Volume 6 Issue 2
International Pharmaceutical Industry
Supporting the industry through communication
The EU Unitary Patent Overview and Practical Considerations Diabetes Care New Technologies in the Fight against a Global Pandemic Ready for Battle How Preclinical Development brings New Vaccines to the War on Disease Parenteral Packaging Raw Material Substitution and Procurement Impact www.ipimedia.com
06 Editor’s Letter REGULATORY & MARKETPLACE
International Pharmaceutical Industry
Supporting the industry through communication
DIRECTORS: Martin Wright Mark A. Barker EDITOR: Cecilia Stroe firstname.lastname@example.org EDITORIAL ASSISTANT Orsolya Balogh email@example.com BOOK MANAGER: Anthony Stewart firstname.lastname@example.org BUSINESS DEVELOPMENT: John Unikowski email@example.com DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks firstname.lastname@example.org FINANCE DEPARTMENT: Martin Wright email@example.com RESEARCH & CIRCULATION: Heather Bayran Heather@pharmapubs.com COVER IMAGE: iStockphoto © PUBLISHED BY: Pharma Publications Unit J413, The Biscuit Factory Tower Bridge Business Complex 100 Clements Road, London SE16 4DG Tel: +44 (0)20 7237 2036 Fax: +44 (0)01 480 247 5316 Email: firstname.lastname@example.org www.ipimedia.com All rights reserved. No part of this publication may be reproduced, duplicated, stored in any retrieval system or transmitted in any form by any means without prior written permission of the Publishers. The next issue of IPI will be published in Septermber 2014. ISSN No. International Pharmaceutical Industry ISSN 1755-4578. The opinions and views expressed by the authors in this magazine are not necessarily those of the Editor or the Publisher. Please note that although care is taken in preparation of this publication, the Editor and the Publisher are not responsible for opinions, views and inaccuracies in the articles. Great care is taken with regards to artwork supplied, the Publisher cannot be held responsible for any loss or damage incurred. This publication is protected by copyright. 2014 PHARMA PUBLICATIONS Volume 6 issue 2 - Summer - 2014
08 FDA Issues Guidance on Reporting Requirements for Web-Based Promotion of Drugs and Biologics The FDA has finally given some guidance on what drug companies must do to comply with federal reporting requirements when marketing their products through social media websites and other interactive media. Nick Nelson of Haynes and Boone LLP summarises this new and long-awaited guidance from the FDA. 10 A Merging and Acquisition Perspective in Pharmaceutical Industry It is very difficult to estimate how many mergers and acquisitions in the pharmaceutical industry have succeeded. It is even more difficult to define what success means. K. Sreekanth Reddy, V. Balamuralidhara, Shilpi Khattri and T. M. Pramod Kumar of JSS College of Pharmacy, JSS University, Mysore look into the challenges of corporate takeovers, showing us why 80% of mergers do not meet their pre-merger financial goals and 50% become failures. 18 Achieving Operational Excellence in Drug Safety with an Effective Quality Management System The International Conference on Harmonisation (ICH), European Medicines Agency (EMA) and US Food and Drug Administration (US FDA) have laid out their expectations with respect to Quality Management Systems (QMS) for PV. Chitra Lele, PhD – Chief Scientific Officer, Sciformix Corporation – reviews the QMS-related requirements and specifications, and compares and contrasts the requirements of various organisations, primarily to elaborate on how these requirements can be implemented, what constitutes a robust QMS and how it can be built into PV operations. 22 Keeping Data Secure and Validated in the Cloud – Addressing the Misconceptions Surrounding Cloud Computing in Pharma The requirement to demonstrate compliance, while still maintaining process efficiency and ease of use for marketing teams and timeto-market for life science companies, has led to a surge in interest in cloud computing systems for the management of commercial compliance. David Bennett of Zinc Ahead discusses the use of cloud computing within life sciences, focusing on the misconceptions that surround cloud computing systems in the three areas of data security, validation, and compliance. The article reviews different cloud environments and the benefits for life sciences - emphasising the importance of data validation and compliance in conjunction with privacy and security when specifying a cloud computing system. 26 The EU Unitary Patent – Overview and Practical Considerations The preparations have spanned almost 40 years, and there have been many significant obstacles to overcome. However, the “Unitary Patent” and the dedicated “Unitary Patent Court (UPC)”are now an inevitability. Jon Gowshall and Charlotte Fox of Forresters give an overview of the new system and look at some of the practical implications of the Unitary Patent and UPC for patent owners. The UPC agreement was signed on 19 February 2013, and will come into force as soon as it has been ratified by enough countries (thirteen including the UK, Germany, and France), probably in 2015. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 28 Outsourcing Computational Chemistry for Drug Discovery Computational chemistry is a highly-skilled scientific field that has delivered proven results for drug discovery, particularly in the areas of lead identification and optimisation. Many companies maintain an in-house team or expert who can perform data analysis and carry out molecular modelling. The trend to outsource is making computational chemistry methods affordable and accessible for smaller research organisations. Dr Martin Slater of Cresset outlines the scientific and business reasons for outsourcing this important drug discovery method. INTERNATIONAL PHARMACEUTICAL INDUSTRY 1
32 Determining Thermal and Colloidal Stability with High-Throughput Dynamic Light Scattering Stability is a key quality attribute of therapeutic bio-molecules, critical for establishing drug-like properties and suitability for use in humans. However, establishing the stability of a candidate molecule or formulation can be a long and tedious process. Sophia Kenrick of Wyatt Technology Corp. explains how, in order to minimise time, effort and funds spent on long-term stability studies, developers of biologics look to high-throughput screening methods that can reliably test and rank hundreds of combinations of candidates, excipients and buffer conditions. 36 Regulatory Focus on Nanomedicines in US and Europe Vidhya Sabbella, Valluru Ravi, T. M. Pramod Kumar and K. Sreekanth Reddy, of JSS College of Pharmacy, JSS University, Mysore, give an overview of nanotechnology and its drug delivery system, as well as the regulatory approach for the approval of nanomedicines in the regulated markets like United States and Europe. The use of nanoscale technologies to design novel drug delivery systems and devices is a rapidly developing area that promises breakthrough advances in therapeutics and diagnostics. CLINICAL & MEDICAL RESEARCH 42 Ready for Battle: How Preclinical Development Brings New Vaccines to the War on Disease Few medical advances have made as large an impact on world health as vaccines. Yet the battle isnâ€™t over. As new infectious diseases emerge, as old ones grow resistant, and as our understanding of human immune response increases, researchers are developing novel vaccines, creative delivery tools, and innovative approaches. Stephene Rose of MPI Research explains why the preclinical realm is especially important to identifying and advancing the most promising candidates that could save innumerable lives.
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48 Current Perspective on TBI Dr Adrian Harel of Medicortex conveys the urgency of developing mitigating therapeutics for the secondary and long-term damaging effects of TBI. His article makes clear that in order to ensure effectiveness, new treatment options must be multifaceted and include neuroprotective, neurorestorative and anti-inflammatory agents. Soon the day may come when brain injuries of children, seniors, athletes, service personnel, and others, will be treated in much the same way injuries in other parts of the body are currently being treated. 54 Label-free Cell-based Assay for Peptide-receptor Interaction Characterisation Both the drug development process and fundamental studies of mechanisms underlying biological interactions require analytical methods that mimic the in vivo situation as much as possible. But this can be approached by using label-free cell-based assays. Davide Proverbio and Teodor Aastrup of Attana AB, and Jana Valnohova, Shane C. Wright and Gunnar Schulte of Karolinska Institutet, present a new cell-based assay that they developed for characterising interactions between peptides and their target receptors in a label-free environment. LABS AND LOGISTICS 58 Aseptic Pharmaceutical Processing: It All Begins in The Lab The drive towards novel drug presentation and injectablegrade products is generating increased demand for aseptic pharmaceutical processing, including aseptic spray-drying (ASD). But what considerations need to be made for aseptic spray-drying programmes at laboratory stage to enable them to be efficiently scaled up from feasibility assessment to large-scale manufacture? Sam de Costa of Nova Laboratories shares his insights and considerations for a smooth transition.
Summer 2014 Volume 6 Issue 2
BERLIN . NEW YORK . TOKYO
requirements of the European Medical Devices Directive. As a result, shows Stewart Gordon-Smith of Meech International, it is becoming increasingly important that professionals in the medical and pharmaceutical industries have at least a basic understanding of the most important elements of cleanroom injection moulding, as well as how to avoid potential pitfalls. SPECIAL FEATURE 74 The Rise and Rise of Prefillable Syringes Prefillable syringes are fuelling one of the medical device industry`s fastest growing and most innovative markets. Cecilia Stroe, Managing Editor of IPI, takes you inside one of the most modern production facilities for ready-to-fill syringe systems and cartridges in the world. The plant is operated by Gerresheimer Group, a leading partner to the pharma and healthcare industry. PACKAGING 78 The Hidden Challenges of Pharmaceutical Serialisation In the almost 40 years since counterfeiting of pharmaceutical products was recognised as a problem by the World Health Organization (WHO), the industry has waged a constant battle against increasingly sophisticated and organised counterfeiters, with drug packaging serving as one of its foremost defences. Craig Stobie of Domino looks into the technical challenges and commercial benefits of implementing item-level serialisation.
62 Maintaining Integrity of the Supply Chain For the pharmaceutical industry, the prevalence of counterfeit drugs can represent loss of reputation, loss of valuable R&D efforts and intellectual property, loss of revenue, and increased costs. Sue Lee of World Courier asks what can pharmaceutical professionals do to ensure that their organisations and the patients they serve are not impacted by counterfeit drugs? The answer is to identify their highest risk products and shipments and to secure their supply chain to the fullest extent possible. MANUFACTURING 64 Novel Treatment to Help Fight Drug-resistant Bacteria MRSA poses a significant public health problem around the world, yet our approach to treating infections is currently fuelling a wider issue around antibiotic resistance. In this article, Dr Paul De Bank explores how a new type of wound dressing, developed by researchers at the University of Bath, could help in the fight against superbugs. 68 How to Eliminate Cleaning and Be Rewarded with Substantially Improved OEE “Tumbling” is a widely-used way of dry powder blending in the oral solid dosage (OSD) manufacturing environment. In his article, Wim Spook of Matcon demonstrates how IBC blenders, when compared with other methods of dry powder blending, can significantly increase your blending capacity and reduce your manufacturing costs.
82 Parenteral Packaging: Raw Material Substitution and Procurement Impact The industry of glass primary packaging is seeing a rapid shift towards the usage of plastic substitutes for specific end uses (biotech drug packaging, prefilled syringes etc). M. Abhiraj of Beroe Inc. deals with the underlying facts related to the issue of glass substitution, taking into consideration the cost of recalls and total cost of ownership, but also the impact substitution has over procurement factors such as raw material sourcing, industry integration, and manufacturing of packaging. 88 New Technologies in the Fight Against a Global Pandemic The global market for insulin therapies is growing at a much higher rate than total sales of prescription drugs. For people with diabetes who are dependent on insulin, pen systems that can be equipped with insulin cartridges and injection needles have long since surpassed all other injection systems. Dr Johannes Rauschnabel of Bosch Packaging Technology provides an analysis of the new technologies used by manufacturers for the safe filling of insulin cartridges, which ensure high output, low product loss, and optimal patient protection. 92 Influence of Primary Components on Parenteral Delivery Systems, Biologic Therapies and Patient Outcome The administration of parenteral biologics relies on interconnected attributes associated with compatibility of delivery components to the safety and efficacy of the final product. Diane Paskiet and Simon Côté of WestPharma address the importance of characterising individual components in contact with a biologic, to understand the risks to the delivery system as a whole and the effect on patient outcome. And selecting an appropriate delivery system for these therapies is critically important. 99 Exhibitions and Conferences
72 Cleanroom Injection Moulding Demand for cleanroom conditions in injection moulding packaging processes has expanded almost exponentially in recent years, as growing numbers of medical and pharmaceutical manufacturers come to rely on the technology to meet the manufacturing 4 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Summer 2014 Volume 6 Issue 2
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Editor’s letter There`s been quite a debate surrounding buyouts and takeovers in the pharmaceutical industry recently. This issue of IPI brings you the viewpoint of K. Sreekanth Reddy, V. Balamuralidhara, Shilpi Khattri and T. M. Pramod Kumar of JSS College of Pharmacy, JSS University, Mysore on the matter, with insightful observations on what lies behind the M&A deals. Used by pharmaceutical and biotech companies as a strategic tool to create value, mergers and acquisitions are meant to boost their pipelines and improve efficiencies. But among experts there is a concern that less money is being spent on research and development as a “side-effect” of M&A. In his article, Stephene Rose of MPI Research argues that vaccine R&D is actually undergoing a “renaissance”. Far from investing less money, apparently biopharmaceutical companies are ramping up their investments with more than 120 new vaccine products now in development. No wonder - the timing it is certainly right: the vaccine market has more than quadrupled since the turn of the century, from $5 billion in 2000 to $24 billion in 2013. And it will more than quadruple again by 2025, according to the World Health Organization. Find out which factors are driving this demand and why the “make or break” happens in the preclinical stage. One tool that has become indispensable in the pharmaceutical industry is computational
chemistry. It has been compared to searching for a needle in a haystack, but it has rapidly evolved over the last 50 years and has inevitably changed the way research is carried out, becoming an integrated part of many drug discovery pipelines. However, drug discovery and development is a very costly and time-consuming process, and maintaining such an in-house team can be out of reach for many small drug discovery companies. IPI has Dr Martin Slater of Cresset explain how they can access this technology in a cost-effective way: the opportunity to outsource computational chemistry projects has definitely put this technology within reach of any research organisation. A key quality of therapeutic bio-molecules, critical for establishing drug-like properties and suitability for use in humans, is stability. But again, establishing the stability of a candidate molecule or formulation can be an arduous process. It is the reason developers of biologics have turned to high-throughput screening methods. The ability to screen protein formulations at the early stages of development enables scientists to concentrate on the most suitable candidates and to save substantial amounts of time, and sample and testing equipment. Sophia Kenrick of Wyatt Technology Corp. presents her experiment demonstrating that thermal and colloidal stability of proteins, two indicators of propensity to aggregate, as well as actual aggregation states, are all determined simultaneously during the screening process with DLS tools in order to rank the effectiveness of candidates and formulation conditions.
When developing new pharmaceutical drugs or probing for biological interactions, one surely needs the right tools. Aiming to obtain the same high level of experimental details as in biochemical assays and the biological reliability from cell-based assays, Davide Proverbio and Teodor Aastrup of Attana AB, and Jana Valnohova, Shane C. Wright and Gunnar Schulte of Karolinska Institutet, have developed a new label-free cell-based assay for kinetic interaction analysis of smaller biomolecules, such as a 15 kDa peptide. This methodology will have applications for researchers working with relatively small biomolecules that represent promising therapeutic agents in the treatment of cancer, diabetes and cardiovascular diseases. And because there is definitely a nanomedicine revolution underway, Vidhya Sabbella, Valluru Ravi, T. M. Pramod Kumar and K. Sreekanth Reddy of JSS College of Pharmacy, JSS University, Mysore question in their paper the FDA`s current approach to regulating nanomedicines. There are currently no proper regulatory guidelines developed specifically for products incorporating nanoscale technology, although these are already impacting the pharmaceutical industry, particularly in regard to the design, formulation and delivery of therapeutics. Cecilia Stroe Editor
Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan
Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT
Catherine Lund, Vice Chairman, OnQ Consulting
Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma
Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters
Jim James DeSantihas, Chief Executive Officer, PharmaVigilant
Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company
Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation
Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group
Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP
Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics
Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation
Georg Mathis Founder and Managing Director, Appletree AG Heinrich Klech, Professor of Medicine, CEO and Executive Vice President, Vienna School of Clinical Research 6 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Robert Reekie, Snr. Executive Vice President Operations, Europe, Asia-Pacific at PharmaNet Development Group Sanjiv Kanwar, Managing Director, Polaris BioPharma Consulting Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai) Stefan Astrom, Founder and CEO of Astrom Research International HB Steve Heath, Head of EMEA Medidata Solutions, Inc T S Jaishankar, Managing Director, QUEST Life Sciences
Patrice Hugo, Chief Scientific Officer, Clearstone Central Laboratories Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy Summer 2014 Volume 6 Issue 2
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FDA Issues Guidance on Reporting Requirements for Web-based Promotion of Drugs and Biologics The FDA has finally given some guidance on what drug companies must do to comply with federal reporting requirements when marketing their products through social media websites and other interactive media. This alert summarises this new and long-awaited guidance from the FDA.
to the FDA. The following is a summary only. The complete guidance is available here.
Background on ‘Post-marketing Submissions’ to the FDA Drug companies must submit to the FDA copies of all documents used to promote pharmaceuticals and biologics in the United States. This includes print, television advertisements, and online advertisements. The FDA reviews these “post-marketing submissions” (so called because they typically are submitted to the FDA immediately after they have been published) to ensure that they comply with regulations requiring elements such as disclosure of known risks and citations to evidence supporting all claims made in the promotional materials.
This category of site includes micro-blog sites such as Twitter, social networking sites such as Facebook, and “other sites that are under the control or influence of the firm.” To determine whether a company has control or influence, the FDA looks to whether the company – or anyone acting on its behalf – is “influencing or controlling the promotional activity of communication in whole or in part.”
Scenario 1: Promotional communications on sites that are owned, controlled, created, influenced, or operated by, or on behalf of, the firm.
If a drug company “has editorial, preview, or review privilege” over the content of
the promotional materials provided to a website, then the company is responsible for that content and should submit such materials to the FDA. This would seem to include any promotional materials the company disseminates through its official Facebook, LinkedIn, or Twitter account. Scenario 2: Promotional materials on third-party sites. A company is responsible for promotion on third-party sites if the company has “any control or influence on the thirdparty site, even if that influence is limited in scope.” As with the sites described in scenario 1 above, if the drug company collaborates or has editorial, preview, or review privileges, then it is responsible for its promotion on the site and should submit the promotional documents to the FDA.
With the emergence of social media sites – where a drug company may have limited control over how its products are discussed and how its marketing materials are disseminated – the reporting obligations have been unclear. Must a company provide the FDA with a copy of every tweet or Facebook post about its product? In July 2012, after many years of silence from the FDA on the issue, Congress gave the agency a two-year deadline to issue some guidance. On January 13, 2014, the FDA released “Guidance for Industry: Fulfilling Regulatory Requirements for Post-marketing Submissions of Interactive Promotional Media for Prescription Human and Animal Drugs and Biologics.” The document notes that it is a draft only but notes that the document “when finalized, will represent the [FDA’s] current thinking on this topic.” New Guidance from the FDA The document lists three broad scenarios in which a company (or “firm”) should submit its online promotional materials 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Summer 2014 Volume 6 Issue 2
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Monthly Disclosure of Websites Once every month, a company should submit to the FDA an updated listing of all non-restricted (i.e., nonpassword protected) sites for which it is responsible, or in which it remains an active participant, and that include interactive real-time communications. For these monthly submissions, the party need not include in the Forms screenshots of the actual interactive or real-time communications. Companies should include a separate document for each site that includes the site name, URL, and date range, as well as a cross-reference to the date of the most recent submission of the site. The company should advise the FDA on the first day that the company stops being active on the site. If a company provides only financial support (for example, through an unrestricted grant) but has no other control or influence on the site, then the firm is not responsible for information on the third-party site. Also, if a firm is merely providing promotional materials to a third-party site but does not direct the placement of those materials within the site – and has no other control or influence on that site – the firm is only responsible for the content it places there and only must submit to the FDA the material that was submitted to the site.
the comments to the FDA. Second, if a blogger paid by the company maintains a blog about the company’s product, the company likewise is responsible.
Scenario 3: A firm is responsible for the content generated by an employee or agent who is acting on behalf of the firm to promote the firm’s product.
Submission of Websites that Have Interactive Parts that Update in Real Time
A drug company’s reporting obligations to the FDA extend to promotional activities that are conducted on the company’s behalf. For example, if an employee or agent, acting on the company’s behalf, comments on a third-party site about the firm’s product, the firm is responsible for the content its employee or agent provides. This obligation extends to content on a blogger’s site if the blogger is acting on behalf of the company, and to user-generated content (UGC) such as comments in discussion forums if those comments are made on behalf of the company. The FDA’s guidance offers two examples of this scenario. First, if a sales rep acting on behalf of the company posts comments about the innovative release mechanism of the company’s product on an independent third-party site, the company is responsible for submitting www.ipimedia.com
New Recommendations for Submitting Interactive Promotional Media The new guidelines acknowledge that some websites include promotional content that changes in real time, and it is impractical for companies to submit copies of each instance of the constantly evolving webpage. For these situations, the FDA offers the following guidance.
At the time that a promotional website is initially displayed, the company should submit the entire website using Form FDA 2253 or Form FDA 2301 (the “Forms”). The company should include annotations to describe the parts that are interactive and allow for real-time communication. Any subsequent changes to the site (other than changes in the real-time information) should be annotated and resubmitted to the FDA. Submission of Third-Party Sites in which a Company’s Participation is Limited to Interactive or Real-Time Content The company should submit the home page of the third-party site, along with the interactive page within the third-party site and the company’s first communications therein, using the Forms. The company may include annotations that describe its communications within the third-party site.
Additional Requirements for ‘Restricted’ Websites If a site has restricted access such that the FDA may not have access to the site, the company should submit all content related to the discussion (including all UGC about the topic) to provide context for the review. Screenshots or other visual representations of the actual site should be submitted monthly using the Forms. Conclusion The new guidelines leave some uncertainty. For example, the degree of influence or control that a company exerts over a website that will trigger a company’s reporting obligations will be a case-by-case determination that the company itself must make. Another gray area is when an employee acts “on behalf of” the company such that the employee’s online comments must be submitted to the FDA. Despite this lingering uncertainty, the new guidance is a welcome glimpse into the FDA’s current thinking on what a company must do to comply with federal post-marketing submission requirements.
