Natoli Toolbox outfitted with all the right set-up tools specified by your press manufacturer. Make your job easier, contact us to order yours...TODAY!

NATOLI ENGINEERING COMPANY, INC., 636.926.8900 • info@natoli.com

natoli.com