Nick Nelson is an associate in the Business Litigation Practice Group in the Dallas office of Haynes and Boone, LLP. His practice focuses on trade secret, trademark, and copyright litigation and all facets of media law. Email: email@example.com. INTERNATIONAL PHARMACEUTICAL INDUSTRY 9
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Merging and Acquisition Perspective in the Pharmaceutical Industry Abstract The objective of this article is to give an overview on merging and acquisition in the pharmaceutical industry. A merger has been defined as an arrangement whereby the assets, liabilities and businesses of two (or more) companies become vested in, or under the control of, one company (which may or may not be one of the original two companies), which has as its shareholders, all or substantially all the shareholders of the two companies. The acquisition process is very complex, with many dimensions influencing its result. Achieving acquisition success has proven to be very difficult, while various studies have shown that 50% of acquisitions were unsuccessful. Pharmaceutical companies have limited profits due to restrictions in product pricing, so they have to think of other strategies. At present, mergers and acquisitions are used as strategic tools for success. As the whole world is moving towards globalisation and liberalisation is spreading its wings, then in future, after 10 or 15 years, mergers and acquisitions will become tools to survive. Mergers and acquisitions add value to companies by increasing corporate control in the market. This paper also focuses on the trend of merger and acquisition deals in the pharmaceutical industry in the past 10 years. This paper also studies the motive behind merger and acquisition deals, and the reasons for failures of merger and acquisition deals in pharmaceutical companies. Key words: Merging and acquisition, dimensions, globalisation, liberalisation Introduction A merger is a combination of two companies to form a new company, while an acquisition is the purchase of one company by another in which no new company is formed. Mergers and acquisitions (M&A) is the area of corporate finances, management and strategy dealing with purchasing and/ or joining with other companies. In a merger, two organisations join forces to become a new business, usually with 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY
a new name. Because the companies involved are typically of similar size and stature, the term “merger of equals” is sometimes used. In an acquisition, on the other hand, one business buys a second and generally smaller company which may be absorbed into the parent organisation or run as a subsidiary. A company under consideration by another organisation for a merger or acquisition is sometimes referred to as the target. A merger, acquisition, or co-marketing deal between pharmaceutical companies may occur as a result of complementary capabilities between them. A small biotechnology company might have a new drug but no sales or marketing capability. Conversely, a large pharmaceutical company might have unused capacity in a large sales force due to a gap in the company pipeline of new products. It may be in both companies’ interest to enter into a deal to capitalise on the synergy between the companies. The distinction between a “merger” and an “acquisition” has become increasingly blurred in various respects (particularly in terms of the ultimate economic outcome), although it has not completely disappeared in all situations. From a legal point of view, a merger is a legal consolidation of two companies into one entity, whereas an acquisition occurs when one company takes over another and completely establishes itself as the new owner (in which case
the target company still exists as an independent legal entity controlled by the acquirer). Either structure can result in the economic and financial consolidation of the two entities. In practice, a deal that is an acquisition for legal purposes may be euphemistically called a “merger of equals” if both CEOs agree that joining together is in the best interest of both of their companies, while when the deal is unfriendly (that is, when the target company does not want to be purchased) it is almost always regarded as an “acquisition”. Most organisations look to mergers and acquisitions (M&A) and other such partnerships as one of their first options to addressing the problems they face. The big pharma companies look to the smaller companies and biotech to provide competences or additional resources to help spur R&D as well as marketing and sales (M&S) growth, and the smaller companies in turn get muchneeded funding to continue their work, either as partners or as a part of the larger company. 1. Buy Growth Companies – activity primarily aimed at increasing the growth of prescription sales 2. Buy Scale Companies – activity to increase product pipeline, R&D, M&S etc. 3. Multi M&A Companies – employ two or more of the strategies 4. Organic Growth Companies – avoid M&A as a core strategy
Table 2- Four classified M&A growth strategies Summer 2014 Volume 6 Issue 2
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The goal is to take a look at examples of M&As that have occurred and to provide some perspectives on how each combined company performed. It is not meant to be an in-depth study of the various kinds of M&As – see Table 2. Discussion An acquisition or takeover is the purchase of one business or company by another company or other business entity. Such purchase may be of 100%, or nearly 100%, of the assets or ownership equity
altogether, and neither of the previous companies remains independently. Acquisitions are divided into “private” and “public” acquisitions, depending on whether the acquired or merging company (also termed a target) is or is not listed on a public stock market. An additional dimension or categorisation consists of whether an acquisition is friendly or hostile. Whether a purchase is perceived as being “friendly” or “hostile” depends
Table 2 – M&A Overview (1995-2014) of the acquired entity. Consolidation occurs when two companies combine together to form a new enterprise
Announced Mergers & Acquisitions: Biotechnology & Pharmaceuticals, 1985-2013* 12 INTERNATIONAL PHARMACEUTICAL INDUSTRY
significantly on how the proposed acquisition is communicated to and perceived by the target company’s board of directors, employees and shareholders. It is normal for M&A deal communications to take place in a socalled “confidentiality bubble” wherein the flow of information is restricted pursuant to confidentiality agreements. In the case of a friendly transaction, the companies cooperate in negotiations; in the case of a hostile deal, the board and/ or management of the target is unwilling to be bought or the target’s board has no prior knowledge of the offer. Hostile acquisitions can, and often do, ultimately
become “friendly”, as the acquirer secures endorsement of the transaction from the board of the acquire company. This usually requires an improvement in the terms of the offer and/or through negotiation. “Acquisition” usually refers to a purchase of a smaller firm by a larger one. Sometimes, however, a smaller firm will acquire management control of a larger and/or longer-established company and retain the name of the latter for the post-acquisition combined entity. This is known as a reverse takeover. Another type of acquisition is the reverse merger, a form of transaction that enables a private company to be publicly listed in a relatively short timeframe. A reverse merger occurs when a privately held company (often one that has strong prospects and is eager to raise financing) buys a publicly listed shell company, usually one with no business and limited assets. As per knowledge-based views, firms can generate greater values through the retention of knowledge-based resources which they generate and integrate. Extracting technological benefits during and after acquisition is an ever-challenging issue because of organisational differences. 1. Merger and Acquisition Strategy Before any strategy is formulated, a company needs to have a clear-cut policy regarding merger and acquisition. This policy must be complementary to its vision and mission. Once a policy decision to expand business through merger and acquisition has been taken, the first step is to establish a ‘Merger and Acquisition Cell’. The roll of the cell would be to identify the potential companies, which would depend on macro-level issues discussed above and the broad guidelines laid down by the company for such a move, e.g. to diversify the business or expand the existing business or for upgrading the technology. This cell should be assisted by business analysts, representatives of financial institution/ investment bankers, technical experts, valuators and lawyers specialising in this field. For faster decision-making, which is vital in such cases, the cell must have direct access to the business leader/ decision-making authority. Sophisticated software that can handle financial analysis, projections, valuation, and so on is available in the market and help can be sought from this source. Once the targeted company has been identified, Summer 2014 Volume 6 Issue 2
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the option of finalising a deal through negotiation must be considered. However, if that is not feasible for any reason and takeover is vital for the organisation, a hostile takeover should be considered. For a hostile takeover, the stock of the targeted company should be bought quietly through a third party. The whole process must be managed confidentially. Components Model of Acquisition: 1. Improper documentation and changing implicit knowledge makes it difficult to share information during acquisition. 2. For the acquired firm, symbolic and cultural independence which is the basis of technology and capabilities are more important than administrative independence. 3. Detailed knowledge exchange and integrations are difficult when the acquired firm is large and highperforming. 4. Management of executives from the acquired firm is critical in terms of promotions and pay incentives to utilise their talent and value their expertise. 5. Transfer of technologies and capabilities are the most difficult tasks to manage because of complications of acquisition implementation. The risk of losing implicit knowledge is always associated with the fast pace of acquisition. An increase in acquisitions in the global business environment requires enterprises to evaluate the key stakeholders of an acquisition very carefully before implementation. It is imperative for the acquirer to understand this relationship and apply it to its advantage. Retention is only possible when resources are exchanged and managed without affecting their independence. 2. Documentation The documentation of an M&A transaction often begins with a letter of intent. The letter of intent generally does not bind the parties to commit to a transaction, but may bind the parties to confidentiality and exclusivity obligations so that the transaction can be considered through a due diligence process involving lawyers, accountants, tax advisors, and other professionals, as well as businesspeople from both sides. After due diligence is completed, the parties may proceed to draw up www.ipimedia.com
a definitive agreement, known as a “merger agreement,” “share purchase agreement” or “asset purchase agreement”, depending on the structure of the transaction. Such contracts are typically 80 to 100 pages long and focus on four key types of terms: •
Conditions, which must be satisfied before there is an obligation to complete the transaction. Conditions typically include matters such as regulatory approvals and the lack of any material adverse change in the business. Representations and warranties by the seller with regard to the company, which are claimed to be true at both the time of signing and the time of closing. If the representations and warranties by the seller prove to be false, the buyer may claim a refund of part of the purchase price. Covenants, which restrict operation of the business between signing and closing. Termination rights, which may be triggered by a breach of contract, a failure to satisfy certain conditions, or the passage of a certain period of time without consummating the transaction.
3. Snapshot of M&A Results The performance of the combined companies was assessed using a variety of financial measures, such as: • • • •
Profit margin (earnings before interest and taxes/total revenues) Capital turnover (total revenues/ capital employed) Return on capital employed (EBIT/ capital employed) Market capitalisation
Of the 22 transactions large scale (i.e. valued above $5 billion) M&A activities studied, Data Monitor found that only three delivered fast growth performance over the next five-year period. The study results had the following observations: “Only three M&A events have delivered fast growth performance over subsequent five year period”. •
Only small-sized acquisitions have delivered subsequent fast sales growth performance over the next five years (Centocor, Knoll and Genentech). No big or medium-sized acquisitions have contributed to fast sales growth
performance in the next five-year period. Nearly all big and medium-sized acquisitions have delivered a flat sales growth performance in the five-year period after the merger. Only two large-scale acquisitions have provided medium sales growth performance in the five years after the merger (Warner-Lambert, acquired by Pfizer; and Zeneca, acquired by Astra).
It is important to note that the small or flat growth in many ways stabilised their balance sheet in an environment where many of them are facing patent expiry over the next few years as the so-called ‘patent cliff’ looms. This is seen as relative success to many because without this small growth, many companies would have had a steep decline in growth as their branded products lost patent protection. The current healthcare situations will continue to impact the companies as the after-effects of the recent recession continue to reverberate around the world. This is truly a global economy and the business environment continues to evolve even as companies continue to implement new approaches to improve their product pipeline and look for new patients and markets to serve. While doing this they need to do rigorous business assessments to ensure that their strategies are financially sound, informed by strong portfolio management to target areas where they can provide novel medicines in therapeutic areas not addressed, establish rigorous process improvement to ensure that they maintain and improve their operations to gain efficiency and minimise safety issues and institute comprehensive risk management in almost everything they do. Additionally, the one area that should not be underestimated is the effort it will require to integrate companies after a merger. They will also need to set up organisations to make the partnerships successful and do the due diligence to ensure that they are able to operate and conduct business in countries where business and cultural norms are far different from their current experiences. 4. Merger and Acquisition Motives 4.1 Improve Global Competitiveness All the economies above, created through combination and exploitation of common resources, can also be called structural economies. By reorganisation we mean INTERNATIONAL PHARMACEUTICAL INDUSTRY 13
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a dynamic process reappraising, or even destroying, the last structure for a new one. The “organised” sector of India’s pharmaceutical industry consists of 250 to 300 companies, which account for 70 per cent of products on the market, with the top 10 firms representing 30 per cent. However, the total sector is estimated at nearly 20,000 businesses, some of which are extremely small. Approximately 75 per cent of India’s demand for medicines is met by local manufacturing. Global competitiveness has increased. To survive on the world platform the pharmaceutical companies are using merger and acquisition as a strategic tool. 4.2 Move Up the Value Chain The strategic decision of acquiring is thus based on the strong will to create value. Facing such a matter, company’s managers and board members need to understand the distinct concept of the value when judging a proposed acquisition. Mergers and acquisitions are motivated generally by two kinds of income: cost savings (or economy of cost) and increased revenues. 4.3 Create and Enter New Markets Both multinational companies (MNCs) and domestic players are also examining the prospects offered by the local market as the government moves forward with initiatives aimed at providing India’s more than one billion inhabitants, for the first time, with access to the life-saving drugs they need. A further huge boost to the local market is coming from the rise of India’s new affluent consumers, who lead more Western-style lives and are demanding innovative drugs to treat the chronic illnesses that these changing lifestyles may produce. India’s leading drug manufacturers are becoming global players, utilising both organic growth through the gradual development of their business, and mergers and acquisitions. 4.4 Increase their Product Offering As already explained, the R&D function is extremely expensive and the company’s size will determine the possible amount of investment. Like marketing, R&D is a supporting function, but is able to create a long-term competitive advantage. The merging of R&D will concern particularly the means available, and the resources in terms of competencies. Thus they can increase their product offering by utilising the various synergies. 4.5 Consolidate their Market Shares 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The market share growth results from the transfer of the market share from the target to the bidder. The market share of a firm corresponds to the proportion of production volume or the turnover the firm possesses in a given sector of a global market in relation to other competitor companies. The growth concept is relative to a quantitative increase of its turnover or its production. If the company growth is higher than that of the competitors, the growth concept means that the company has a market share growth, but if all the competitors increase their turnover, there is not an increase of the market share. Thus, an entity expands its market share when turnover volume (sales) increases compared to its competitors 4.6 Compensate for Continued Sluggishness in their Home Market India currently represents just US $6 billion of the $550 billion global pharmaceutical industry, but its share is increasing at 10 per cent a year, compared to 7 per cent annual growth for the world market overall.1 Also, while the Indian sector represents just 8 per cent of the global industry total by volume, putting it in fourth place worldwide, it accounts for 13 per cent by value,2 and its drug exports have been growing 30 per cent annually. The “organised” sector of India’s pharmaceutical industry consists of 250 to 300 companies, which account for 70 per cent of products on the market, with the top 10 firms representing 30 per cent. However, the total sector is estimated at nearly 20,000 businesses, some of which are extremely small. Approximately 75 per cent of India’s demand for medicines is met by local manufacturing. 4.7 Obtaining a Good Buy While the acquiring firm lists “obtaining a good buy” as a reason for their acquisitions, the underlying implication that markets may consistently undervalue corporate assets is questionable. If all potential acquirers have similar perceptions about the value of potential targets and the market for corporate control is competitive, then the potential acquirers would bid up the price of targets which appeared to be bargains until the acquiring firms would, at the margin. 4.8 To Improve the Efficiencies Firms may combine their operations through mergers and acquisitions of corporate assets to reduce production
costs, increase output, improve product quality, obtain new technologies, or provide entirely new products. The potential efficiency benefits from mergers and acquisitions include both operating and managerial efficiencies. 4.9 Financial and Tax Benefits Pharmaceutical companies have limited profit margins due to their governing legal frameworks. Mergers and acquisitions may lead to financial efficiencies. Firms may diversify their earnings by acquiring other firms or their assets with dissimilar earnings streams. Earning diversification within firms may lessen the variation in their profitability, reducing the risk of bankruptcy and its attendant costs. A lot of tax benefits are available and companies are taking advantage of that. 4.10 Reasons for Failure of Merger and Acquisition It is very difficult to estimate how many mergers and acquisitions in the pharmaceutical industry have succeeded. It is even more difficult to define what success means. Some estimate, however, that close to 80 per cent of mergers do not meet their pre-merger financial goals and that almost 50 per cent are failures. The common measure of stock market reactions one day – or even a few months – after the merger is undoubtedly inadequate. In many mergers and acquisitions shareholders’ value is created for the short term only, but more important is that positive synergy should be retained for the long term. On the analysis of available literature, in spite of theories that the stock market, in evaluating and valuing a merger, takes into account all the managerial and human factors, they clearly do not reflect the human and cultural costs of mergers – particularly in light of the fact that the managers and leaders involved in a merger often voice their inability to predict its exact outcome. 4.11 The Paradox of Manager vs. Shareholder The strategic investments of the firm should aim to create value for the owners of the firms, especially the shareholders. Nevertheless, most acquisitions in the last decades seem to generate poor performance concerning the acquiring firms, and even when the results appear to be positive, they are lower for the bidders’ shareholders than those of the targets, and the value which is generated in the process is retained for a very short Summer 2014 Volume 6 Issue 2
THE DOMINO EFFECT
When the Patient Recruitment Leader MediciGlobal is not Involved BECAUSE MediciGlobal wasn’t involved in recruiting for the trial, there were not enough patients. BECAUSE the trial did not have enough patients, the trial fell behind schedule. BECAUSE the trial fell behind schedule, the pipeline was changed. BECAUSE the pipeline was changed, revenue targets were missed. BECAUSE revenue targets were missed, investors lost faith. BECAUSE investors lost faith, the stock price plummeted. BECAUSE the stock price plummeted, the board issued a statement. BECAUSE the board issued a statement, “the CEO is cleaning out his desk”.
Wouldn’t it have been easier just to call MediciGlobal?
finding patients lost to follow up
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period of time. Different studies therefore prove that the acquisition strategies would benefit the targets’ shareholders by creating value. But this does not hold true in every scenario. There is hence a misunderstanding of the stakes of the acquisition game from both sides. Such a discrepancy can only lead to bad acquisition strategy and planning. This leads to a clash between the management of the company and the shareholders of the company. 4.12 No Planned Integration Cost The peculiarities of external horizontal growth are based on the combination of two entities, and especially of tangible, financial and above all human, resources. The bidding company and the target, whatever their activities, are composed of men and women living within the firms’ communities. The rules, the behaviours and the customs mean the culture is specific to each entity. The cultures of both entities may be mixed, and their combination may result in efficient synergies, but they can also be incompatible and lead to failure. There is also a lot of reorganisation and restructuring in the company during the days when the M&A process is going on. The process of M&A by which a company is bought or sold can prove difficult, slow and expensive. 4.13 The Problem of Social Compatibility The risk of demotivating is very high in the case of horizontal mergers. In fact, in such a type of acquisition, there are numerous duplications, which lead to mergers of several business units, therefore to large employee cutbacks. Such an assumption is even more verified when the bidder and the target used to be direct competitors. Such a situation entails anxiety, linked to asymmetric advantages, autonomy loss, and different cultures. 4.14 Difference in Working Culture It is also unsuccessful because the merger of two organisations is actually a merger of individuals and groups working in companies; this has a great impact on individuals working in a company such as creating ego clashes among individuals working in a company. 4.15 Miscommunication regarding Strategies There is also failure of M&A when the purchaser’s plans and strategies are not clear to the employees of the acquired 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY
firm. Merger and acquisition helps a company to grow in a better way, but it has a great impact on the employees working in a company and on working conditions. The employees of the companies merging and acquiring are mostly affected by M&A. For this reason, there is mostly a failure of M&A. When two companies who have different styles of functioning merge, there is a clash between the companies which pulls them in different directions apart from their aims. A company enters into M&A activity without recognising the impact on the organisation and the overall effect on the human element within the two merging companies. When M&A activities do not meet corporate objectives it results in lost revenue, and customer dissatisfaction. Many personnel issues such as salaries, benefits and pensions are also affected due to M&A. Since the organisational structures are different, differences in compensation packages and designation can routinely be expected. Conclusion Pharmaceutical mergers and acquisitions add value to the companies by increasing the corporate control in the market. Serial acquirers appear to be more successful with mergers and acquisitions than companies who only make an acquisition occasionally. Preservation of tacit knowledge, employees and documentation are often difficult to achieve during and after an acquisition. Strategic management of all these resources is a very important factor for a successful acquisition. The key principle behind merging a strong company is to create shareholder value over and above that of the two companies. It is also important to assess the impact of combining on innovations, as mergers and acquisitions in innovative markets may pose a threat for subsequent entry of new products by stifling competition at the R&D and product development stage. References 1. h t t p : / / w h a t i s . t e c h t a r g e t . c o m / definition/mergers-and-acquisitionsMA [cited 2013-11-15] 2. Marc & Dirk research paper, “Determinants of M&A Success in the Pharmaceutical and Biotechnological Industry” Vol VIII, March 2011 3. http://mergerandacquisitionsurveys. com/ [cited 2013-11-16] 4. http://www.imaainstitute.org/docs/ announced%20mergers [cited 201311-16]
5. http://www.imaainstitute.org/docs/ kummer_mergers%20acquisitions%20 m&a%20pharmaceutical%20 industry%20south%220strategy.pdf [cited 2013-11-17] 6. http://www.diva-portal.org/smash/ get/diva2:4101/FULLTEXT01.pdf [cited 2013-11-19] 7. h t t p : / / w w w . s c r i b d . c o m / doc/123417000/Iccia1026-Pharma [cited 2013-11-18] 8. Shuchi Gautam: Merger and Acquisition Scenario in Pharmaceutical Industry http://research.ijcaonline. org/iccia/number4/iccia1026.pdf 9. Vivek Sharma: Merger and Acquisition. http://www.scribd. com/doc/65747909/Merger-andAcquisition [cited 2013-11-15] 10. http://valueearning.com/page/ merger_or_acquisition.html [cited 2013-11-15] 11. h t t p : / / r e p o s i t o r y . u p e n n . edu/cgi/viewcontent. cgi?article=1032&context=od_theses_ msod [cited 2013-11-22]
K. Sreekanth Reddy M. Pharm Regulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email: sreekanthkaja@ ymail.com Balamuralidhara V. - Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email: baligowda@ gmail.com Shilpi Khattri - Ph.D. Research Scholar, Regulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email: shilpikhattri@ gmail.com T. M. Pramod Kumar - Professor & Head of Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email: firstname.lastname@example.org Summer 2014 Volume 6 Issue 2
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Achieving Operational Excellence in Drug Safety with an Effective Quality Management System Abstract: With drug safety evolving into a key priority area for the biopharmaceutical industry, the emphasis on quality and compliance has increased substantially. Regulatory agencies have made it clear that quality is integral to drug safety, and pharmacovigilance (PV) quality systems constitute the foundation of PV operations. The International Conference on Harmonisation (ICH), European Medicines Agency (EMA) and US Food and Drug Administration (US FDA) have laid out their expectations with respect to quality management systems (QMS) for PV. The past few years have also seen a steep rise in outsourcing of safety operations, (case processing, call centre, aggregate report writing, signal evaluation amongst others etc.) and this has put the spotlight on how sponsor organisations provide oversight to outsourced operations with the ultimate goal of ensuring high quality and compliance of the deliverables. This paper will review the QMS-related requirements and specifications, and will compare and contrast requirements by various organisations, primarily to elaborate on how these requirements can be implemented, what constitutes a robust QMS and how it can be built into PV operations. Means of ensuring quality and compliance through appropriate oversight will be discussed. Introduction The role of pharmacovigilance or product vigilance (PV) has changed from capturing and reporting adverse events, to a business imperatively responsible for risk assessment, risk management and risk mitigation. The volume and complexity of drug safety data that is captured, processed, analysed and reported has grown substantially. Regulatory oversight of company safety activities for approved pharmaceutical products is now much more holistic than the previous limited view of assuring adequate and compliant procedures that licence-holders established to meet their legal obligations. Regulations 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY
are targeted towards strengthening companies’ PV systems and defining clear roles and responsibilities across both the regulatory agencies and the industry. The present largely reactive system is being transformed into one that is proactive, robust and more useful clinically. All of the above developments have resulted in an acute need for companies to optimise their PV systems and processes. They have led many companies to outsource safety operations to specialised providers who have the required scientific expertise as well as operational excellence to provide effective and cost-optimised solutions in a globally distributed model. Operational complexity increases with the inclusion of multiple groups and hand-offs. The core challenge, in this rapidly evolving environment, is adapting to the changing regulatory requirements and adhering to them diligently. Being able to adapt fast with respect to proactive patient safety and regulatory compliance necessitates efficiency and scalability in operations and consistency in quality. With increased emphasis on quality and compliance, regulatory agencies have made it clear that quality is integral to product safety and PV quality systems constitute the foundation of PV operations. The International Conference on Harmonisation (ICH), European Medicines Agency (EMA) and US Food and Drug Administration (US FDA) have laid out their expectations with respect to quality management systems (QMS) for PV. The regulatory expectations mentioned and analysed in this article are based on EMA’s Good Pharmacovigilance Practices (GVP) Module I – PV Systems and their Quality Systems1 and on FDA’s Guidance for Industry – Good PV Practices and Pharmacoepidemiologic Assessment (Mar 2005)2. Though a lot of ICH3 and FDA4 quality publications relate to manufacturing, there is an expectation that these will also be applied to PV. FDA’s Office of Regulatory Operations has also issued the ORA Quality Manual in March 20125.
What is a QMS? EMA’s GPV Module I enumerates the following quality objectives of a PV system: • •
Complying with legal requirements for PV tasks and responsibilities Preventing harm from adverse reactions in humans arising from the use of authorised medicinal products within or outside the terms of marketing authorisation or from occupational exposure Promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public Contributing to the protection of patients’ and public health
The goals of a QMS are compliance with the law, prevention from harm, promotion of safe drug use and patient/ public health protection. Quality documents and guidances across regulatory bodies state that a QMS addresses quality planning, quality adherence, quality control/quality assurance and quality improvements, and comprises of organisational structure, responsibilities, procedures, processes, resource management, compliance management and record management. Organisational structure, responsibilities and resource management pertain to the availability of a sufficient number of competent and appropriately qualified and trained personnel with clear roles and responsibilities (job descriptions), and also pertains to the availability of other infrastructure such as computers and facilities. Quality planning is about being prepared for and anticipating issues and problems, along with the need to stay up-to-date on new regulations, technology and processes. Compliance management refers to the need to have execution and controls Summer 2014 Volume 6 Issue 2
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in place to manage compliance with requirements outlined by the Competent Authorities (CAs) with respect to quality, completeness of PV data, assessment and timeline compliance, independence of PV activities and effective communication. A key element of compliance management is to have valid, traceable processes with audit trails and to have the right technology. Other aspects of compliance management are defining and monitoring of key performance indicators (KPIs), ensuring root cause analysis (RCA) and corrective and preventive action plans (CAPAs) and conducting periodic audits. Compliance management processes to monitor the performance of a PV system also include evaluation of the effectiveness of actions taken with medicinal products for the purpose of minimising risks and supporting their safe and effective use in patients. Given the complexities of safety evaluation and reporting, compliance management thus subsumes a majority of the elements of operational excellence which are critical to ensuring quality and compliance of a PV system. Record management is about documentation of a quality system; everything should be documented in a systematic and orderly manner in the form of written policies and procedures, quality manuals and quality records. Data security and privacy are critical requirements. Quality system documentation by the marketing authorisation holder (MAH) in the PV system master file (PSMF) is also a part of record management. Most of the above requirements are similar in the FDA and EMA guidances. The EMA has more requirements, for example, with respect to training (even personnel with no direct PV responsibilities are required to have adequate training) and is more specific and explicit in stating certain requirements, for example, the compliance management elements which are mentioned above. EMA identifies certain PV processes as critical, and quality requirements for these processes are outlined in the respective GVP modules. PV processes identified as critical include: • •
Continuous safety profile monitoring and benefit-risk evaluation Risk management and risk minimisation
20 INTERNATIONAL PHARMACEUTICAL INDUSTRY
• • • • • •
Collection, processing and reporting of individual case safety reports (ICSRs) from any source Signal management Aggregate safety reporting/ periodic safety update reports Meeting commitments and responding to requests from the CAs Interaction between PV and product quality defect systems Communication about safety concerns and changes to the benefit-risk profile between MAHs and CAs, and also notifying these changes to the patients and healthcare professionals Keeping product information upto-date Implementation of variations to marketing authorisations for safety reasons
Aspects of Operational Excellence and Oversight in QMS Until about 2009, compliance to reporting timelines of expedited reports by the MAH was the only valid metric of the effectiveness of an AE processing operation evaluated by global health authorities. Driven by the public focus on drug safety led by recalls of a few prominent drugs, the regulators began to look closely at the way the pharmaceutical companies were classifying cases. Suspected unexpected serious adverse reactions (SUSARs) are reportable under existing guidelines, whereas AEs listed on a drug label are normally not reported individually but are compiled into aggregate periodic reports. There were some findings from US FDA inspections of questionable criteria being used to ‘downgrade’ reportable SUSARs. As a consequence regulators started looking closely at ‘case quality’. Collection, processing and reporting of ICSRs is often outsourced since it is resource-intensive, primarily processdriven and largely operational in nature. MAH oversight of outsourced processes is increasingly coming under regulatory scrutiny. Increased complexity of drug safety monitoring, increased volumes and greater regulatory and public scrutiny, along with the ensuing need to outsource parts of the process have enhanced the focus on operational excellence. It is critical to outline the systems, processes and other tools and controls which the
MAH will use to achieve operational excellence, thereby ensuring quality and compliance. Irrespective of whether PV is done in-house or is outsourced, description of such systems, process and tools is an integral part of the QMS. When parts of the process are outsourced, measures taken to achieve operational excellence are often outlined as part of the oversight plan of the MAH. Thus specification of how the oversight will be provided, the tools and controls that will be used, has become an important component of the QMS. Relevant details of the processes, measures and controls are included in a quality agreement and/or a quality management plan (QMP) and an oversight and/or governance document signed by the MAH and its PV partner. These include the KPIs which will be used to monitor performance, how they will be measured, what are the thresholds, for example. The oversight/ governance document mentions how operational and management teams from both organisations will monitor the performance of the PV system, the escalation and resolution mechanism, the communication channels and individual roles, responsibilities and accountabilities. There may be an oversight SOP in some cases. Some of the KPIs used to monitor performance of the outsourced operations and which constitute service level agreements (SLAs) are: 1. regulatory reporting compliance (per cent cases submitted to regulators on time; 2. case quality metrics; 3. case turnaround time (internal case processing timelines); 4. number of daily case closures. Depending on the size of the outsourced operations and the processes which are outsourced, other factors such as deviation from planned volume per week or per month, system uptime, in-bound late cases and employee turnover may also be monitored as KPIs. The KPIs constitute operational excellence parameters and measuring and tracking them is a way to achieve operational excellence. The QMS, through the quality agreement or QMP, outlines the process Summer 2014 Volume 6 Issue 2
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for documentation and evidence of monitoring of KPIs and may also include aspects of governance and escalation mechanisms. It should also contain some description of how the MAH will oversee other aspects of the outsourced operations on a day-to-day basis, for example, ensuring that adequately qualified and experienced individuals are recruited, required training is conducted and documented, individuals are signed-off on the project based on pre-defined criteria, ensuring adequacy of infrastructure and facilities of the service provider. The QMP may also include details of any process improvements/enhancements which may be applied for attaining operational excellence and ensuring compliance. These details may include six-sigma or lean methodology applied to improve the process, automation of parts of the process to minimise the risk of errors and misses, additional quality gates and any templates, tools, checklists, that may be deployed. The QMP thus drives operational excellence and also enables effectiveness measurements.
in the context of E2B submissions. In view of the subjective nature of case assessment and further variability that is introduced in the process when it is outsourced to third parties, regulatory authorities like the MHRA have defined specific expectations of case quality and of third party case processing. The US FDA has not yet defined what they expect from “good” quality cases. Over the past few years, companies started to baseline their operations and establish measurement criteria to comply with the newly articulated expectations of the health authorities. There is wide variation in what each company expects as operational metrics to measure quality of cases they report to the health authorities. This is due to the inherent variability in medical assessment of causal relationship between a reported AE and a suspect drug, as well as assessment of seriousness of the AE given the confounding factors such as concomitant medications and concomitant medical conditions. Thus, there aren’t any industry-wide benchmarks for quality.
Case Quality The ultimate objective of all these processes and control mechanisms described above is to ensure quality and compliance of the PV system. Reporting compliance is of utmost criticality and operational excellence methods are instrumental in helping achieve this, especially when volumes of cases/reports are large. But quality is also increasingly being scrutinised and it is intertwined with compliance. For instance, in the case of ICSR processing, wrong event coding, wrong assessment of seriousness or listedness and wrong identification of Day 0, could lead to non-compliance on reporting timelines. Thus, ensuring good case quality becomes a pre-requisite for ensuring compliance. Besides, if the quality of the case narrative is poor, even for non-reportable cases, its impact on the quality of evaluation and reporting of aggregate safety may be substantial. Hence, in a way, good case quality is the foundation of a good quality PV system.
The quality of a case may be measured in terms of case level quality or field level quality. The data fields may be weighted in order to come up with a weighted measure of quality. Some companies may prefer to categorise errors into critical and non-critical, some may categorise them into critical, major and minor, while some others may want to consider all errors on par, regardless of their criticality. The number of data fields reviewed to find errors can also vary widely; for example, it could be as low as 4 or 5 and could be as high as 50 to 60. The SLAs also vary accordingly.
Beginning 2009 when the UK MHRA and EMA (Volume 9A) provided guidance on what they considered “acceptable” case quality, much of the industry used ad-hoc measures to assess the quality and overall disposition of the cases. In February 2011 the MHRA published ‘Best Practice in Reporting of ICSRs’ that outlines quality expectations www.ipimedia.com
Conclusion The QMS is essential to, and needs to drive, the biopharmaceutical PV operations. It is not a mere obligation or a mandate. It needs to be a living system that determines the way the PV system works in the company and needs to lay down the framework that guides compliance and quality of the PV system. Whether explicitly stated or not, all guidances have similar expectations from a QMS, though some are more specific than others. In the context of increased outsourcing of PV operations, of particular relevance are the components of the QMS that outline how operational excellence will be achieved, how it will lead to better compliance and quality, and how effective oversight will be provided.
The prescribed framework of the QMS which includes quality planning and compliance management requires focus on methods and tools to drive operational excellence, resulting in enhanced quality and compliance. These components of the QMS are also increasingly coming under regulatory scrutiny. References 1. Guideline on good pharmacovigilance practices (GVP), Module I – Pharmacovigilance systems and their quality systems; EMA, June 2012 2. FDA’s Guidance for Industry – Good PV Practices and Pharmacoepidemiologic Assessment (Mar 2005) 3. ICH Quality documents Q8, Q9, Q10, Q11 4. Pharmaceutical Quality for the 21st Century: A Risk-Based Approach (http://www.fda.gov/oc/cgmp/ report0507.html) 5. ORA Quality Manual, March 2012, Document # ORA-QMS-POL.002, version #2.0, Department of Health and Human Services, FDA Office of Regulatory Affairs and Quality Management System
Chitra Lele is Chief Scientific Officer at Sciformix Corporation, with over 20 years of experience in the healthcare industry. She has been part of the company’s leadership from its inception and has been instrumental in establishing and growing the organisation. Prior to Sciformix, Chitra was Executive Director responsible for Indian operations of Pfizer Global R&D. With a PhD in Statistics from Stanford University, her prior experience includes work as a biostatistician in cancer epidemiology at both Stanford and University of California. Email: firstname.lastname@example.org INTERNATIONAL PHARMACEUTICAL INDUSTRY 21
REGULATORY & MARKETPLACE
Keeping Data Secure and Validated in the Cloud – Addressing the Misconceptions Surrounding Cloud Computing in Pharma In the life sciences industry, companies are required to ensure and prove that their promotional materials comply with the regulatory guidelines of the FDA’s Office of Prescription Drug Promotion in the US, the Association of the British Pharmaceutical Industry (ABPI) in the UK, and European Medicines Agency in Europe. The requirement to demonstrate compliance, while still maintaining process efficiency and ease of use for marketing teams and time to market for life science companies, has led to a surge in interest in cloud computing systems for the management of commercial compliance.
Cloud storage is a network of online data repositories where the data is stored and hosted by a third-party server. Cloud computing, however, incorporates application software and other technology as well as the storage system. The focus of this article is cloud computing and systems that provide mechanisms for digital asset management, review and approval.
Most life sciences companies name security of data as their biggest fear when considering the adoption of a cloud computing system. However, the other key issue that many companies initially fail to give due consideration and attention to is the need to actively maintain a validated compliant environment whilst containing the significant associated administrative costs and human overhead.
While it is possible to have all the benefits of a cloud-based system, it is essential to look more closely at the technical architecture to ensure that it not only provides a fully secure environment for your data, but it can also be maintained in a truly validated and compliant state at all times and, most importantly, without any unwarranted overheads. This article discusses the use of cloud computing within life sciences, focusing on the misconceptions that surround cloud computing systems in the three areas of data security, validation, and compliance. The article reviews different cloud environments and the benefits for life sciences - emphasising the importance of data validation and compliance in conjunction with privacy and security when specifying a cloud computing system. Not All Clouds are Equal… It is important to distinguish between cloud storage and cloud computing. 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The National Institute of Standards and Technology name four different types of cloud computing systems1 - private cloud, community cloud, public cloud and hybrid cloud2.
Private cloud (single tenant). The cloud infrastructure is provisioned for exclusive use by a single organisation comprising multiple consumers (e.g., business units) Community cloud. The cloud infrastructure is provisioned for exclusive use by a specific community of consumers from organisations that have shared concerns (e.g., mission, security requirements, policy, and compliance considerations) Public cloud (multi-tenant). The cloud infrastructure is provisioned for open use by the general public. It may be owned, managed, and operated by a business, academic, or government organisation, or some combination of them. It exists on the premises of the cloud provider Hybrid cloud. The cloud infrastructure is a composition of two or more distinct cloud infrastructures (private, community, or public) that remain unique entities, but are bound together by standardised or proprietary technology that enables data and application portability (e.g. cloud bursting for load balancing between clouds)
As recognition of the benefits filter through, cloud computing is being adopted rapidly across different market sectors. A report published by International Data Corporation (IDC) concludes that a market-developed cloud computing system has proven
advantages over an internally developed system3: reduced costs of ownership, reduced time to market for applications, reduced annual system downtime, better business performance and accelerated pace of innovation3. The Cloud and the Pharmaceutical Industry: The cloud is not a new concept, and research suggests that 71% of companies across North America are using this technology. However, analysts from IDC have shown in their research that 54.6% of pharmaceutical companies are not using cloud-based services4. This is despite knowledge of the benefits that using a cloud-based system can bring to the management of life science data. Those life sciences companies that are early adopters are utilising the cloud throughout the entire product lifecycle from clinical research right through to the management of post-approval promotional materials. Cloud computing works best in the areas of the life sciences industry that have been standardised, are large-scale, or where there is a missioncritical aspect to the project. It therefore lends itself naturally to the management of post-approval promotional materials that require a standard process for their development, approval and storage, as well as being subject to rigorous requirements relating to elements such as electronic records and signatures, healthcare data privacy, contingency planning and business resilience. So why is life sciences falling behind its peers in terms of cloud computing adoption, and particularly when it comes to promotional materials? There are a number of misconceptions that commonly surround discussions on cloud adoption in life sciences, which often lead to adoption failure or the deployment of an incorrect system. Dispelling the Misconceptions Surrounding Cloud Computing Myth 1: Maintaining validation with a cloud is virtually impossible This myth arises out of the experience of multi-tenant cloud users. Multi-tenant Summer 2014 Volume 6 Issue 2
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(or public) cloud systems use vendorprovided architecture where all users’ data reside in the same environment without physical segregation. When the vendor provides patches and upgrades to the system, all clients are subject to that change automatically which affects the core application code base and, therefore, repositions the clients’ validated instance into an invalidated status. Such an outcome is clearly a sub-optimal environment for managing compliant data and processes. However, in a private cloud environment (which consists of single tenant architecture) different clients benefit from a separate code base and secure data repository from one another. This means that deployment patches and upgrades can be conducted at a time that suits each client individually. This is a practical and proven environment which does enable users to stay ahead of validation requirements and maintain a state of validated compliance. By understanding the cloud provider’s systems and infrastructure, it is possible to create controls to ensure that your private cloud remains in a validated state. This requires the provider to have the technical and procedural controls in place to define their operation. Regulatory bodies demand that third-party providers implement and follow a formal quality system such as ISO9001:2008. To accomplish this, they must leverage much validation support documentation from the cloud provider in advance of an upgrade, including: • • •
Application software testing (prerelease functionality testing based on client’s configuration) Application installation (installation qualification (IQ)) User acceptance testing/ performance qualification (UAT/ PQ) test scripts (to validate the entire system architecture at point of use)
Phrases such as “validated outof-the-box”, “validation ready”, and “pre-validated”, are often synonymous with vendor-acquired solutions. These assertions should be carefully analysed to ensure that the level of validation is consistent with the FDA’s requirements for computer systems validation. The FDA expects the final, deployed version of the solution to be validated, www.ipimedia.com
and therefore a vendor’s claim of prevalidation alone will not be acceptable. The FDA has an expectation that the acquirer verifies that the whole cloud computing solution is in fact, validated. Myth 2: Private cloud environments, while more conducive to validation and compliance, take longer to implement Multi-tenant systems are sometimes marketed as being made available pre-validated for IQ and operational qualification (OQ) in order to streamline customers’ system validation efforts. While this means that the cloud system can be in the hands of a user quickly, it does not result in ultimate time savings. The client must attempt to anticipate the provider’s patch and upgrade schedule in order for the system to remain continuously validated. If a private cloud is deployed, more time is needed up front in order to plan a validation strategy, but this enables the creation of controls to ensure the system remains in a validated state for the long term. This investment in planning ahead will result in time and cost savings further down the road. Myth 3: The biggest issue when specifying a cloud computing solution is data security In a literature review conducted by Saleem et al.5, data security, privacy, and integrity were named as the utmost area of concern when considering deploying a cloud system in life sciences in 70% of instances. So while it is clear that security is indeed a major fear, it should not be the major issue. In reality, many recent studies have noted that secure cloud services are now available which unequivocally support security, privacy and audit requirements necessary for comprehensive compliance6. Validation and compliance should be the driving factors when scoping out a cloud platform for post-approval materials. The controls and auditing requirements of the regulatory landscape, specifically 21 CFR Part 11 and Annex 11, mean that any cloud system selected needs to maintain a secure architecture environment, ensuring the integrity of data and electronic signatures. A failure in compliance could cost a company immeasurable sums in fines, lost revenues, and loss of reputation. Myth 4: It is not possible to ensure data security, privacy and integrity in a cloud Which type of cloud platform provides the most security for your application?
To ensure security of data: As private clouds are customer-owned, they offer a more secure environment as they can only be used by their owners. This is in contrast to the shared space of a multi-tenant environment. As large IT organisations discover potentially harmful issues with public cloud systems, many are now considering their own private infrastructures7. Private cloud services are used only by their owners, and thus can provide the most secure environment. Private clouds are typically the starting point for most life sciences implementations6. To ensure security of software: It is vital that all servers and applications must be protected through appropriate, logistical security measures. Special consideration must be given to processes such as user authentications and user access restrictions, intrusion prevention security systems, and full back-up and disaster recovery protection system. To ensure security of data centre: Firstly, consideration must be given with regard to physical security in terms of the protection of the data centre itself, through appropriate personnel staffing and site security. Also, consideration must also be given to environmental factors. This is in light of the natural disasters over recent history and their implications on this sector, an example being Hurricane Sandy in 2012. Therefore, appropriate systems must be installed in order to prevent major data losses. Myth 5: You cannot segregate your data from another company’s using the cloud A single-tenant, private cloud environment allows users’ software to be segregated from other companies’, as each client has its own code base, physically separating one client from another. A private architecture enables the establishment of logical and physical boundaries and controls around the data, setting permissions with regard to who can have access to the computing environment. Compliance through Cloud-based Software Solutions – A Case Study Astellas, a global R&D-driven pharmaceutical company, has implemented a private cloud-based compliance solution in reaction to the increasingly tight regulatory environment. Alan McDougall, Medical and Regulatory INTERNATIONAL PHARMACEUTICAL INDUSTRY 23
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07/05/2014] 4. IDC Health Insight (2013). Advancing cloud computing in North American manufacturing and health: from IT efficiency to business innovation. IDC, May 2013. 5. Saleem, Y. et al., ‘High security and privacy in cloud computing paradigm through single sign on.’ Life Science Journal, 9,4, 2012 6. Irwin Goverman, Chris Weitz, Julie Hall, Cloud Computing: Prime time for the life sciences, Deloitte, April, 2013 7. Gene Ruth, Private cloud storage favoured by IT organizations, Gartner, 2012
Director at Astellas Pharma Limited, specifically cited the onset of the Physician Payments Sunshine Act on August 1, 2013 in his reasoning for the move to cloud-based compliance: “Transparency is a keyword at the moment in terms of pharmaceutical companies publishing their clinical trial data, but also in being fully transparent with all the transactions they have with healthcare professionals (HCPs) including payments to HCPs which will soon be published. So a compliance system has to be able to cope with the increasing complexities that we face.” Having previously utilised a paperbased compliance system, Astellas Pharma Ltd implemented a cloud-based compliance software system to counteract the previous system’s inefficiencies, specifically regarding the compliance and validation of both promotional and non-promotional materials. According to Alan McDougall, increasing compliance efficiency has been the result: “compliance in Astellas has been significantly enhanced by implementing a cloud-based system. The differences the system has brought to Astellas are essentially the speed and quality of approvals. Materials are now approved much faster with improvements in approval quality together with enhanced compliance with our code of practice – it is now not possible for materials to be released without being fully signed off by the appropriate reviewers.” Conclusions and Recommendations Cloud computing is already delivering huge benefits to the life sciences industry. The industry has been prone to numerous misconceptions that have resulted from the presence of public multi-tenanted 24 INTERNATIONAL PHARMACEUTICAL INDUSTRY
cloud systems which are less suitable for compliance-centric applications, particularly in a validated environment. Private cloud environments in fact provide a secure solution that enables both the data to be segregated, and for functionality changes to be safely, effectively and productively managed in order to remain in a continuous validated state. The life sciences company is ultimately responsible for the authenticity and security of its data within the compliance framework; many would benefit from more focussed mapping of their validation framework to ensure that a solution can remain economically maintained and validated for the long term. To download a full copy of the whitepaper on keeping your life science data secure and validated in the cloud, please visit http://bit.ly/1dKcL5z References 1. The NIST Definition of Cloud Computing, Recommendations of the National Institute of Standards and Technology, 800-145, <http:// csrc.nist.gov/publications/ nistpubs/800-145/SP800-145. pdf> [Accessed 07/05/2014] 2. Goran Čandrlić, 2013, Cloud Computing - Types of Cloud <http://www.globaldots.com/ cloud-computing-types-of-cloud/> [Accessed 07/05/2014] 3. Randy Parry et al., 2009, Force.com Cloud Platform drives huge time to market and cost savings <http:// www.salesforce.com/fr/assets/ pdf/whitepapers/whitepaper-idcforce-roi-study.pdf> [Accessed
David Bennett is president of Global Sales and Marketing at Zinc Ahead, the world’s leading provider of cloud-based compliance solutions for the life sciences industry. Having graduated with a degree in business studies from the University of the West of England in 1981, David is a seasoned international software business leader with twenty years experience as General Manager, Sales and Marketing leader and CEO in international software companies. Over the last 13 years, Zinc has firmly established itself as the gold-standard compliance solution for life science companies and now employs over 125 staff across its 6 global offices. As the global life sciences industry has progressively become more tightly regulated, the sector has turned to specialist third-party vendors to implement solutions that ensure compliance with these regulations. Zinc has been at the forefront of this trend for well over a decade and now has more than 45,000 users of its systems in 170 countries worldwide. All of the world’s top 20 pharmaceutical companies use Zinc’s products. Headquartered in Oxford, with further offices in Princeton, San Francisco, Sydney, Tokyo and Basel, Zinc is one of the UK’s fastest growing technology firms with growth of 40% annually. 60% of Zinc’s revenue is generated from its overseas operations and the company was awarded a Queen’s Award for Enterprise (International Trade) in 2013. David is based in Oxford. Email: email@example.com Summer 2014 Volume 6 Issue 2
Scotland. The home of golf and pharmaceutical services. New discoveries are par for the course here.
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SCOTLAND. SUCCESS LIKES IT HERE.
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The EU Unitary Patent – An Overview and Practical Considerations I am relatively new to the IP profession, having joined around four years ago, but those who have been in it longer tell me how, for as long as they can remember, there have been plans to create a panEuropean patent. The preparations have spanned almost 40 years, and there have been many significant obstacles to overcome. However, the “Unitary Patent” and the dedicated “Unitary Patent Court (UPC)”are now an inevitability. The UPC agreement was signed on 19 February 2013, and will come into force as soon as it has been ratified by enough countries (thirteen including the UK, Germany, and France), probably in 2015. In this article, I will give an overview of the new system and look at some of the practical implications of the Unitary Patent and UPC for patent owners. Disadvantages of the Current European Patent System At present, there is no such thing as a single patent which covers all of the countries in Europe, i.e. a “European patent”. Rather, you can file a patent application through the European Patent Office (EPO) which, when granted, will become a bundle of national patents. The procedure up to grant is centralised at the EPO, but after that the patentee must choose which European Patent Convention (EPC) countries they would like the patent to take effect in. They must then validate patent in those countries, which usually involves filing translations and can be extremely expensive. After validation, the only actions you can take centrally at the EPO are to limit the claims of the patent, or oppose a patent (up until nine months after grant). All other actions must be done on a countryby-country basis, including the payment of renewal fees, amendment (other than limiting the claims), revocation (by a third party), and especially enforcement against infringers. This has several consequences for litigation as the courts in European countries differ greatly in their laws and approach. One consequence is that parties are able to “forum shop” to choose the best country to meet their aim of enforcement or revocation. The UK, for example, has typically been patentee
unfriendly and quick to give revocation decisions. German courts, on the other hand, tend to give very quick infringement decisions and injunctions before validity is tested, and then are generally slow to reach a decision on validity. This system can be unfavourable, if you are on the “wrong” side of it. Another consequence is that there may be different outcomes to litigation in different countries. For example, the AstraZeneca SEROQUEL XR formulation patent was upheld in The Netherlands and Spain, but was found invalid in the UK and Germany. This leads to considerable uncertainty for all parties involved. Also, under the current system you must seek an injunction in each country separately as it is not possible to obtain a pan-European injunction (although there has been some recent case law that suggests otherwise). Overall, the present system is very fragmented. There is a need for a less fragmented, more cost-effective system to stimulate innovation and assist applicants with lower budgets. The New System – Unitary Patents and the Unified Patents Court Procedure Applications will be examined centrally at the EPO as they are now. At the grant stage, the patentee must decide whether or not they want the granted patent to have unitary effect, i.e. become a Unitary Patent. There will be a transitional period after the new system comes into force, which will be at least seven years. Territories The Unitary Patent will be a single patent which covers 25 EU countries, making up most of the EU region. Importantly, the unitary effect will not cover Spain and Italy as these countries chose not to take part due to the translation arrangements. It also will not cover any non-EU countries that are part of the EPC, e.g. Turkey, Switzerland, and Norway. However, these countries can still be validated nationally using the existing procedures. Translations Eventually, the only translations required
26 INTERNATIONAL PHARMACEUTICAL INDUSTRY
for a Unitary Patent (if the EPO application was prosecuted in English) will eventually be a French and German translation of the claims. High quality machine translations will ultimately be available online, so no further translations are needed. During the transitional period, if an application was prosecuted in English it will also be necessary to translate the full patent into one other language (of any EU member state) in addition to the French and German claims. It, of course, makes sense for patentees to choose the cheapest language. Renewal Fees A single renewal fee is payable for a Unitary Patent, rather than a separate fee in each country. This could result in significant savings in terms of administration and monitoring systems as well as agent fees. In theory this should make the system more attractive for budget constrained applicants. However, the amount of the renewal fee has not yet been decided and may be significant (see below). Litigation Patentees will be able to enforce their Unitary Patent centrally at the UPC and obtain a single injunction across all 25 participant states. The Unitary Patent will thus be a powerful tool against competitors. However, this is balanced by the fact that the patent may also be attacked and revoked centrally. The UPC will have three types of first instance court: the central division (with branches in Paris, London and Munich), as well as local divisions in certain countries, and regional divisions in certain groups of countries. The UK will have a local division based in London. Each court will have both local judges as well as judges from elsewhere in Europe. Courts will have discretion on many issues, most notably on whether or not to bifurcate (hear infringement and validity actions separately). If the court considers it to be appropriate, it can refer a case up to the Court of Justice of the European Union.
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“Opting Out” of the New System The Unitary Patent Court will eventually have exclusive jurisdiction over all European patents, whether validated traditionally (individually) or with Unitary effect (i.e. the Unitary Patent). However, during the transitional period, patentees will be able to “opt out” of the new system and use national courts instead, provided that an action has not already been started at the UPC. This will apply not only to patent granted by the EPO during this period, but also to existing patents granted by the EPO. If you elect for the patent to have unitary effect however, you cannot opt out of using the UPC. If you opt out, you will be able to opt back in later, provided that no actions have been started in a national court. You can opt in and out more than once in the transitional period. If you do not opt out, your patent will automatically have Unitary effect once the new system is up and running. Practical Considerations European Filing Strategy For the time being, there is no need to change your patent filing strategy, as the decision on whether or not your patent should have Unitary effect does not need to be made until the grant stage. Opting Out Whether or not you should opt out of the new system will depend on your circumstances and the importance of the patent(s) in question. If you intend to enforce a patent straight away after grant, there will be an advantage to electing to have unitary effect, since you could save costs by taking action in a single court and obtaining a panEuropean injunction. However you should weigh this benefit against the fact that the UPC will be new and untested so there will be a great deal of uncertainty regarding the outcome. You may not wish to expose your important patents to this uncertainty. Cautious patent owners should opt out of the system initially and wait to see how the new system plays out, before opting back in later if necessary. On the other side of the fence, there will be opportunities for making life difficult for your competitors during the transitional period. One strategy might be to place a “watch” on competitor www.ipimedia.com
patent applications, and file revocation actions at the UPC before they opt out. This would prevent them from opting out, since once an action is started this opportunity is lost. However, we do not know at present whether there will be any time after grant that will make this strategy feasible. Advantageously, if competitors do opt out, and you bring a revocation action in a national court, they will not then be able to sue centrally for infringement in the UPC (although it is uncertain if this will be permitted in countries where bifurcation is utilised). Fees The fee schedule is currently unknown. However, there is speculation that there will be a fee for opting out of the system. If the amount of this fee is large, owners will need to budget for a significant increase in patent spend in 2015, simply to remove their patents from the new system, particularly if they have a large number of patents. The cost of the single renewal fee may be high, as the profits will be shared between the patent offices of the 25 participating countries. This may have an impact on whether or not patent owners will choose to opt out of the system. You could save money by opting out if only a handful of countries are of commercial interest. Likewise, the cost of enforcement may be high, which could mean that smaller, or budget constrained companies, would do better to choose national patents and enforce these through national courts. Forum Shopping Despite the efforts to prevent it, there are still likely to be ripe opportunities for forum shopping under the new system, due to the new court structure. Local variations in patent laws may seep in due to the location of the courts and the nationality of the judges. Courts in countries that are used to applying bifurcation, e.g. Germany, may well continue to do so. Therefore, once the system is up and running, you should give serious thought to where to bring an action. Final Comment For the time being, patent owners do not need to be too concerned with the Unitary Patent or the UPC, but you should be aware that these changes are on the horizon. In the words of Hagrid from J.K Rowling’s Harry Potter series, “what’s
comin’ will come, and we’ll meet it when it does”.
Jon Gowshall’s background is biochemistry, and so his primary technical fields are biotechnology, pharmaceuticals and medical devices. Jon has wide experience of patent law and practice, including UK litigation and freedom to operate opinions. Jon’s core area of expertise is law and practice at the European Patent Office (EPO), where he has considerable experience, including in opposition and appeal procedures. He is a tutor of UK trainee attorneys for the European law examination. Jon is primarily based in our London office, but spends several weeks each year in Munich for dealings with the EPO. Jon has been a UK and European patent attorney since 1989 and a partner since 1993. He is a member of the council of epi (Institute of Professional Representatives before the European Patent Office) and the council of CIPA (the UK Chartered Institute of Patent Attorneys). Email: firstname.lastname@example.org
Charlotte Fox joined Forresters in 2010 after graduating from Cambridge University with a BA in Natural Sciences. During her time at Cambridge she explored a wide range of scientific subjects before finally focusing on zoology with an emphasis on genetics. Out of term time, she worked in a small pharma start-up, where she was involved in developing recombinant antibodies to target MRSA. Since joining the Life Sciences and Chemistry team at Forresters, Charlotte have been involved in a wide range of work, but she has gained particular expertise in prosecuting European Patents in the field of biotechnology and pharmaceuticals. She also has experience with opposition and appeals at the European Patent Office. Email: email@example.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 27
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
Outsourcing Computational Chemistry for Drug Discovery The trend to outsource is making computational chemistry methods affordable and accessible for smaller research organisations. Dr Martin Slater, Director of Consulting Services at Cresset, outlines the scientific and business reasons for outsourcing this important drug discovery method. Computational chemistry is a highlyskilled scientific field that has delivered proven results for drug discovery, particularly in the areas of lead identification and optimisation. Many companies maintain an in-house team or expert who can perform data analysis and carry out molecular modelling. Computational chemistry is an integrated part of many discovery pipelines, and is ideally placed to help medicinal chemists answer questions such as: • Which compound should I make next? • Which structures have the best chance of succeeding against this target? • How can I best optimise this compound to reduce this side-effect? • Given a choice of targets, which should I choose? • How can I generate a back-up series for this project? • Have I missed any potential hits from my data set? However, maintaining an in-house team can be expensive. The overheads include recruiting and training expert staff, buying a range of software and making a significant investment in computational hardware. This can effectively price computational chemistry out of the market for some smaller drug discovery companies. It has led others to question how they can access this technology in a cost-effective way. The Advantages of Outsourcing The opportunity to outsource computational chemistry projects puts this technology firmly within the reach of any research organisation. Outsourcing carries many advantages, both for organisations with in-house computational chemistry, and those without. The first and most obvious advantage is 28 INTERNATIONAL PHARMACEUTICAL INDUSTRY
that by choosing to outsource rather than maintain an in-house team, you remove the overhead of buying and maintaining hardware and software and of recruiting and training users. Some computational methods, such as library design, may only be useful at the start of a new drug discovery project. It does not make sense to maintain in-house expertise for skills that are only used once or twice a year. The word ‘consultant’ may conjure up negative connotations, but in scientific fields, a consultant really has to know their stuff. By choosing to outsource computational chemistry to consultants, you ensure that you are getting years of scientific experience, not only in your particular field, but across a range of protein targets and compound types. Confidentiality remains paramount, but expertise gained by constantly working on diverse compounds and targets brings fresh perspectives to your project that can be hard to gain in-house. Outsourcing gives you just-in-time delivery with a single point of contact. By working with consultants, you are in control of how and when you receive the deliverables, and whether you would like extra work done when projects reveal unexpected results. Most consultants are open to the option of adding extra services. For example, as described in case study 1, you may wish to outsource not only the computational work, but also your procurement services for a particular project, ensuring you receive the compounds when you want them, while only dealing with a single vendor. Outsourcing gives you access to a range of industry software. Most consultants will use the best-in-breed software, rather than sticking to software from just one vendor, even if the consulting services are provided by a software vendor. An added advantage of choosing consulting services from a software vendor is that they can offer early access to methods that they have developed but not yet released as software. For example, qualitative models add value in situations where the 3D-QSAR cannot, as they do
not depend upon the development of an equation to predict activity (Figure 1). The customer’s dataset is processed to find molecules that describe critical features or excluded volumes. These are put into a model, which is then used visually to explain the observed SAR or computationally to score new designs or in virtual screening. Figure 1: Consultants can add value by giving access to new methods that are still under development. In this case, a qualitative model has been created from ligand data alone, showing allowed (green) and disallowed (magenta) regions around a p38 ligand.
Popular Outsourcing Projects Virtual screening is an effective means of switching chemical series to identify new intellectual property. Virtual screening can be ligand-based or protein-based, depending on the available information. In either case, a 3D model is developed of the desired properties of the ideal compound. This is used to search a database to come up with possible new chemotypes. Ligand-based virtual screening is a very popular way to produce ideas for new projects in disease areas where very little information is available for the biological target. Library design. Libraries of chemical compounds are the lifeblood of modern pharmaceutical discovery programmes. The quality of library design can determine a project’s success or failure. Both molecular modelling and cheminformatics techniques are important for building a focused screening library with novel and diverse chemical structures 1. Scaffold hopping. One of the best ways to discover new intellectual property is to perform scaffold hopping on known active compounds. Scaffold hopping is a useful technique during the discovery phase of a project when there are no starting points other than a complex natural product. The aim is to find new chemical structures with similar biological activity to the Summer 2014 Volume 6 Issue 2
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
original by changing components of the molecule. A related software capability called ‘fragment replacement’ explores changing one component of the active molecule at a time. Rather than searching for commercial compounds to purchase, fragment replacement provides ideas for new molecules that can be synthesised. SAR data analysis. SAR analysis is an expert field, which is why many customers prefer an outsourced solution. Our scientists use a variety of techniques to study SAR. These range from simple ligand alignment to more involved methods such as 3D-QSAR, qualitative model development or activity cliff detection. Choosing the Right Outsourcing Model Outsourcing models vary, depending on customer requirements. Project-based work is very popular, in particular for virtual screening, compound library design and the analysis of SAR data. By contrast, some companies enter ongoing collaborations where consultant computational chemists work closely and iteratively with in-house medicinal chemists to add insight to their work on a daily basis. Collaborative working models, such as that described in case study 2, can often lead to the most productive results. The synergy between medicinal chemists and computational chemists adds a new dimension to their thinking and understanding, often with innovative and ultimately profitable results. From a billing point of view, consultants may charge a daily rate, or a project rate. Some vendors are so flexible that it is possible to buy a flexible bank of pre-paid service hours, valid for a fixed time period, usually the next 12 months. Project-based work may be narrowly defined, or can be more open-ended. For open-ended, collaborative projects it is vital to have clear and frequent communication between consultant and client regarding milestones, agreed review points, and deliverables. Most vendors will negotiate arrangements to suit the particular requirements, sometimes adding extra bespoke services, such as procurement, as described in case study 1. Case Study 1: From Virtual Screening to Plated Compounds The usual result from a computational chemistry project is a list of compounds to make or purchase. However, it can be helpful for consultants to go further and manage the customer’s procurement 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY
process so that the result is plated, assayready compounds. A recent consulting project involved a customer who started the project with a known target. They had a number of published active compounds and were looking for some new chemistry for assays they had booked with a biology CRO. The virtual screening work resulted in recommendations for 250 screening compounds. For additional diversity, the consultants used Spark to do some bioisosteric replacements around the core of the known active compounds. These new bioisosteres were used for a further virtual screen that resulted in a further 50 compound recommendations. The customer chose to completely outsource the procurement of these compounds to the same consultants who had carried out the virtual screening project. The procurement process was managed using a dedicated chemistry provider and specialist shipping agents. The compounds were bought from the various vendors, weighed, dissolved, plated and delivered to the biology CRO to be screened. The compound procurement for this project was multinational, including the UK, Europe, Eastern Europe and the US. The final delivery was to a California-based biology CRO. Case Study 2: A Collaborative Project Resulting in New Lead Molecules The small molecule drug discovery company Senexis had developed a series of N‐methylated peptides that block the aggregation of β‐amyloid (Figure 2). They engaged consultants to work with them collaboratively to identify a novel series of drug-like, non‐peptide small molecules that would produce the same effect. The consultants` field-based software was ideal for identifying the key properties of the peptides, providing the seed for a virtual screening experiment. The consultants identified several possible new chemotypes, which they sent to Senexis’s chemists for review. Senexis embarked on a programme of medicinal chemistry and biological testing that resulted in two distinct chemotype sets. Working from these two chemotypes, the consultants used Forge to produce templates for four active structures (two from each set) to find the common field pattern across all of the conformations. From this they deduced the bioactive conformation and pharmacophore for activity.
Further searches using these more reliable field patterns from the bioactive conformations revealed more information and ideas for the Senexis chemists to work with. Their resulting lead molecules were SEN1269 and SEN1186 (Figure 3). The collaborative nature of this consulting project resulted in new perspectives for the Senexis chemists, providing them with several possible leads and enabling them to make informed choices about which to pursue.
Figure 2: An example ‘L-meptide’ search molecule from Senexis Ltd., used by Cresset’s consultants as the basis for finding non-peptide small molecules with similar activity.
Figure 3: The core of SEN1269 and SEN1186, the lead molecules identified as the result of a collaborative outsourcing project between Senexis and Cresset. References 1. Harris, Hill, Sheppard, Slater, Stouten, ‘The Design and Application of Target-Focused Compound Libraries’, Combinatorial Chemistry & High Throughput Screening, 2011, 14, 521531 521. Dr Martin Slater is Director of Consulting Services at Cresset. Cresset provides flexible scientific consulting and contract research solutions for a variety of organizations. The team uses Cresset’s innovative field-based chemistry software, the XED molecular mechanics force field, as well as more traditional approaches. Cresset consultants have worked on over a hundred diverse consulting projects with many of the world’s top pharmaceutical, biotech and agrochemical companies. Email: firstname.lastname@example.org
Summer 2014 Volume 6 Issue 2
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Determining Thermal and Colloidal Stability with High-Throughput Dynamic Light Scattering Introduction Stability is a key quality attribute of therapeutic bio-molecules, critical for establishing drug-like properties and suitability for use in humans. However, establishing the stability of a candidate molecule or formulation can be a long and tedious process. In order to minimise time, effort and funds spent on long-term stability studies, developers of biologics look to high-throughput screening methods that can reliably test and rank hundreds of combinations of candidates, excipients and buffer conditions. Experimental techniques utilised in these screens must determine a variety of stability-indicating parameters (SIPs), since no one parameter has yet proven to be the silver bullet indicative of longterm shelf life or stability under a variety of environmental stresses, such as freezethaw or elevated temperatures. Some of the most useful SIPs to date are: short-term aggregation (the formation of, usually, small aggregates); thermal stability (the tendency of a protein to unfold and/or aggregate with temperature, usually as a consequence of exposure of the hydrophobic core); and colloidal stability (the tendency of molecules to associate due to weak, attractive forces related to surface charges, hydrophobic surface residues and similar moieties). These SIPs are not entirely independent of each other. For example, even though colloidal stability generally pertains to reversible association, the enhanced proximity under self-attractive conditions can enhance irreversible aggregation rates. Conversely, increased surface charge may reduce colloidal attraction and improve colloidal stability, yet degrade thermal stability as the charges destabilise the proteinâ€™s tertiary structure. A variety of techniques such as differential scanning calorimetry, intrinsic and extrinsic fluorescence, circular dichroism, infrared or Raman spectroscopy and static light scattering have been applied to assess SIPs. One technique in particular stands out for its great versatility: dynamic light scattering (DLS). DLS provides quantitative insight into a broad range of phenomena related to stability, as it can simultaneously 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY
quantify aggregation and distribution of aggregate sizes; thermal stability, discriminating between pure unfolding and aggregation through a temperature transition; and colloidal stability, via the concentration dependence of diffusion. The same data may be analysed to determine changes in average molar mass and specific volume. The stability of a bio-molecule is not a wholly intrinsic property, but depends on buffer composition and the concentration at which the protein is formulated. Protein stability must be quantified as a function of pH, ionic strength, specific ion type and excipient profile for an optimal and successful formulation. Fortunately, DLS is amenable to high-throughput, low-volume screening of hundreds of conditions per hour by means of a plate reader utilising industry-standard microwell plates. High-throughput screening by dynamic light scattering (HTS-DLS) is accomplished by means of the DynaProÂŽ Plate Reader II (Wyatt Technology, Santa Barbara, CA) which accommodates 96, 384 or 1536-well plates, performing temperature scans of all samples in parallel from 4C - 85C. The multiplexed approach provided by HTS-DLS can be extended to a variety of other formulation conditions for rapid characterisation of protein behaviour. The simultaneous measurement of thermal and colloidal stability offers qualitatively novel information: the direct interaction between thermal and colloidal stability mechanisms, reflected in the temperature dependence of the colloidal interaction parameter in the vicinity of a thermal transition. This article demonstrates HTS-DLS measurements revealing the impact of thermallyinduced protein unfolding on colloidal interactions, yet another quantitative metric for rapid ranking of protein formulations. The Interaction Parameter DLS directly measures fluctuations in scattering intensity due to Brownian motion, which are analysed to determine the translational diffusion coefficient Dt and hence an effective measure of molecular size, the hydrodynamic
radius Rh. DLS can also provide a rough measure of size distributions in order to assess populations of monomers and aggregates [reference article in IPI Winter 2009, page 22 http://issuu. com/mark123/docs/ipiwinter]. Though not as rigorous as a separation technique such as size exclusion chromatography coupled to light scattering detectors (SEC-MALS), this is often sufficient for screening purposes and will even indicate the presence of size populations that differ by 3-5x in radius. As a consequence of non-specific protein-protein interactions arising primarily from charged and hydrophobic residues, Dt is a function of concentration, c. Analysis of Dt vs. c leads to the firstorder diffusion interaction parameter kD (not to be confused with the equilibrium dissociation constant Kd), per equation 1: Eq. 1
Positive values for kD are indicative of repulsive intermolecular interactions while negative values indicate attraction. The diffusion interaction parameter is directly related to the second virial coefficient A2, a commonly-accepted thermodynamic measure of colloidal stability and propensity for aggregation 1,2. A2 is generally more difficult to measure with low volume and high throughput, so kD serves as a convenient proxy. As a result, kD can be utilised to rapidly compare different protein formulations and guide the selection or engineering of more stable bio-molecules 3,4,5. Materials and Methods A DynaPro DLS plate reader ran HTSDLS measurements for simultaneous thermal, colloidal and mixed stability analyses, also assessing the degree and size distribution of aggregation. A significant benefit of this instrument is measuring the sample entirely in situ in the well, eliminating concerns of carryover common to microfluidic platforms while boosting throughput. A monoclonal antibody (mAb1) was dissolved in 50 mM bis-tris-propane buffer (BTP) at pH values of 6.5, 7.5, 8.5 Summer 2014 Volume 6 Issue 2
the automation solution
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and 9.5 to a final concentration of 15 mg/mL. This stock solution was filtered to 0.1 µm and then diluted and arrayed in a 384-well microtiter plate (Aurora) at five replicates of six different protein concentrations between 0.47 mg/mL and 15 mg/mL, for each of the four pH values, loading 20 µL of solution into each well. The plate was centrifuged at 400g for 1 minute and each well was then capped with 1-2 drops of paraffin oil to prevent evaporation. Prior to measurement, the plate was centrifuged again at 400g for 1 minute. Initial measurements at 25 °C included control samples of bovine serum albumin and lysozyme in the same plate, not discussed here (though the measurements appear in some figures). An extended series of measurements was then conducted as a function of temperature, ramping from 25 °C to 85 °C at a rate of 0.1 °C/min. During the ramp the mAb1 solutions were measured sequentially, completing five 2-second acquisitions for three replicate wells at each concentration and pH, every 0.50C. Instrument control, data acquisition and analysis were carried out via the DYNAMICS® software (Wyatt) and Microsoft Excel. Dt and Rh were determined from autocorrelation analysis and kD was calculated from the linear regression of Dt vs. c. Aggregation onset temperature Tonset was determined per concentration and pH by fitting the plot of Rh vs. temperature to an appropriate model.
protein attraction. This antibody exhibits kD < 0 for all pH values tested (Figure 2), indicating a predisposition to assemble into oligomeric species. Thermally-induced Aggregation At pH 8.5 mAb1 rapidly aggregates into large complexes beyond the thermal transition around 55 °C, with Rh at 75 °C ranging from 80 nm to 800 nm (Figure 3). Tonset decreases with concentration, ranging from 55.0 to 56.8 °C (Figure 3, inset). The final aggregation state is highly dependent on the concentration, varying by over two orders of magnitude in average particle size between the lowest and highest concentrations. A second transition occurs at 70-75 0C, possibly related to the unfolding of another IgG domain, that results in large-scale aggregation into particles
Figure 4: The hydrodynamic radius exhibits a sigmoid relationship as a function of temperature for all antibody concentrations at pH 9.5, showing little change in the midpoint with concentration.
Figure 2: Interaction parameter, kD, as a function of pH for three proteins.
>1 µm. The high degree of aggregation suggests that the observed concentration dependence past the thermal transition is primarily a consequence of higher molecular collision rates. This can be confirmed by varying the temperature ramp rate.
34 INTERNATIONAL PHARMACEUTICAL INDUSTRY
The qualitative difference in aggregation processes the two conditions are further elucidated in the size distributions obtained with DLS regularisation analysis. At 80C, the pH 8.5 sample with 1.88 mg/mL concentration exhibits a bimodal distribution with populations of 30-100 nm and 300-3000 nm, while the pH 9.5 sample at the same concentration presents a single distribution at 80-300 nm, as shown in Figure 5.
Figure 5. Size distributions obtained at 80 C via regularization. Left: pH 8.5; right: pH 9.5.
Figure 1: Measured hydrodynamic radius as a function of concentration and pH for three proteins.
Results and Discussion Interaction parameter as a function of pH MAb1 exhibited increasing Rh (decreasing Dt) as a function of concentration (Figure 1), corresponding to a negative kD and hence protein-
IgG, to a stable value between 15 and 22 nm, depending on concentration, for temperatures above 62 °C (Figure 4). The small size and stability of the aggregates at this pH suggest reversible oligomerisation. This can be confirmed by reversing the temperature ramp and/ or varying the ramp rate. Around 75 °C, the antibody appears to enter a second unfolding transition, similar to pH 8.5 though with much smaller magnitude of aggregation and little effect at the lower concentrations.
Figure 3: Hydrodynamic radius as a function of temperature and concentration for an antibody formulation at pH 8.5. High order aggregate formation is evident for temperatures >56 °C.
In contrast, at pH 9.5, mAb1 exhibits a shift from Rh = ~4.8 nm, typical of
Interaction Parameter through the Thermal Transition Below the thermal transition, kD is negative and approximately constant with temperature increase for both pH values. The magnitude of kD at pH 8.5 is about twice that of pH 9.5, indicating stronger intermolecular attraction, Summer 2014 Volume 6 Issue 2
DRUG DISCOVERY, DEVELOPMENT & DELIVERY
which correlates to the vastly different aggregation behaviour. In the vicinity of the folding-unfolding transition and onset of aggregation, kD exhibits distinct transition behaviour versus pH. At pH 8.5 kD undergoes a dramatic stepchange from between 53 °C and 59 °C (Figure 6 and inset). Strikingly, the shift begins several degrees before any appreciable aggregation appears and is suggestive of increased protein-protein attraction due to pure unfolding. Beyond 59 °C, kD is constant (though noisy due to the numerical difficulty of ascribing a single average radius when the population is bimodal). As seen in Figure 3, the degree of aggregation depends on concentration, but this would appear to be due primarily to higher collision rates and therefore the measured value of kD beyond ~ 56 0C probably is not indicative of a true thermodynamic interaction, but rather of the history and kinetics of the aggregation process.
Figure 6: Diffusion interaction parameter (symbols, left axis) and radius (solid line, right inverted axis) at lowest concentration as a function of temperature at pH 8.5. Inset: same, highlighting the transition region.
A similar change in kD signals the unfolding transition at pH 9.5: once again kD becomes more negative (more attractive) several degrees prior to aggregation. Instead of a stepchange, however, we now observe a local minimum occurring just as the measured hydrodynamic radius begins to indicate aggregation (Figure 7). Upon aggregation, the magnitude of kD decreases to become less negative. This trend in kD indicates once more that attractive interactions increased during the first unfolding transition as the hydrophobic core is exposed. However in this condition, once a stable structure has been achieved, these interactions are partially mitigated as the exposed regions are now hidden from the solution. A secondary unfolding transition around www.ipimedia.com
75 0C is clearly reflected in kD. 3.
Figure 7: Diffusion interaction parameter (symbols, left axis) and radius (solid line, right inverted axis) at lowest concentration as a function of temperature at pH 9.5. Inset: same, highlighting the transition region.
Conclusion The ability to screen protein formulations at the early stages of development enables scientists to concentrate on the most suitable candidates and so save substantial amounts of time, sample and testing equipment. This experiment demonstrates that thermal and colloidal stability of proteins, two indicators of propensity to aggregate, as well as actual aggregation states, are all determined simultaneously during the screening process with DLS tools in order to rank the effectiveness of candidates and formulation conditions. Thermal stability is quantified as Tonset and colloidal stability as kD. The temperature dependence of kD provides unique insight into the effect of unfolding on colloidal interactions, as the unfolding process reveals moieties previously ‘hidden’ from buffer and other proteins. Not discussed here, DLS can also indicate chemical stability and the average molar mass and specific volume of molecules in solution as a function of temperature, as well as solution viscosity6 which is another important factor in formulating highconcentration bio-therapeutics. Therefore HTS-DLS provides substantial quantities of information for the rapid screening of candidate molecules, buffer conditions and excipients in order to drive higher productivity. References 1. Some D., Hitchner E. & Ferullo J., Characterizing Protein-Protein Interactions via Static Light Scattering: Nonspecific Interactions. American Biotechnology Laboratory 27 (2), 1620 (2009). 2. Kuehner D. E. et al., Interactions of lysozyme in concentrated electrolyte
solutions from dynamic light-scattering measurements. Biophysical Journal 73, 3211-3224 (1997). Lehermayr C., Mahler H.-C., Mader K., Fischer S. Assessment of Net Charge and Protein-Protein Interactions of Different Monoclonal Antibodies. J. Pharm. Sci. 100(7), 2551-2562, (2011). He F., Woods C. E., Becker G. W., Narhi L. O., Razinkov V. I. HighThroughput Assessment of Thermal and Colloidal Stability Parameters for Monoclonal Antibody Formulations. J. Pharm. Sci. 100(12), 5126-5141 (2011). Saito S., Hasegawa J., Kobayashi N., Tomitsuka T., Uchiyama S., Fukui K. Effects of Ionic Strength and Sugars on the Aggregation Propensity of Monoclonal Antibodies: Influence of Colloidal and Conformational Stabilities. Pharm. Res. 30(5), 12631280, (2013). He F., Becker G. W., Litowski J. R., Narhi L. O., Brems D. N., Razinkov V. I. High-throughput dynamic light scattering method for measuring viscosity of concentrated protein solutions. Anal. Biochem. 399(1), 141-143, (2010).
Sophia Kenrick develops and supports new applications for Wyatt Technology light s c a t t e r i n g instrumentation, especially in the field of protein-protein interactions. She received her BSE in Chemical Engineering from Arizona State University and PhD in Chemical Engineering from the University of California, Santa Barbara. E-mail: firstname.lastname@example.org. Daniel Some is responsible for the development and support of Wyatt Te c h n o l o g y ’s instrumentation and software for characterising macromolecular interactions, as well as marketing Wyatt’s entire product line. He received a B.Sc. degree from the Technion - Israel Institute of Technology, and a Ph.D. in Physics from Brown University. E-mail: email@example.com. INTERNATIONAL PHARMACEUTICAL INDUSTRY 35
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Regulatory Focus on Nanomedicines in the US and Europe This article aims to present an overview of nanotechnology and its drug delivery system, as well as the regulatory approach for the approval of nanomedicines in regulated markets like the United States and Europe. The use of nanoscale technologies to design novel drug delivery systems and devices is a rapidly developing area that promises breakthrough advances in therapeutics and diagnostics. Nanomedicine is an area of nanotechnology, and the goal of nanomedicine is to provide the most effective treatment without side-effects. It is likely to have a wide impact on medical devices and medicinal products, with the potential for the development of new therapies, such as smaller implantable devices or improved dosing and targeting of medicines. Legislation governing nanomedicines is limited around the world, particularly in the US and Europe. These organisation strategies for nanotechnology assert that nanotechnology has the potential to enhance quality of life and industrial competitiveness, and therefore lobbies aggressively for minimal legislation on nanotechnology.
conventional drugs used for the treatment and management of chronic diseases such as cancer, asthma, hypertension, HIV and diabetes. Nanotechnology (sometimes shortened to “nanotech”) is the manipulation of matter on an atomic and molecular scale. A more generalised description of nanotechnology was subsequently established by the National Nanotechnology Initiative, which defines nanotechnology as the manipulation of matter with at least one dimension sized from 1 to 100 nanometres.
Keywords: N a n o t e c h n o l o g y, N a n o m e d i c i n e , Legislation, Strategies Introduction: A drug delivery system (DDS) can be defined as the system that achieves the administration of a therapeutic agent to the patient and improves the drug’s efficacy and safety by controlling the concentration, rate, time, and place of release of drugs in the body. The primary purpose of drug delivery systems is to deliver the drug efficiently and precisely to a targeted site in an appropriate period of time, while maintaining a high concentration of the drug in the diseased site and as low as possible in the healthy tissue. Nanotechnologybased delivery systems can also protect drugs from degradation. These properties can help reduce the number of doses required, make treatment a better experience, and reduce treatment expenses. Nanotechnology definitely promises to serve as the drug delivery carrier of choice for the more challenging 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Fig: Different surface unmodified nanomedicines. (A) Polymeric nanoparticles; (B) solid lipid nanoparticles; (C) polymeric micelles; (D) dendrimers; (E) liposomes; and (F) magnetic nanoparticles. Nanotechnology-based Drug Delivery Systems:
1. Nanoparticulate drug delivery system • Liposomes • Microemulsions • Nanoparticles • Nanomedical Devices • Polymers • Micelles • Nanocapsules
2. Natural polymers in nano drug delivery • Polysaccharide • Starch • Chitosan • Proteins • Gelatin 1. Nanoparticulate Drug Delivery System Nanoparticles used as drug delivery vehicles are generally < 100 nm in at least one dimension, and consist of different biodegradable materials such as natural or synthetic polymers, lipids, or metals. Nanoparticles are taken up by cells more efficiently than larger micromolecules and, therefore, could be used as effective transport and delivery systems. For therapeutic applications, drugs can either be integrated in the matrix of the particle or attached to the particle surface. A drug targeting system should be able to control the fate of a drug entering the biological environment. Nanosystems with different compositions and biological properties have been extensively investigated for drug and gene delivery applications. 2. Natural Polymers in Nano Drug Delivery Natural biopolymers such as starch, chitosan and gelatin have found use in industries as diverse as food, textiles, cosmetics, plastics, adhesives, paper, and pharmaceuticals. The food industry uses these polymers as a thickening agent in snacks, meat products, fruit juices. They are also used in the manufacture of disposable items like fast food utensils and containers. From a pharmaceutical standpoint, these polymers have been extensively used in solidoral dosage forms, where they have been used as binders, diluents, disintegrant and matrixing agents. In recent times, nanotechnology has started to make significant advances in biomedical applications, including newer drug delivery techniques. There has therefore been considerable research into developing biocompatible, biodegradable submicron devices as drug delivery systems using natural polymers; this is because they occur widely in nature, and are generally biocompatible, biodegradable, safe and Summer 2014 Volume 6 Issue 2
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non-immunogenic. There are reports of these polymers being made into colloidal particles that act as carriers for both large and small drug molecules, conferring on the drug molecules properties which enhance delivery actively or passively, thereby tuning them for use as controlled, ocular, transdermal or intranasal delivery systems. In more advanced areas of drug delivery, these polymers have also been tested for gene therapy and tissue engineering. Regulations of Nanomedicines USFDA: The FDA has recognised that “because development of nanotechnology-based drugs is still in its infancy, there are no established standards for the study or regulatory evaluation of these products.” As a step forward, the FDA is developing a comprehensive database of products containing nanomaterials that were the subject of drug applications to CDER. It should be pointed out that because of the significant amount of preapproval studies required by the FDA, developing nanomedicines such as RNAnanoparticle complexes is the most costly and most long-term endeavour in the nanomedicine context. •
• • •
• • •
A product will be regulated by the FDA as a drug if it is recognised in an official pharmacopoeia; is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; or is intended to affect the structure or any function of the body of man or other animals (and is not food) Nanotechnology may challenge the drug device distinction because it can be difficult to distinguish between chemical and physical modes of action at the nanoscale More knowledge needed about biological interactions and detection and measurement Agency-wide regulatory/science coordination for nanoscale materials needed Current testing approaches to assess safety, effectiveness and quality of products with nanoscale materials should be evaluated Promote/participate in development of characterisation methods and standards for nanoscale materials Development of models for behaviour of nanoscale particles in vitro and in vivo Physio-chemical properties of
nanoparticles can biodistribution:
• Size • Surface Charge • Stability • Density • Crystallinity • Surface Characteristics • Solubility • Bioavailability of encapsulated and free drug may need to be assessed separately Table 1: List of Nanomedicine Products Approved in US S.No Platforms
Anorexia, Cachexia in AIDS 2005 patients
Metastatic breast cancer
Helioblock sx sunscreen cream
i. NDA 1 • The product-specific approvals under the full Section 505(b) (1) NDA process pose the fewest concerns for FDA assurance of the safety of
38 INTERNATIONAL PHARMACEUTICAL INDUSTRY
nanotechnology-based drugs. On request, the FDA may require applicants to supply information about a drug’s particle size as part of its review of the product’s safety early in the IND process. However, since particle size is not expressly required to be disclosed by the applicant, either the applicant must voluntarily disclose that the product is nanotechnology-based, or the FDA is likely not to become aware the product utilises nanotechnology until later in the process. In 2010, CDER asked its reviewers in the Office of Pharmaceutical Sciences (OPS) to document nanotechnology-
related information received in drug application submissions. However, this procedural update only requires OPS reviewers to gather nanotechnology-related information Summer 2014 Volume 6 Issue 2
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that is reported on a drug application and to search internal reporting databases for particular nanotechnology-related terms; it does not create any new reporting or disclosure requirements for those who submit the drug application. ii. ANDA • For drugs that contain the same or similar active ingredients as previously approved drugs, premarket approval may proceed via a Section 505(b) (2) application or an ANDA. • The FFDCA does not differentiate between active ingredients on the basis of particle size, so a nanotechnology-based active ingredient might be considered the same as a traditional drug, thereby shortening the time necessary for approval and, consequently, getting the product to market faster. 1. To date, there have been no generic nanotechnology-based drugs approved under the ANDA pathway. 2. In other words, because a nanotechnology-based drug will likely exhibit different pharmacokinetic properties than a traditional drug, it may not perform in exactly the same manner. Nanotechnology may also be used to produce inactive ingredients, which could influence absorption or toxicity of the product. EMEA: There is a wide range of Community legislation related to issues relevant for nanotechnology and nanomaterials, currently in existence or being elaborated. These issues primarily have to do with risk assessment. Examples of legislation relevant for nanomedicine are the following: (a) Medicinal products marketed in the European Union are covered by comprehensive EU legislation. Medicinal products are defined in the EU legislation as follows: (a) Medicinal product: Any substance or combination of substances presented for treating or preventing disease in human beings. Any substance or combination of substances which may be administered to human beings with a view to making a medical diagnosis or to restoring, correcting or 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY
modifying physiological functions in human beings is likewise considered a medicinal product. All medicinal products marketed in the European Union must obtain an EU product authorisation. Directive 726/2004 lays down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use, and establishes a European Medicines Evaluation Agency (EMEA). EMEA’s task, according to its mission statement, is “to contribute to the protection and promotion of public and animal health by mobilising scientific resources from throughout the EU to provide high quality evaluation of medicinal products, to advise on research and development programmes and to provide useful and clear information to users and healthcare professionals developing efficient and transparent procedures, to allow timely access by users to innovative medicines through a single European marketing authorisation, and in particular through a pharmacovigilance network and the establishment of safe limits for residues in food producing animals”. The European regulatory system for medicinal products offers two routes for authorising medicinal products: A “centralised procedure” with applications made directly to EMEA, leading – if approval is obtained – to the grant of a European marketing
authorisation by the Commission. Use of this procedure is compulsory for products derived from biotechnology, and optional for other innovative medicinal products. A “mutual recognition” procedure, which is applicable to the majority of conventional medicinal products. Applications are made to the Member States selected by the applicant and the procedure operates by mutual recognition of national marketing organisations. Purely national authorisations are still available for medicinal products to be marketed in one Member State. Both procedures are based on a wide range of requirements laid down in implementing rules and – de facto binding – guidance documents. National clinical trials preceding an EU authorisation must observe the rules laid down in the Declaration of Helsinki, which means, among other things, that they must be assessed by an ethical review committee. Seen in an international context, this EU regulatory system is unique in providing a network between all national regulatory bodies, coordinated by EMEA. (b) Medical devices are also covered by EU regulation, but the Directive on medical devices does not make placing on the market subject to a prior marketing authorisation issued by public authorities. A medical device is defined as “any instrument, apparatus, appliance, software, material or other article, whether used alone or in combination, Summer 2014 Volume 6 Issue 2
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Medicinal Product Abraxane (paclitaxel)
Nanotechnology Purpose Solvent-free
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together with any accessories, including the software necessary for its proper application intended by the manufacturer to be used for medical purposes for human beings for the purpose of diagnosis, prevention, monitoring, treatment or alleviation of disease, investigation, replacement or modification of the anatomy or of a physiological process, control of conception, and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such meansâ€?. The Directive does not apply to human blood, blood products, blood cells of human origin, human 1 tissue engineered products, etc. However, depending on risks involved, devices can only be placed on the market if they have been subject to a conformity assessment procedure involving a third party - a so-called Notified Body - designated by a Member State. The Directive deals primarily with risk management. Manufacturers are obliged to carry out an assessment of the risks and to adopt a risk management strategy. This means that they have to adopt measures to eliminate risks, or to reduce risks as far as possible, take the necessary protection measures in relation to risks that cannot be eliminated and, as a last resort, inform users of the residual risks due to any shortcomings of the protection measures adopted, and advise any other protective measure regarding risks that cannot be eliminated. The Directive on medical devices includes a risk-benefit analysis.
Conclusion: The healthcare revolution brought about by nanomedicine could dwarf all other trends in the history of medical technology. There are currently no proper regulatory guidelines developed specifically for nanomedicines due to inadequate knowledge regarding nanoparticle behaviour. As the market for nanomedicines is growing, the development of regulatory guidance assumes priority. Currently, the nanomedicine market is poised at a critical stage wherein clear regulatory guidance is imperative in providing for clarity and legal certainty to manufacturers of nanomedicine. As the properties of nanomedicines often differ, the regulations vary with those of the regular pharmaceutical products. Thus, jurisdictions should continue to broaden legislation monitoring the development of nanotechnology. Since regulatory agencies around the world are simultaneously struggling with regulatory issues of nanomedicines, there may be benefits from attempting to harmonise national regulations. The agency should begin to prepare now for the coming revolution in nanomedicine. References 1. http://www.stlr.org/html/volume4/ miller.pdf 2. h t t p : / / w w w . n a n o . o r g . u k / articles/16/ 3. http://www.nanopharmaceuticals. org/FDA.html 4. http://jolt.richmond.edu/v16i2/ Article4.pdf 5. h t t p : / / w w w . f d a l a w b l o g . net/fda_law_blog_hyman_
phelps/2010/08/fda-seeksinformation-on-safety-andeffectiveness-of-nanodevices-.html 6. h t t p : / / w w w . n a n o t o x . c o m / industries/nanomedicines-a-nanomedical-devices.html 7. h t t p : / / w w w. p h a r m a i n f o . n e t / reviews/nanomedical-devicesoverview 8. h t t p : / / w w w. m d d i o n l i n e . c o m / ar ticle/exploring-world-nanomedical-devices 9. h t t p : / / e c . e u r o p a . e u / b e p a / european-groupethics/docs/ publications/opinion _21_nano_ en.pdf 10. http://regulation.upf.edu/dublin10-papers/5B2.pdf 11. http://www.nanopharmaceuticals. org/Liposomes.html 12. 12. http://cdn.intechopen.com/ pdfs/32559/InTech-Nanoparticles_ preparation_using _microemulsion_ systems.pdf 13. http://www.sciencedaily.com/ articles/n/nanoparticle.htm
Vidhya sabbella - M. Pharm Regulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email: Vidhya.firstname.lastname@example.org Valluru Ravi - Assistant Professor, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email: email@example.com T. M. Pramod Kumar - Professor & Head of Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Mysore. Email: firstname.lastname@example.org K. Sreekanth Reddy M. Pharm Regulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email: sreekanthkaja@ ymail.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 41
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Ready for Battle: How Preclinical Development Brings New Vaccines to the War on Disease Most of us share a common childhood memory: a white-coated doctor whose kindly manner seemed at odds with the sharp hypodermic needle he or she jabbed into your arm. But the fact is, that momentarily painful poke might have saved your life. Today, medical researchers around the globe are pursuing collaborative, cutting-edge work to make sure many more people will live to share childhood memories. Few medical advances have made as large an impact on world health as vaccines. According to the Biotechnology Industry Organization, vaccines prevent an estimated 10.5 million cases of infectious diseases worldwide each year, including 2.5 million child deaths from diphtheria, tetanus, pertussis, and measles. Further, recent studies concluded that a concerted effort to expand vaccination globally over the next decade could reap an economic benefit of $231 billion.1,2 Yet the battle isn’t over. As new infectious diseases emerge, as old ones grow resistant, and as our understanding of human immune response increases, researchers are developing novel vaccines, creative delivery tools, and innovative approaches. The preclinical realm, where I and my colleagues work, is especially important to identifying and advancing the most promising candidates that could save innumerable lives. Historical Perspective The science of immunology began where today’s medical breakthroughs get their start: with a carefully reasoned hypothesis. In 1796, English physician Edward Jenner noticed that milkmaids who contracted cowpox, a relatively nonthreatening skin disease, usually were immune to its much deadlier cousin, smallpox. Thinking that inoculation with pus from cowpox blisters might protect a person from smallpox, Jenner tested his hypothesis on the eight-year-old son of his gardener. 42 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Fortunately, Jenner’s idea worked. While he wasn’t the first to inoculate a patient, his effort began the practice of vaccination that went on to save millions of lives over the next two centuries. Of course, modern medical research sets much higher standards than in Jenner’s day. Ethical tenets, scientific practices, and strict regulatory rules demand far more rigorous testing before a vaccine, or any drug, is used in humans. Many of the regulations in place today developed over the course of the 20th century—often in the wake of tragedy. The United States (US) Biologics Control Act of 1902 was established after a diphtheria antitoxin contaminated with tetanus spores killed 13 children in St Louis. Other regulations continued to emerge—notably the Pure Food and Drug Act of 1906, which grew to encompass vaccines under 1938’s Federal Food, Drug and Cosmetics Act. These and other regulations prompted the US government to consolidate and revise them as the Public Health Service Act of 1944, one of the nation’s most significant healthcare laws. Among its provisions were licensing requirements for vaccine makers. A Double-edged Sword One of the biggest regulatory impacts on vaccines occurred in 1955. A faulty process for inactivating the virus used in polio vaccines by Cutter Laboratories resulted in an estimated 40,000 cases of polio, killing 10 children and debilitating 200 more. The US Surgeon General stopped all polio vaccinations and mandated thorough inspections of all vaccine producers by the Laboratory of Biologics Control (eventually becoming the Center for Biologics Evaluation and Research, an arm of the US Food and Drug Administration [FDA]). Stricter standards and testing requirements ensued and have continued in the following decades.3 Of course, the need for safe and effective vaccines is global in nature. According to the World Health Organization (WHO), the world’s poorest regions remain hard-hit by
infectious diseases for which vaccines already exist but are not available. Add to this the heavy toll from diseases that have no vaccines, or for which current treatments are inadequate, and the need for quality vaccines and robust research and development (R&D) becomes clear. To that end, national regulatory agencies have a variety of standards that vaccine makers must meet. In an effort toward harmonisation, the WHO works across those agencies to define critical issues and provide guidance where needed, with the goal of assuring high quality vaccines for patients everywhere.4 Meeting the growing rigorous standards of today means new vaccines are much more likely to work effectively with minimal risk. But it’s a double-edged sword; the demand for greater safety and efficacy means R&D can take as long as 10 to 15 years from concept to patient, and cost $1 billion or more.5 Further, liability concerns all but gutted vaccine production by the late 1900s as major lawsuits began chasing drug companies away. While some tort protections were put in place, the legal risks and limited financial gain discouraged vaccine R&D into the 21st century.6 Fortunately, the pendulum has begun to swing the other way. Emerging and resurgent diseases have increased the demand for innovative vaccines. Also, new technologies promise to make the search more fruitful. Vaccines’ New Age As a result, vaccine R&D is undergoing a renaissance. In recent times, researchers have created new vaccines and adjuvants that mount an immune response against an array of foreign bodies, including cancer cells and certain drugs or chemicals. Many of those same foreign bodies, or antigens, can form the building blocks of vaccines themselves.7 So diverse are the possibilities that biopharmaceutical companies are ramping up their investment once again, with more than 120 new vaccine Summer 2014 Volume 6 Issue 2
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products now in development. The timing is right: the vaccine market has more than quadrupled since the turn of the century, from $5 billion in 2000 to $24 billion in 2013. It will more than quadruple again by 2025, according to the WHO. 8 A number of factors are driving this demand. One is the emergence of new infectious diseases, the spread of old ones to new areas, or new infectious strains. HIV and SARS are well-known newer diseases, and West Nile virus is an example of a threat that has spread to other parts of the world. Half the global burden of infectious disease is comprised of HIV, resurgent tuberculosis, and malaria. Then there is H1N1 influenza, a new strain of flu that has killed dozens of people across the United States in recent months. Another factor driving development is the opportunity to structure new vaccines to treat a wider range of conditions. Alzheimer’s disease, the most common neurodegenerative disease in the developed world, is gaining attention from vaccine researchers. Also, cancer immunotherapy can involve vaccines that prompt the immune system to attack cancer cells. This particular effort was named the top breakthrough of 2013 by the scientific journal Science.9 There is also the concern of bioterrorism - the deliberate use of viruses, bacteria or toxins to kill people, animals or plants. Anthrax, plague, and smallpox are commonly referenced as bioterrorism weapons, but the potential for genetically engineered agents adds urgency to the need for strong vaccine development and production capabilities. In 2011, the US Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report named vaccination as one of the 10 greatest public health achievements of the previous decade.10 The need to expand the effective use of vaccines will continue. That means robust and successful development will be critical to creating new vaccines and saving lives. Make or Break in Preclinical Even so, the combined pressures of cost, time, and increasingly demanding safety standards have placed greater focus on identifying the most promising 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY
candidates early in the process. Adding to the challenge is the complexity of some diseases, such as tuberculosis, malaria, and HIV/AIDS, and the ongoing concern of serious side-effects. Indeed, research in immunology has revealed that the human immune system itself is far more complicated than once believed, with an intricate web of communication between innate (non-specific) and adaptive immune subsystems that researchers have barely begun to understand. While this raises a multitude of new questions, it also opens new avenues of study for generating an immune response, possibly leading to treatments tailored specifically to certain pathogens.11 Further, scientists are looking at ways to enhance the effectiveness of vaccines through advanced genetic engineering techniques and by identifying new adjuvants. Methods of delivery are under study as well, from increased use of mucosal routes through nasal sprays to needle-free transdermal patches and electroporation, which involves using electrical fields to place a drug directly into cells.
package for evaluating vaccines include the following: Bioinformatics, which involves analysing biological data to predict toxicity. Experts in this field tap rich databases and use sophisticated information systems to drive decisions on potential vaccines early in development. In vitro analysis, using an array of scientific techniques and technologies to evaluate the pharmacologic activity of a vaccine. These tests can signal whether a compound is safe and potent enough for further testing. In vivo analysis, testing a vaccine’s safety and effectiveness in a selected animal model before first-in-human clinical trials. These tests cover important areas: • •
Regardless of where this new era of research leads, one thing is clear: Potential vaccines that move beyond the exploratory level face rigorous scrutiny at the preclinical stage. The goal of preclinical vaccine studies is two-fold: to assess safety and determine immunogenicity, i.e., whether the vaccine candidate prompts an immune response. Tissue-culture, cell-culture, and animal models help scientists determine toxicity and predict cellular response to the vaccine in humans, as well as suggest safe dosages and administration. Challenge studies—vaccinating an animal model and then exposing it to the target pathogen to gauge immune response— also may be part of the preclinical mix. Traditionally, the preclinical phase has lasted one to two years. New technologies and processes are compressing that timeline so defensible, scientifically sound decisions can be made more quickly. This accelerates development of the most promising candidates while rapidly eliminating failures. Quality Preclinical Tools The elements of a quality preclinical
Efficacy and safety – selecting the safest and most effective dose; Single-dose acute toxicity tests – measuring toxicity after one inoculation (not always required depending on the species used and the type of vaccine under study); Repeat-dose toxicity tests – assessing toxicity of a compound administered repeatedly over a set period of time meets Good Laboratory Practices(GLP) and covers key parameters, e.g., ophthalmology examinations, FDA-approved Draize Test score of the injection site, body temperature, electrocardiograms, body weight, food consumption, histopathology, and a range of clinical pathology measures); Biodistribution – how long a compound stays in the body and how it is eliminated; Immunopharmacology – evaluating the potential of a vaccine to protect against a disease and demonstrating the reversibility of any immunopharmacologic effects (may involve assessing acute phase proteins, histopathology and specific clinical pathology measures, and may be combined with a repeat-dose toxicity test for a detailed evaluation of the compound); and, Local tolerance – evaluating the injection site using Draize scoring and histopathology, usually in combination with a repeat-dose toxicity test. If a vaccine candidate targets women child-bearing age or children, Summer 2014 Volume 6 Issue 2
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reproductive toxicology studies may be needed. Separate safety pharmacology studies come into play if a test vaccine has any possibility of impacting the cardiovascular, respiratory, and/or nervous system; parameters such as body temperature and electrocardiograms would be measured in a repeat-dose toxicity study to evaluate these potential effects. Finding the Right Partner Having a high-quality preclinical study package is just one element, albeit critical, for evaluating the next breakthrough vaccine. It’s worth noting the limitations inherent in preclinical development. Pathogenesis and immune response in an animal model, whether good or bad, may be unique to the species and might not translate to humans. Since many preclinical studies are now outsourced, it is critical for the sponsor to find the right partner with breadth and depth of experience in vaccine development and related technologies. As we’ve seen, this is a fast-moving area of research, driven by the growing global focus on preventative medicine and the increased demand due to emerging and resistant diseases. Success in medicine’s ongoing war on infectious diseases will rely heavily on partnership. In fact, 2011-2020 is designated the Decade of Vaccines Collaboration by the WHO, the Gates Foundation, the GAVI Alliance, and others. The goal is to harness the collective resources and expertise of different industries to develop and provide critical vaccines to all populations. The Global Vaccine Action Plan supporting this effort was endorsed by 194 states at the World Health Assembly.12 That spirit of partnership extends to every level—between the contract research organisation (CRO) and the sponsor, and across the wider communities involved in vaccine research, from research scientists to biopharmaceutical companies to government regulators. Strong, quality partnerships convey practical near- and long-term benefits: decreased R&D costs, broader expertise, efficient development and faster, reliable results. These are crucial advantages in developing any new drug and especially key in the hunt for breakthrough vaccines. The stronger the partnership and the 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY
greater the expertise in the preclinical realm, the more effective we will be in turning a carefully reasoned hypothesis into a life-saving vaccine. References 1. “Healing The World: How To Save Millions of Lives,” Biotechnology Industry Organization, http://www. bio.org/articles/healing-world, retrieved 16 March 2014. 2. Hitt, E., Ph.D., “Decade of Vaccines Will Save Lives and Money Globally,” Medscape Medical News, 9 June 2011, http://www.medscape.com/ viewarticle/744285, retrieved 17 March 2014. 3. Bren, L., “The Road to the Biotech Revolution - Highlights of 100 Years of Biologics Regulation,” FDA Consumer, 2006 Jan-Feb, http://www.fda.gov/AboutFDA/ WhatWeDo/History/FOrgsHistory/ CBER/ucm135758.htm, retrieved 16 March 2014. 4. Global Vaccine Safety Initiative, World Health Organization, http:// w w w. w h o . i n t / v a c c i n e _ s a f e t y / initiative/en/, retrieved 16 March 2014. 5. Herper, M., “The Truly Staggering Cost of Inventing New Drugs,” Forbes, 2 Oct 2012, http:// www.forbes.com/sites/ matthewherper/2012/02/10/thetruly-staggering-cost-of-inventingnew-drugs/, retrieved 16 March 2014. 6. Offit, P., “Why Are Pharmaceutical Companies Gradually Abandoning Vaccines?” Health Affairs, 2005; 24(3):622-630, h t t p : / / w w w. m e d s c a p e . c o m / viewarticle/504779_2, retrieved 16 March 2014. 7. Brennan, F. R., & Dougan, G. (2005). “Non-clinical safety evaluation of novel vaccines and adjuvants: new products, new strategies.” Vaccine, (23), 3210-3222. 8. Kaddar, M., “Global Vaccine Market Features and Trends,” Dept. of Immunization, Vaccines and Biologicals, World Health Organization, http://who. int/influenza_vaccines_plan/ resources/session_10_kaddar.pdf, retrieved 17 March 2014. 9. Couzin-Frankel, J., “Breakthrough of the Year: Cancer Immunotherapy,” Science, 20 December 2013: Vol. 342 no. 6165 pp. 1432-1433, h t t p : / / w w w. s c i e n c e m a g . o r g /
content/342/6165/1432.full, retrieved 17 March 2014. 10. “Ten Great Public Health Achievements—United States, 20012010,” Morbidity and Mortality Weekly Report, 20 May 2011, 60(19);619-623, http://www.cdc. gov/mmwr/preview/mmwrhtml/ mm6019a5.htm, retrieved 17 March 2014. 11. Danielsson, O., “From Cookery to High Precision Science,” Medicinsk Vetenskap nr 1 2010, Karolinska Institutet, http://ki.se/en/research/ from-cooker y-to-high-precisionscience, retrieved 16 March 2014. 12. Global Vaccine Action Plan 20112020, World Health Organization, http://www.who.int/immunization/ global_vaccine_action_plan/ G VA P _ d o c _ 2 0 1 1 _ 2 0 2 0 / e n / , retrieved 17 March 2014.
Stephene Rose, MBM, BS, is a Senior Study Director at MPI Research, with more than 20 years of experience in the contract research industry. She is responsible for the overall planning and conduct of preclinical investigations for GLP and non-GLP drug and medical device evaluations in vaccine therapeutics and general toxicology, as well as partnering with Sponsors to further expand their own discovery and development efforts. Before joining the company in 2011, Ms. Rose gained valuable experience at Charles River Laboratories as a technical training manager and a research scientist and Study Director. She spent several years at Covance Laboratories, as a study technician, study coordinator, associate toxicologist, supervisor, and toxicologist. Ms. Rose received her BS in biology in 1993 from Virginia Polytechnic Institute and State University and her MBM in 2009 from the University of Phoenix. She has published several articles and posters in the field of general toxicology and is an active member of the American Society for Microbiology and the Society of Toxicology. www. mpiresearch.com Email: firstname.lastname@example.org
Summer 2014 Volume 6 Issue 2
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Current Perspective on TBI Traumatic brain injury (TBI) is a major cause of mortality and long-term disability due to cognitive, emotional, and physical impairments. Frequently, individuals with mild traumatic brain injuries (mTBI) do not present with clinically apparent neurologic and morphologic brain lesions. These patients are often not able to get adequate treatment and care, and as a result, may suffer lasting disabilities, which significantly reduce their quality of life1. Traumatic Brain Injury Characteristics There is no single profile which characterises the presentation of TBI, an epidemic of great magnitude matched only by the sheer complexity of the cerebral pathophysiology involved. The patientâ€™s profile is the result of the location, depth, and volume of focal lesions and the extent of diffuse axonal injury (DAI). Additionally, age, previous injury, use of alcohol, and comorbid conditions, such as hypoxia or hypertension, further contributes to a specific collection of observed deficits, all contributing to producing unique brain pathologies2,3. TBI is a result of dysfunction in neuronal metabolism and the microscopic anatomy of the brain that occurs in two distinct phases. DAI occurs during the initial phase of injury as the direct result of the traumatic force. A secondary delayed phase of brain injury includes inflammatory cascade activation, edema, ischemia, release of free radicals, excitatory amino acids, metal ion discharged, and programmed cell death, eventually leading to neurological and functional deficits 4. Impairments include: memory loss, inability to concentrate, speech problems, motor and sensory deficits, and behavioural problems. Some psychiatric disorders, such as post traumatic stress disorder (PTSD), are more likely to be a psychological consequence of secondary neuronal damage induced by the physical trauma or traumatic event. Because no pharmacological treatment has currently been proven to prevent secondary damage processes, brain injuries, to-date, are essentially untreatable disorders. Neuroprotective strategies intended to halt or mitigate 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY
secondary neuronal damage at the early stage of injury (2â€“3 hours post-injury) offer a potential therapeutic window of opportunity. These may help block or slow down the development of subsequent neurological and neuropsychiatric impairments5. Undiagnosed and untreated, mild traumatic brain injuries (mTBI) can produce significant cognitive deficits due to progressive neurodegeneration and neurosomatic damage6. mTBI can place an incredible burden on society, both economically and socially, causing an estimated 75% to 90% of traumatic brain injuryrelated morbidity hospitalisations and emergency room visits7.
acute and chronic effects of concussion on central nervous system structure and function remains incomplete, and little research has been conducted specifically on changes in the brain following concussions in youth10. Some researchers have hypothesised that immature brains are more plastic and thus better able to recover from concussion, while others have argued that a developing brain is more susceptible to injury12. Regions involved in abstract processes, reasoning, judgment, and emotion, including impulsivity, controlled principally by frontal areas, remain less developed through the teenage years and into the early 20s13.
TBI by the Numbers The frequency of brain injury is currently higher than that of any other disease, including complex diseases such as breast cancer, AIDS, Parkinsonâ€™s disease, and multiple sclerosis 3. A TBI occurs every 15 seconds in the United States, generating 1.7 million new head injury victims per year8. These events are responsible for 53,000 deaths9 and today, 5.3 million Americans are living with TBI-related disabilities2 at a cost of more than US $77 billion on average per year 3. Falls account for over 500,000 emergency room visits annually and another 60,000 hospitalisations. These figures do not include US military personnel or veterans.
Impact The child and adolescent brain offers a significant challenge in this type of injury and demonstrates the need for specific knowledge and management of their developing central nervous system 14 . Children and teens who sustain a TBI or concussion take longer to recover than adults, and while their symptoms may appear mild, the injury can lead to significant life-long impairment affecting memory, behaviour, learning, and emotions. The main issues that need to be addressed are the ability to diagnose and treat the initial brain changes following injury, measure treatment effectiveness, and provide a predictive and measurable outcome of long-term, post-injury changes13.
Most Vulnerable Age Groups Most vulnerable are children aged 0 to 4 years, and adolescents, 15 to 19 years. There are approximately 765,000 emergency department visits annually for youth aged 25 and younger8. Adults aged 75 years and older have the highest rates of TBI-related hospitalisation and death8. Older adults require more ongoing care once discharged from the hospital, and have poorer outcomes 10. The potential public health burden of TBI across all age groups over the next two decades will be significant 11. A growing number of unanswered questions concerning TBI has uncovered the lack of treatment options for a crisis that affects millions3. TBI in Youth Mild traumatic brain injury is a significant pediatric public health concern. A comprehensive understanding of the
TBI in Athletes An estimated 1.6-3.8 million sports and recreation-related concussions (mTBI) occur in the United States each year15. Many cases remain unreported due to the lack of an immediate and a precise diagnosis; moreover, the long-term effects of the original TBI are not usually monitored. Research has indicated that even when the symptoms of concussion appear to be spontaneously resolved (usually within 10 days), the injured brain is still experiencing abnormal brain-wave activity. Potentially, this brain-wave activity can last for years after the original head trauma and lead to significant cognitive problems in later life16. Falls are the leading cause of TBI17, Summer 2014 Volume 6 Issue 2
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occurring mostly during sports or recreation-related activities where there is physical contact between the players, such as in football, rugby and hockey. Nevertheless, cycling, thought to be a safe physical activity, is at the top of the list of TBI causes. A growing body of sports injury research indicates that the cumulative impact of blows to the head over a period of years leads to a greater risk of dementia and other neurodegenerative diseases in later life. Despite attempts to prevent brain injury by mandating helmets and other preventive actions, the number of sports injuries is gradually rising each year, especially in youth, a group increasingly at risk of suffering repeated brain injury. The pathological consequences of TBI have received increasing media attention following reports of progressive neurological dysfunction in athletes who have been exposed to repetitive concussions in high-impact sports18. Athletes with history of concussion have a 5.8-times greater risk of a subsequent concussion and it is suggested that there is a dose–response relationship between the number of previously sustained concussions and future concussion risk12. Pathological evidence of chronic traumatic encephalopathy (CTE) has also been found in a variety of contact sports and other activities in which head trauma occurs12. Military and Blast-Related TBI Approximately 280,861 US military personnel returning from Iraq and Afghanistan have sustained one or more brain injuries19. Throughout recent military conflicts, improvements in body armour, equipment, and medical care 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY
have likely led to an increased number of personnel surviving previously fatal injuries, particularly blast injuries, and subsequent development of TBI20. An increasing number of combat veterans presenting with blast-related TBI18 may also have associated mental health issues compared with other causes of TBI21, 22. Although both exposures involve psychological trauma, a blast injury may result in cognitive processing difficulties and an inability to inhibit the experience of the episode resulting in the association between the blast incident and the development of post traumatic stress disorder (PTSD). “Blast” is most frequently defined as an explosion in the atmosphere characterised by the release of energy in such a short period of time and within such a small volume that it results in the creation of a non-linear shock and pressure wave of finite amplitude, spreading from the source of the explosion. The energy radiating from a conventional blast can be chemical, electrical, thermal, and kinetic or pressure energy23. The pressure waves from explosions cause more complex and multiple forms of extensive damage to the body compared to any other wounding agents. Most of the secondary damage following a blast event does not typically occur at the time of initial injur y24. Military veterans who have been exposed to repeated blast injury by firing heavy weapons or exposure to other types of explosions are at high risk for developing CTE or post concussion syndrome (PCS), which has been pathologically confirmed in soldiers who have experienced multiple blast injuries12.
In 2011, more than 69,000 veterans began receiving Veterans Affairs (VA) disability compensation for neurological conditions, reflecting a general increase in TBI cases over the past five years. The Department of Defense (DoD) Disability Evaluation System (DES) demonstrates that neurological conditions are among the top three most prevalent conditions evaluated for disability, with TBI the most common neurological condition among soldiers and marines25. The wars in Iraq and Afghanistan have produced a considerable number of advances in battlefield medicine that are being translated into civilian practice26. Despite a substantial investment of time, money and effort, clinically effective neuroprotection and neuro-rescue therapies remain elusive 27. Even when no overt damage is observed in neuroimaging, memory, affective and executive dysfunction emerge and may cause substantial disability and life disruption. Current TBI Treatments Over the past 30 years, tremendous efforts and resources have been devoted to studying TBI in search of effective treatments. Because the cerebral physiology is disturbed after mild brain trauma, repeated blows to the head are especially detrimental, making the brain more susceptible to even further injury24, and has been the focus of various pharmacological therapies28. Radosevich et al.28 concluded in the most recent review of current scientific literature that there are few emerging pharmacological therapies for TBI that have been shown to improve survival. The review also concluded there was insufficient data regarding optimal dosing strategies (i.e. dose, duration and timing), for almost all of the agents described in the review. To date, a majority of intervention trials targeting various injury mechanisms during the acute phase of TBI failed to show treatment effectiveness. Additionally, large Phase III pharmacological drug trials have not demonstrated convincing treatment efficacy among selected TBI populations9.
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CLINICAL & MEDICAL RESEARCH
Research and Meeting an Unmet Public Need The relationship between early head injury and increased incidence of neurodegenerative disease is a key area for investigation. The extent of neurological recovery depends on the contribution of post traumatic secondary insults in TBI patients29. A vital area of brain injury research involves the clarification of secondary injury processes, which may be targeted for intensive care management or pharmacotherapy. Researchers acknowledge that while the relationship between CTE and exposure to concussions and subconcussions is incompletely understood, it is crucially important to understand in order to develop effective therapies12. Significant efforts are needed to improve prevention, diagnosis, and treatment of these conditions, as well as the testing of combination therapies targeting multiple pathomechanisms29. Potential Treatment Option Previous attempts at treating the multiphasic brain injury process by focusing on a single biochemical mechanism have failed. Since the development of the secondary brain injury stems from simultaneous and consequent activation of several pathways, an intervention that simultaneously targets multiple factors contributing to the progress of neurodegradation could be more effective in halting secondary degradation. Bloodbrain-barrier (BBB) breakdown, a major hallmark of TBI, is the focus of many researchers who develop their therapies assuming that once the BBB is damaged, any drug, even a drug with poor BBBpenetration abilities, may cross it and enter the brain parenchyma. A more effective TBI therapeutic agent must exhibit strong BBB permeability, vital for those regions of the brain where the BBB was not compromised; yet, the brain’s parenchyma suffers from secondary injury. An Innovative Approach To ensure effectiveness, new treatment options must be multifaceted and include neuroprotective, neurorestorative and anti-inflammatory agents. One such multifunctional drug should have at least three different mechanisms of action that simultaneously intervene in different biochemical and physiological pathways. Each of these drug agents must address multiple pathophysiologic mechanisms involved in the degenerative 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY
process associated with TBI, and would include ion metal binding capacity, thereby preventing excess release of free radicals and a series of protein degradation cascades and oxidation that could lead to widespread molecular damage and neuronal cell death. Additionally, these drugs would exhibit further anti-inflammatory, and/or antibacterial neuroprotective functions. This synergistic approach is expected to prevent the cascade of events leading to brain degeneration. Since multiple, interdependent cascades of biological reactions cause neurodegeneration, intervention must address several pathways simultaneously to be effective. Single pathway agents have a high probability of missing the opportunity window in which their target is valid, thus remaining ineffective. Cell death cascade occurs over a few days; therapeutic agents containing these mechanisms of action would be administered as close as possible to the injury event and for a few weeks following the injury to slow down the deterioration and allow for optimal rehabilitation. Soon the day may come when the brain injuries of children, seniors, athletes, service personnel, and others, will be treated by a medication that inhibits the spread of brain damage and prevents further deterioration, in much the same way injuries in other parts of the body are currently being treated. This combined approach of using a drug that could cross the bloodbrain-barrier, capable of metal ion removal, and possess anti-oxidation, anti-inflammatory, and/or anti-bacterial activities may be the best overall strategy for treating individuals with TBI. References 1. Ohta M., et al. Attenuation of axonal injury and oxidative stress by edaravone protects against cognitive impairments after traumatic brain injury. Brain Res. 1490, 184-192 (2013). 2. Carter C.G. & Sanders K.M. Traumatic brain injury. Massachusetts General Hospital comprehensive clinical psychiatry. Stern T.A., Rosenbaum J.F., Fava M., Biederman J. & Rauch R.L. (eds.) 1107-1121 (Mosby Elsevier, Philadelphia, 2008). 3. Prins M., et al. The pathophysiology of traumatic brain injury at a glance. Dis Model Mech. 6, 1307–1315 (2013). 4. Sahler C.S. & Greenwald B.D. Traumatic brain injury in sports: a review. Rehabil Res Pract. 39, 1–10 (2012). 5. Chen Y., Huang W. & Constantini S. Concepts and strategies for clinical management of blast-induced traumatic brain injury and posttraumatic stress disorder. J Neuropsychiatry Clin Neurosci. 25, 103–110 (2013). 6. Kan E.M., Ling E-A. & Lu J. Microenvironment changes in mild traumatic brain injury. Brain Res Bull. 87, 359372 (2012). 7. Langlois J.A., Rutland-Brown W. & Wald M.M. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 21, 375–378 (2006). 8. http://www.cdc.gov/traumaticbraininjury/statistics. html, visited on 8 January 2014. 9. Lu J., Gary K.W., Neimeier J.P., Ward J. & Lapane K.L.
11. 12. 13. 14.
15. 16. 17.
23. 24. 25. 26.
Randomized controlled trials in adult traumatic brain injury. Brain Inj. 26, 1523–1548 (2012). Hu J., Ugiliweneza B., Meyer K., Lad S.P. & Boakye M. Trend and geographic analysis for traumatic brain injury mortality and cost based on MarketScan database. J Neurotrauma. 30, 1755–1761 (2013). Dams-O’Connor K., et al. Traumatic brain injury among older adults at level I and II trauma centers. J Neurotrauma. 24, 2001–13 (2013). Mez J., Stern R.A. & McKee A.C. Chronic traumatic encephalopathy: where are we and where are we going? Curr Neurol Neurosci Rep. 13, 407 (2013). Toledo E., et al. The young brain and concussion: imaging as a biomarker for diagnosis and prognosis. Neurosci Biobehav Rev. 36, 1510-1531 (2012). Ryan N.P., et al. Predictors of very-long-term sociocognitive function after pediatric traumatic brain injury: evidence for the vulnerability of the immature “social brain.” J Neurotrauma. 31, 649-57 (2014). Bigler E.D., Deibert E. & Filley C.M. When is a concussion no longer a concussion? Neurology. 81, 1415 (2013). De Beaumont L., Henry L.C. & Gosselin N. Long-term functional alterations in sports concussion. Neurosurg Focus. 33, 1-7(2012). Coronado V.G., et al. Centers for Disease Control and Prevention (CDC). Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. MMWR Surveill Summ. 60, 1-32 (2011). DeKosky S.T., Blennow K., Ikonomovic M.D. & Gandy S. Acute and chronic traumatic encephalopathies: pathogenesis and biomarkers. Nat Rev Neurol. 9, 192–200 (2013). http://www.dvbic.org/sites/default/files/uploads/ dod-tbi-worldwide-2000-2013-Q3-as-of-05%20Nov2013.pdf, visited 30 December 2013. Gubata M.E., et al. Trends in the epidemiology of disability related to traumatic brain injury in the US Army and Marine Corps. J Head Trauma Rehabil. 29, 65-75 (2013). Sayer N.A., Nelson D. & Nugent S. Evaluation of the Veterans Health Administration traumatic brain injury screening program in the upper Midwest. J Head Trauma Rehabil. 26, 454–467 (2011). Carlson K.F., et al. Psychiatric diagnoses among Iraq and Afghanistan war veterans screened for deploymentrelated traumatic brain injury. J Trauma Stress. 23, 1724 (2010). Moore D.F. & Jaffee M.S. Military traumatic brain injury and blast. NeuroRehabilitation. 26, 179–181 (2010). Blennow K., Hardy J. & Zetterberg H. The neuropathology and neurobiology of traumatic brain injury. Neuron. 76, 886-899 (2012). http://www.amsara.amedd.army.mil/Documents/ DES_AR/DES%20AR2012%20final%2 0copy.pdf, visited 8 January 2014. Lennquist S. Incidents Caused by Physical Trauma. Medical response to major incidents and disasters: a practical guide for all medical staff. Lennquist S. (ed) 111- 196 (SpringerVerlag, Berlin, Heidelberg, 2011). Duckworth J.L., Grimes J. & Ling G.S. Pathophysiology of battlefield associated traumatic brain injury. Pathophysiology. 20, 23-30 (2013). Radosevich J.J., Patanwala A.E. & Erstad B.L. Emerging pharmacological agents to improve survival from traumatic brain injury. Brain Inj. 27, 1492–1499 (2013). Dietrich W.D. & Bramlett H.M. Trauma of the nervous system: basic neuroscience of neurotrauma. Neurology in clinical practice e-book, 6th Edition. Daroff R.B. & Mazziotta J.C. (eds.) 931-941 (Saunders, Philadelphia, 2012).
Dr Adrian Harel is President, Founder, and principal investigator of Medicortex USA Ltd. He is an experienced neurobiologist with a record of accomplishment in business management and leadership of early-stage drug discovery companies. Medicortex’s staff includes experts in medicinal chemistry, neurobiology, animal models, cell biology, and other areas of expertise that promise to generate success in the execution of Medicortex’s goals. Website: www.medicortex.com E-mail: email@example.com
Summer 2014 Volume 6 Issue 2
CLINICAL & MEDICAL RESEARCH
Label-free Cell-based Assay for the Characterisation of Peptide Receptor Interactions Abstract Both the drug development process and fundamental studies of mechanisms underlying biological interactions require analytical methods that approximate the in vivo situation as much as possible. This can be achieved by using label-free cellbased assays, since they eliminate nonnatural treatment, e.g. purification and labelling, of both the target receptor and the drug candidate molecule. In this paper, we present a new labelfree assay that we have developed for characterising interactions between peptides and their target receptors in a cellular environment. We will describe one such interaction that was assessed by monitoring the binding profile in realtime and by quantifying its kinetic rate constants for association and dissociation, as well as its affinity. In addition, the absence of off-target interactions with the cell membrane was confirmed by analysis of the binding profile. Key words Cell-based assays, peptide, biomolecules, biosensor, QCM Introduction When developing new pharmaceutical drugs or probing for biological interactions, it is of the utmost importance to have the right tools. Often, the choice of methods will have an impact on the results and this becomes even more crucial when dealing with complex experimental data. On the subject of experimental design, one may have to consider how to appropriately label a molecule in order to increase the experimental sensitivity or to purify target receptors to avoid off-target interactions. More often than not, a handful of techniques need to be used in combination and the results from each method weighed and compared with the results from other methods in order to obtain high quality information. Experiments performed in vivo remain the gold standard for providing the most physiologically relevant data, but, on the other hand, they can be expensive and rather difficult to interpret. In comparison, biochemical experiments offer highthroughput molecular profiling, but this is not always representative of what
54 INTERNATIONAL PHARMACEUTICAL INDUSTRY
takes place in living cells. Unlike in vivo and biochemical studies, cell-based experiments are often more biologically reliable than biochemical experiments and offer greater flexibility and details than in vivo experiments, albeit with an intermediate throughput. This work aims to develop a new labelfree assay for small biomolecules, such as small peptides, which have shown great promise in the treatment of cancer, diabetes, cardiovascular diseases and other therapeutic areas1, 2,3 . In principle, this technique, can be used to merge the high level of experimental detail obtained in biochemical assays with the biological reliability of cellbased assays. A prime example that illustrates the difference between biochemical and cell-based assays is to compare the binding affinity of a given analytereceptor interaction obtained using both techniques. The cell-based affinity of HerceptinÂŽ (Traztuzumab, Genetech) at its receptor HER2 is 5nM 4, whereas the biochemical affinity is 0.1 nM5, i.e. an interaction which is 50 times stronger compared to the cell-based assay. Likewise, there are several examples showing the opposite effect where the interaction was up to 50 times weaker in the cell-based assays 6, 7. The reason for the differences in affinity between the respective assays can be addressed by analysing the kinetics of the interaction, i.e. the association and dissociation rates. The affinity (KD) is defined by the ratio between the dissociation rate (kd) and the association rate (ka): Eq. 1
A slower dissociation rate, kd results in a stronger interaction (lower KD) and a slower association rate results in a weaker interaction (higher KD). In the past, the radioactive labelling of molecules, that was required for obtaining cell-based interaction kinetics data, was both cumbersome and could affect the receptor-ligand interaction. In 2009, Lindegren and Ingemarsson 8 presented a label-free cell-based approach to obtain interaction kinetics for HerceptinHER2 using the Attana Cellâ„˘ 200 QCM biosensor, which was later employed by Pei et al.9 to study the interaction between lectins and carbohydrates on the cell surface. These studies opened the door for more mechanistic studies and soon thereafter, Peires et al.10 demonstrated that a slower dissociation rate in a cellbased assay compared to a biochemical assay could be explained by the natural clustering of the target receptors in the cell membrane. The clustering enables both rebinding and avidity interactions, resulting in a slower dissociation rate from the cell surface, and this new knowledge was successfully applied in a follow-up study for the development of a Summer 2014 Volume 6 Issue 2
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CLINICAL & MEDICAL RESEARCH
drug delivery system using nanotubes11. Typically, important physiological events like avidity and rebinding are not taken into account using classical biochemical sensor surfaces, where the receptors are artificially evenly distributed. Together with the dissociation rate, analysis of the association rate could provide valuable information. As observed by Aastrup and co-workers, different association rates of Herceptin-HER212 were detected in different cell lines. The differences could be attributed to the variances in accessibility of the HER2 receptor, with a low accessibility leading to a decreased association rate. Here, our goal was to apply the same strategy, but to push the limits even further by moving from antibodies and lectins to a smaller 15 kDa peptide as an analyte. Due to the decrease in mass of the analyte, the frequency shift of the QCM would be less, assuming an interaction existed between the analyte and the receptor. Consequently, optimised assay conditions are required. Experimental set-up Analyte: 15 kDa peptide (confidential for future work) Cell lines: HEK293 cells Cell chip preparation: HEK293 cells were grown in standard cell culture flasks in DMEM cell media (Gibco high glucose 4.5g/L D-glucose 41966-029) supplemented with 10% fetal calf serum (Gibco heat inactivated serum 10500069), 1% antibiotics (Gibco Pen-Strep 15140-122) in a humidified atmosphere of 5% (v/v) CO2 in air at 37˚C. Upon reaching 80% confluency, 60,000 cells were trypsinised using standard protocol and seeded onto COP-1 cell surfaces (Attana AB) that were pre-treated with ECM overnight (dilution 1:300 in DMEM: stock 8.39 mg/ml, Sigma-Aldrich E1270). Five hours after seeding, the cells were transiently transfected with plasmid DNA encoding a GFP-tagged receptor using Lipofectamine 2000 (Life Technologies 11668027). Negative control cells were treated in the same way, but the plasmid DNA was replaced with PBS in the transfection mix. Twentyfour hours post-transfection, the medium was removed and the cells were fixed with 3.7% (v/v) formaldehyde (SigmaAldrich 25249, Stock 37% diluted in PBS) for 10 minutes at 4˚C. Fluorescence microscopy images of the cells seeded on the COP-1 surfaces were obtained 56 INTERNATIONAL PHARMACEUTICAL INDUSTRY
using a Nikon Eclipse 80i with specific emission and excitation filters. Kinetics and affinity studies: Experiments were performed using an Attana Cell™200 QCM biosensor (Attana AB). The QCM biosensor uses the piezoelectric effect of quartz. An alternating electric potential over the quartz crystal sets the crystal in oscillation. The oscillating frequency is dependent on the mass of the crystal and interacting material. Hence, when a molecule interacts with the crystal, the frequency will change and the interaction can be characterised, such as kinetic rate constants and affinity. By growing cells on the quartz crystal surface, the cells become an integrated part of the sensor chip and can thus be used for interaction analysis. The cell-coated COP-1 chips were inserted in the biosensor and the
Interaction analysis Assay development Prior to performing the experiments, an optimal cell density was determined in order to achieve a desirable surface coverage of the cells on the sensor chip (See Experimental set-up). Interaction analysis Sensor chips that had been coated with the transfected HEK293 cells were inserted in channel A of the Attana Cell™200 instrument, whereas, non-transfected HEK293 coated sensor chips were used as reference surfaces in channel B. In Figure 1, an illustration depicting the cells immobilised on the chip is accompanied by fluorescence microscopy images of the COP-1 surfaces where both the nuclei of the cells (red) and the GFP-conjugated receptor (green) are visualised in order to ensure sufficient expression and coverage.
Figure 1. Assay development. Illustration of a binding experiment using sensor chips covered with transfected (left) and nontransfected (right) cells with accompanying fluorescence microscopy images of the transfected and non-transfected HEK293 cells on the COP-1 surfaces. The cell density is observed by staining for the nuclei (red) and the presence of the receptor of interest is confirmed by the GFP tag (green).
figure 2. Interaction analysis. Sensograms showing the interaction of a 15 kDa peptide analyte with transfected (left) and non-transfected (right) HEK293 cells on the COP-1 sensor chip. No interaction was detected with the non-transfected cells, indicating that no off-target interactions are occurring. With regard to the transfected cells, a clear dose response relationship can be observed and the association and dissociation can clearly be followed. The red line shows the curve fitting. The affinity was determined to be: KD= 1.9-3.3 x 10-9 M, ka= 1.19-1.21 x 105 M-1s-1 and kd= 2.29-3.92 x 10-4 s-1
temperature was set to 22˚C and the flow rate to 20 µl/min. Running buffer, PBS (pH 7.4), was passed over the chip until stabilisation of the baseline (frequency change ≤ 0.2 Hz over 600 s) was achieved. The binding of the peptide was studied by consecutive injections of the peptide in concentrations ranging from 2 µg/ml to 0.5 µg/ml followed by dissociation in PBS for 700 s. Data was collected using Attester software (Attana AB) and analysed with TraceDrawer (Ridgeview using 1:1 model). The same experiment was performed in duplicate using independent sample preparations.
The analyte was injected at three concentrations ranging from 0.5 μg/ml to 2 μg/ml. In Figure 2, important differences between the transfected and nontransfected cells can be observed. With the non-transfected cells, no binding of the analyte can be detected. In this case, the peptides do not have any off-target interactions with the cell membrane or other molecules present on the membrane itself (carbohydrates, other receptors etc.). In contrast, the transfected cells exhibit a clear concentration-dependent interaction. Since the only difference between the two cell preparations is Summer 2014 Volume 6 Issue 2
CLINICAL & MEDICAL RESEARCH
Shane C. Wright is an early stage researcher at the Department of Physiology and Pharmacology at the Karolinska Institutet in Stockholm, Sweden. He is interested in how ligandreceptor interactions specify downstream signalling. Shane was conferred his B.Sc. (Hon) from the University of Toronto in 2010 and his M.Sc. from the Université Paris VI in 2012. Email: email@example.com
the overexpressed receptor, it is likely that the observed interaction is specific to the receptor and the peptide. The magnitude of the interaction between the peptide and the target is large enough to perform kinetic evaluation. As seen in Figure 2, the association phase of the three different concentrations of peptide is marked by a relatively fast increase in signal during the first 100 seconds while the peptide is injected over the cell surface. This is followed by a slower decrease in signal as the flow of buffer allows for dissociation of the ligand. By local fitting of the Bmax (the maximum binding signal) and global fitting of the association and dissociation rates, a ka of 1.19-1.21 x 105 M-1s-1, a kd of 2.293.92 x 10-4 s-1 and an affinity KD of 1.93.3 x 10-9 M were measured. Conclusion A new label-free cell-based assay for kinetic interaction analysis of smaller biomolecules, such as a 15 kDa peptide, has been developed. Target and offtarget interactions were addressed by comparing transfected and nontransfected HEK293 cells. No off-target interactions between the analysed peptide and lipids or proteins on the cell membrane were observed; kinetic rate constants were measured and affinity for the targeted interaction could be determined to be in the nM-range. Hence, we have demonstrated that a labelfree cell-based assay using the Attana Cell™200 QCM biosensor is applicable for the study of small biomolecules such as peptides which is of interest for www.ipimedia.com
researchers working in the field of drug discovery. References 1. Thundimadathil J, Journal of Amino Acids, Volume 2012 (2012), Article ID 967347 2. Todd J. F, Bloom S. R, Diabetic Medicine 24:3, (2007), 223–232 3. Erdmann K, Cheung B. W. Y, Schröder H, The Journal of Nutritional Biochemistry, 19:10 (2008,) 643–654 4. Product information, Genetech, Inc September 1998 5. Baselga J, Annals of Oncology 12(Suppl.1):S49-S55,2001 6. Troise F, Cafaro V, Giancola C, D’Alessio G, De Lorenzo C. FEBS J. 2008 Oct;275(20):4967-79 7. Löfblom J., Sandberg J., Wernérus H., Ståhl S, Appl Environ Microbiol. 2007 Nov;73(21):6714-21 8. Lindegren S, Ingemarsson B, Discovery Summit 2009 Monte Carlo, Monaco March 2009 9. Pei Z, Saint-Guirons, Käck C, Ingemarsson B, Aastrup T, Biosensors and Bioelectronics 35 (2012) 200205 10. Peiris D, Markiv A, Curley G. P, Dwek M. V, Biosensors and Bioelectronics 35 (2012) 160– 166 11. Madani Y, Tan M, Dwek M, Seifalian A, International Journal of Nanomedicine, (2012):7 905–914 12. Aastrup T, Innovations in Pharmaceutical Technology 46 (2013) 48-51
Dr Davide Proverbio graduated from Milano Bicocca University in 2009 with an MSc in Medical Biotechnology and subsequently obtained a PhD in Biochemistry from the Goethe University in Frankfurt am Main. During his work, focused on the Cell-Free expression and biochemical characterization of GPCRs, he became especially interested in biosensor technologies. Davide joined Attana in January 2014 where he works as an Application Specialist. Email: firstname.lastname@example.org
Jana Valnohova is a PhD student at the Department of Physiology and Pharmacology at Karolinska Institutet. She received her master’s degree in molecular biology and genetics at Masaryk University in Brno, Czech Republic in 2013. At the beginning of 2014, she joined the group of “Receptor Biology & Signaling” under the supervision of Dr. Gunnar Schulte. Email: email@example.com
Associate Professor Gunnar Schulte is a research group leader at the Department of Physiology and Pharmacology at Karolinska Institutet, Stockholm, Sweden. His research team “Receptor Biology & Signaling” focuses on the understanding of molecular mechanisms of signal transduction through G protein-coupled receptors. Gunnar has obtained his undergraduate degree from the Freie University in Berlin, Germany and his Ph.D. in Pharmacology from Karolinska Institutet in 2002. Email: firstname.lastname@example.org Dr Teodor Aastrup is co-founder and CEO of Attana AB. During his leadership, Attana has gone from the idea of characterising molecular interactions exactly as they occur in the body, to supplying the life sciences industry with labelfree cell-based biosensors. Teodor gained his PhD in Corrosion Science from the Royal Institute of Technology in 1999 and worked in the automotive industry prior to founding Attana. He is also CEO and founder of the management consulting company TVAA AB, and a member of the Business Executives Council of the Royal Swedish Academy of Engineering Science and has over 30 peer review scientific publications. Email: email@example.com INTERNATIONAL PHARMACEUTICAL INDUSTRY 57
LABS AND LOGISTICS
Aseptic Pharmaceutical Processing: It All Begins in the Lab The drive towards novel drug presentation and injectable-grade products is generating increased demand for aseptic pharmaceutical processing, including aseptic spray-drying (ASD). But what considerations need to be made for aseptic spray-drying programmes at laboratory stage to enable them to be efficiently scaled up from feasibility assessment to large-scale manufacture? Sam de Costa of Nova Laboratories shares his insights and considerations for a smooth transition. Since we pioneered ASD capabilities, we have seen a sharp growth in enquiries from pharma and biotech companies into the technology, but the most interesting projects are those that we encounter at R&D stage. This article will explore the early considerations for aseptic processing projects, but in order to do so it is first necessary to provide an overview of aseptic spray-drying as compared to traditional techniques. An Enabling Technology Aseptic spray-drying is a process by which a liquid product is introduced to hot gas, creating an injectable-grade dried powder, under wholly aseptic conditions. The process is similar to traditional pharmaceutical spraydrying – which occurs under cleanroom conditions – except ASD does not need a terminal sterilisation step as each step in the process is conducted aseptically. ASD is best compared to the process of lyophilisation - or freeze-drying - in that both achieve a dried pharmaceutical powder from a liquid. However, the comparison must not go too far because of lyophilisation’s limitations or, to put it another way, ASD’s many enabling factors (see Fig.1). It is best to view ASD as a facilitator for entirely unique particle characteristics and, therefore, novel and innovative drug presentations, including parenteral drugs. Particle Engineering ASD’s gentler processing conditions give far more scope to engineer particles for desirable characteristics. Increased bioavailability using ASD is helping pharma and biotech firms develop new 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY
molecules, which is having a positive impact on the pipeline of new drugs. But equally significant is the range of pharmaceutical presentations and delivery methods that ASD facilitates. Vaccines are a key area in which advancements in bioprocess engineering have led to new developments and increasingly effective formulations. Using ASD, we are able to manufacture dried molecules which can be reconstituted at the point of administration using a standard syringe and injectable fluid. Even products which are normally highly unstable can be stored for long periods in non-liquid form, without the need for refrigeration. To achieve stability in producing these vaccines, APIs are mixed with watersoluble glass formers and aseptically spray-dried as solid, non-crystalline glass, thus producing a highly polished microsphere in which the product is immobilised and stabilised. At Nova, we use this technique as the basis for a stabilisation platform known as VitRIS (Vitrified Readily Injectable Suspension). The resulting product can be presented either as an instantly reconstituting powder or a ready-to-inject format by suspending the micro-particles within a non-aqueous liquid. These liquids are typically injectable-grade liquids such as low-density metabolisable oils. This second step requires the ability to match the density of the powder with the density of the liquid to prevent the powder floating or sinking. Trials have shown that this aseptic spray-drying technology can be successfully applied to a large number of pharmaceutical preparations including live and non-live vaccines, insulin, monoclonal antibodies, recombinant growth hormones, proteins, enzymes and nucleic acids. Therefore, the potential applications are significant and could lead to a number of candidates coming forward for drugs aimed at developing nations where logistics and refrigeration present prohibitive barriers to development.
The technology is not limited to single-valency vaccines. We have seen heightened interest in heat-stable multivalent vaccines in a spray-dried format. Using ASD, the separate components of the vaccine can either be jointly or individually spray-dried – under conditions unique to each separate element – before being combined in the final delivery method. Laboratory Set-up Due to the delicate nature of both biopharmaceutical products and the final processed powders, laboratory conditions must be carefully tuned to avoid the product’s quality and safety being compromised. As a basic requirement, any laboratory must adhere to good laboratory practice, but further adaptations must be made to allow for optimal product quality. Spray-dried powders, although variable in moisture content, are generally highly hygroscopic and will easily draw moisture from the surrounding environment. Therefore, a dedicated spray-dried powder handling area must be established where the humidity is controlled, typically to less than 5% RH. Highly labile live biological products or proteins are sensitive to temperature which can rapidly lead to degradation. Therefore it is essential to maintain the feedstock during the entire spray-drying process. In our development laboratories we routinely use temperature-controlled, product dedicated holding vessels during spray-drying. Another consideration would be the type of drying and atomisation gas we use for spray-drying. For cGMP aseptic spray-drying, pharmaceutical-grade nitrogen is used to prevent possible product degradation through oxidation. Therefore it is advisable to adopt similar measures within the lab. Similarly, nitrogen can be used during spray-dried powder filling to overlay powder within storage containers, in line with cGMP procedures. Use of pre-sterilised or low bioburden product contact parts can reduce the risk of cross-contamination. Adhering to the manufacturing practices Summer 2014 Volume 6 Issue 2
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during development can cut down inconsistencies of product quality between the laboratory and manufacturing-grade material. Early-stage Considerations In some instances, clients who have decided to undertake feasibility studies into aseptic processing may not have finalised the product specification. In our experience, if parameters are defined early on they can be implemented for the trials carried out in the laboratory, avoiding delays to the product development pathway. Therefore, a close collaboration between client and CRO/ CMO is essential from laboratory stage. Selection of a suitable laboratoryscale spray-dryer for early studies that can produce spray-dried powder with similar characteristics to a larger-scale manufacturing unit is an advantage. A laboratory with analytical capability to characterise spray-dried powder, residual moisture content, particle size distribution, bulk density, morphology and compressibility will aid understanding of the product and smooth progression of the development phase. One of the chief variables in the spray-drying process is the control of particle size to meet a desired specification. Depending on the product’s applications, particle size can be the most important consideration in the early stages of development. For example, if the product is intended for emergency or field medicine, particle engineering can be carried out to cut dissolution rates. This increased solubility effect can be amplified even further by adding ingredients during the spray-drying process. We have been working on a major project to cut dissolution times for dried powder by adding what we term ‘blowing agents’ to the spray-drying formulation. These agents enable the creation of hollow spheres with a greater surface area than those achieved under normal processing conditions, helping them to dissolve more quickly in liquid. Variables such as the type of nozzle selected will affect the size of particles, and the effect of this particular variable can be simulated in the laboratory, before the product is manufactured under aseptic conditions using larger-scale equipment. Most clients, although they may not know the exact specification of their final
Case study: Using ASD to manufacture human plasma Entegrion Inc. is a US-based life-sciences firm which develops and delivers products that address unmet needs in military healthcare. It has developed a proprietary dehydrated, pathogen-inactivated human plasma, called ResusixTM, which is based on aseptic spray-drying technology. Entegrion has partnered with Nova to manufacture the product. The ResusixTM programme is funded by United States Office of Naval Research (ONR) and is currently at Phase I clinical trial stage. The client sought our expertise in carrying out initial feasibility studies into the product before increasing the manufacturing output to meet clinical trial demands. The current practice for treatment of patients with severe hemorrhage is to supplement coagulation factors and volume replacement using frozen plasma. One of the major drawbacks of using frozen plasma is the time it takes for preparation. In comparison, dehydrated spray-dried plasma can be re-hydrated, and ready-to-use within minutes. The longer shelf stability enabled by ASD manufacture breaks the cold-chain restrictions and makes this an attractive alternative for field and emergency use. Manufacturing of ResusixTM clearly illustrates some of the advantages of aseptic spray-drying. Blood plasma is a complex mixture of proteins such as albumin, globulins, fibrinogen, clotting factors and hormones. It has been demonstrated that the biological activities of all these components are minimally altered by the spray-drying process. ResusixTM consists of pure plasma, without the need to use any stabilisation excipients - a further benefit of the gentle nature of aseptic spray-drying. Since aseptic spray-drying is a continuous process, this technology allows Entegrion Inc. to meet its high commercial expectations, which may not have been possible with alternative drying methods. As the product is administered directly into the bloodstream, it must be of injectable-grade quality. By using ASD we can manufacture and securely package the product under truly aseptic conditions – removing the need for a final sterilisation step which reduces time and cost.
product, will be aware of the commercial advantages they will gain if a certain product presentation is used. It is vital that desired presentations are shared with the CMO at feasibility stage so bespoke processing setups can be established, and product characteristics tailored accordingly. One of our major current projects is the production of a haemostat product applied directly to a wound in powder form. Two separate spray-dried coagulation factors are mixed in the final preparation. Presenting the two components in a dry format allows our client to market this as unique product. Presentations such as vials, pouches, syringes and medical devices are all compatible with aseptic spray-drying, and can be filled aseptically within the same manufacturing facility to reduce costs. If the product is intended for parenteral use, it is first necessary to look at the compatibility of the product with aseptic processing. For example, the filterability of a product must be evaluated at early stage within the laboratory as this can be a critical factor for processing. Scaling Up Production From feasibility stage onwards, the process is fully scaleable to the point that we will soon be able to offer commercialscale manufacturing at a new purpose-
60 INTERNATIONAL PHARMACEUTICAL INDUSTRY
built facility. At feasibility stage, a liquid input of 0.5 kg/h per hour can be supported; at clinical supply stage, 3 kg/h; and at commercial manufacture stage, 20 kg/h. We are developing a commercialscale manufacturing facility, in response to overwhelming demand from clients currently at later-stage clinical supply for a facility which can take the product to the next level. We expect this adoption of aseptic spray-drying by the global pharmaceutical industry to increase substantially. When it comes to manufacturing innovative drugs using novel delivery systems, it is likely to be not only the most effective; it may be the only process capable of doing the job. Dr Sam de Costa is programme manager for thermo-stabilisation and aseptic spray-drying projects at Nova Laboratories Ltd. He has over ten years’ pharmaceutical R&D and medical device development expertise. He has been responsible for the development of the HydRIS and VitRIS stabilisation platforms, which remove the need for cold storage of vaccines. Email: firstname.lastname@example.org Summer 2014 Volume 6 Issue 2
H I L A N D ER S | P H OTO: M O RG A N EK N ER
Diabetics do it better envirotainer.com
What if we only hired diabetics to work in the active cold chain? Would they take more care handling healthcare products? We think they would. They know what happens if they donâ€™t get insulin. Of course we donâ€™t just employ diabetics. But we do share their understanding of the value of what we ship in our containers. We educate the members of the active cold-chain on the difference they make to the lives of diabetics and others who rely on healthcare products. Because people do a better job when they understand the importance of why they are doing it. Anna Klettner is one of those people. She is a diabetic and she works for us.
LABS AND LOGISTICS
Maintaining Integrity of the Supply Chain The cost associated with counterfeit drugs is staggering - both in human and commercial terms. In some cases, patients are deprived of treatment for diseases and conditions that range from mild to severe to life-threatening. In other cases, they are harmed by dangerous substances in the product, or become resistant to traditional therapeutic treatments or vaccines. In all cases, the public loses confidence in the companies that develop these drugs and in the very agencies that have been established to protect them. For the pharmaceutical industry, the prevalence of counterfeit drugs can represent loss of reputation, loss of valuable R&D efforts and intellectual property, loss of revenue and increased costs. Many companies, for instance, now operate their own anti-counterfeit units to police their product lines and reduce the impact of counterfeiting on the organisation. Despite these efforts, the growth of counterfeit drugs is only expected to increase within the parameters of a globalised industry, especially as the cost of healthcare spirals worldwide. What can pharmaceutical professionals do to ensure that their organisations and the patients they serve are not impacted by counterfeit drugs? The answer is to identify their highest-risk products and shipments and to secure their supply chain to the fullest extent possible.
pharmaceutical shipments are important, pharmaceutical professionals should evaluate the severity of risks associated with a specific product prior to shipping, and consider prioritising its journey through the supply chain as required. Questions to consider include:
term relationship with a single closedloop logistics provider able to manage all aspects of the transport and storage of bulk high-value pharmaceutical shipments worldwide. Benefits include:
In 2012 counterfeit Avastin was found in 19 American treatment centres, it was later found that the vials were sourced in Turkey and shipped to Switzerland, then Denmark and finally to the UK, before being exported to a US wholesale distributor hired by a Canadian company which was ultimately owned by an online retail pharmacy. In another case, counterfeit product was slipped into an existing shipment of legitimate drugs destined for a hospital simply by adding an extra zero to the unit count on the paperwork. In yet another case, a legitimate shipment of temperature-controlled drugs was hijacked, with the product later reintroduced into the supply chain without the benefit of quality assurance.
Identifying High-risk Shipments Virtually every medicinal product is a target in today’s world. Although all 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY
• • • •
Who is the targeted patient group? Is it an at-risk group like infants or the elderly who are more susceptible to a counterfeit product? How will the drug be used? Will it be used to treat a chronic condition? Does a single dose have the potential to kill? How is it administered? By a healthcare professional? By the patient? What is the patient impact if the medication contains no active ingredient? An excess of active ingredients? Does the product require cold chain handling to maintain stability/ efficacy? How much annual revenue does the product generate? What role does it play in the product portfolio? Is the product a flagship brand? A blockbuster? How attractive is the product to counterfeiters (i.e. high unit price? product shortage? high volume usage?) What region is the shipment destined for? What regional risk factors exist with respect to counterfeit drugs?
Tightening the Supply Chain As today’s global pharmaceutical supply chain grows increasingly longer and more complex, each link provides added opportunity for counterfeiters. While pending regulatory changes promise to tighten the supply chain with respect to production and distribution entities, and new packaging technologies will make the identification of counterfeit products easier, the logistics of global distribution remains a weak link. How can the pharmaceutical shipper ensure the security of the supply chain over thousands of miles and extended periods of time when the product is no longer in his possession? The best strategy to ensure full supply chain compliance is by partnering with and building a long-
Enhanced control from a proven, trusted source Clear chain of custody at all points during transit Elimination of unnecessary thirdparty risk Local representation and accountability in complex and often unpredictable geographies
By utilising the services of a GxPcompliant logistics supplier, pharmaceutical shippers can automatically ensure that they conform to all current regulatory requirements as they relate to the transport of their highvalue pharmaceutical products. Equally important, they can be assured that the same standard operating procedures (SOPs) are employed worldwide to ensure product security to the greatest extent possible. Shippers may also consider utilising a local warehousing solution in emerging or strategic locations to reduce the costs and peril associated with multiple bulk shipments and to shorten distribution timelines. A fully-integrated logistics provider able to accommodate packaging, cold chain, transport, storage and local in-country or regional distribution is a practical solution for maintaining security in challenging locations. Sue Lee, Technical Portfolio Manager, World Courier Management has worked for World Courier for 25 years. During this time, she has experienced a variety of customer service and operational functions including the setting up of numerous multinational clinical sites for the transportation of biological samples. She has orchestrated the shipping thousands of shipments with very specific temperature requirements to a host of challenging locations, and each presenting their own obstacles and dilemmas. Email: email@example.com Summer 2014 Volume 6 Issue 2
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Novel Treatment to Help Fight Drug-resistant Bacteria MRSA poses a significant public health problem around the world, yet our approach to treating infections is currently fuelling a wider issue around antibiotic resistance. In this article, Dr Paul De Bank explores how a new type of wound dressing, developed by researchers at the University of Bath, could help in the fight against superbugs. Understanding the Problem Meticillin-resistant Staphylococcus aureus (MRSA) is constantly in the public eye. Its prevalence in hospitals and increasingly in the community, combined with the notorious difficulties associated with treating it, means that such infections pose a major problem for public health officials around the world. MRSA infections cause a range of problems, from abscesses on the skin, to much more significant issues, especially when they get into deeper tissue. In the lungs, MRSA can cause pneumonia which in itself can be deadly. Once in the bloodstream, MRSA mortality rates rise up to 40 per cent as the disease can also attack heart tissue, causing endocarditis. Despite rates of MRSA having declined, it is still the most common cause of hospital mortality from infectious diseases. Yet despite this, our approach to treating MRSA infections remains often insufficient. The overuse of antibiotics has fuelled an evolutionary arms race between humans and so-called ‘superbugs’, and has contributed to a dangerous rise in antibiotic resistance. By administering antibiotics orally, a large dose of drug is distributed throughout the whole body. In cases of localised, accessible infections, these large systemic doses of drugs are not necessary and can result in patients suffering unnecessary side-effects. What is more, large doses of orally administered antibiotics could potentially drive the development of antibiotic resistance within the gut flora. Tackling and Treating Chronic Infections At Bath, our response to this problem has been the development of new smart dressings, which could directly fight against drug-resistant bacteria. Our smart wound dressing enables the 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY
local application and slow release of small but effective amounts of antibiotics over a long period of time.1 This will improve the treatment of chronic wounds, such as diabetic ulcers, which are highly susceptible to clinical complications. Chronic wound infections are common, and many are associated with biofilms, which further complicate treatment options and healing. Bacteria in biofilms can be hundreds or even a thousand times more resistant to antibiotics than freefloating planktonic cells. Such resistance presents researchers with significant challenges that must be addressed in respect to wound healing and infection prevention2. Beating Biofilm Resistance The communities of bacteria that attach together to form biofilms, on both biotic and abiotic surfaces, are enveloped in polysaccharides, proteins and DNA that build up a matrix of extracellular substances which help bacteria resist the effects of antibiotics. Bacteria that live within biofilms are more resistant to attack by a host’s immune system, and some have acquired additional resistance to conventional antibiotics. In addition, some antibiotics are unable to penetrate deeply into biofilms due, for instance, to their production of antibiotic-degrading enzymes. These factors combined present clinicians with the increasingly difficult challenge of finding ways to combat biofilms and the related infections. Chronic, infection-prone wounds often require prolonged treatment. To reduce the costly, time-inefficient and potentially painful repeated dressing and redressing of wounds, through our study we have developed unique three-layer electrospun mats to provide an efficient and local drug delivery system . Two prototypes have been developed, made of different polymers. The initial prototype comprised a central layer of poly(ethylene-co-vinyl) acetate (PEVA) sandwiched between outer layers of polyε-caprolactone (PCL) with tetracycline encapsulated in each layer; whereas the second prototype was created using a zein or zein/PCL blend mat that has tetracycline loaded in the central layer
only, with the outer two layers acting as a diffusion barrier. The biological activities of the prototype dressings have been tested against models of biofilm formation, models that are getting ever closer to the actual situation in a wound, and have been effective against a range of bacteria, with particular focus on a clinically-isolated strain of MRSA. Creating a Multi-layer Smart Wound Dressing Electrospinning is a versatile, economical and easily performed technique; it enables the formation of structures possessing several desirable properties, leading to many potential applications such as drugreleasing matrices and wound dressings. The main advantage of electrospun matrices is that the structure of the mammalian extracellular matrix (ECM) can be mimicked using biocompatible nanofibres, the results of which are a three-dimensional scaffold which can replicate the cell-matrix interactions experienced by cells. The technique can be used to generate nanofibres from a wide range of polymers or polymer blends, and offers the possibility of encapsulating therapeutic drugs within the polymer matrix. For drug-releasing nanofibres, the polymers and drug are carefully chosen in order to elicit a sustained release of the encapsulated drug, by diffusion of the drug through the polymer, slow degradation of the polymer nanofibres, or a combination of the two. If antibiotics are encapsulated within electrospun fibres, they can be used to treat or prevent infection, for example after a surgical procedure. The localised drug delivery ensures that the target tissue receives the correct dosage of antibiotic, and other tissues remain unaffected, reducing the occurrence of side-effects associated with systemically delivered drugs following oral, or intravenous, administration. Drugs encapsulated within an electrospun matrix, which has a high surface area to volume ratio, are often released first in a significant “burst” due to drug located near the surface of the fibres, followed by a sustained release of the remaining drug within the Summer 2014 Volume 6 Issue 2
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bulk of the fibre. Whilst good levels of drug loading and controlled release have been previously demonstrated using electrospun matrices, the time taken for 100 per cent release often remains relatively short. Our study has focussed on the development of an electrospun matrix for the encapsulation and sustained release of a model antibiotic, tetracycline (Tet) hydrochloride, with biomedical applications in wound dressing for the treatment and prevention of infections following invasive surgery. Choosing Polymers Our initial studies on Tet encapsulation within PCL and PEVA matrices demonstrated a rapid burst release of almost all of the encapsulated drug from PCL fibres, with a sustained release from PEVA (Figure 1). However, for long-term Tet delivery, we wished to extend the period of release from PEVA even further, while at the same time providing a burst release of drug to quickly eliminate the majority of the bacterial burden within a wound. To do this, we proposed a threelayer (3L) structure with Tet in all layers, consisting of a central layer of PEVA for sustained release and outer layers of PCL which would provide an initial burst and, following drug release, then act as a physicochemical barrier to reduce the rate of release from PEVA. When we examined the Tet release from this 3L matrix, this is exactly what we observed (Figure 1). However, while PEVA is biocompatible, it is also non-degradable and for eventual application of such matrices in vivo, we wanted to design a biodegradable electrospun dressing.
Figure 1: Tet release from single layer electrospun PCL and PEVA mats in comparison to a triple-layer PCL/PEVA/PCL matrix.
Hence, our second prototype combined zein and PCL with the active drug present only in the central layer. Zein, the main prolamin storage protein found in maize 66 INTERNATIONAL PHARMACEUTICAL INDUSTRY
(corn), has interested scientists in its use in electrospun matrices due to its renewable source, biodegradability, biocompatibility and resistance to microbial degradation. Previously suggested for use in packaging, tissue engineering and drug delivery, zein is a hydrophobic protein which enables the possibility of a sustained release for drugs encapsulated within electrospun zein matrices. However, water has a plasticising effect on zein , resulting in shrinkage of the matrix which would be detrimental during wound dressing as the wound would become uncovered. Stabilisation of zein in aqueous conditions to prevent shrinkage has been achieved previously through chemical crosslinking and acid treatment; however, these stabilisation methods were deemed inappropriate as they may chemically or physically degrade the encapsulated drug, rendering it inactive or potentially toxic. An alternative would be to blend zein with a water-stable polymer. Blends of zein and PCL, an FDA-approved biocompatible and biodegradable polymer , were investigated in this study. Electrospinning zein with PCL produced the desired fibrous matrices and no shrinkage was observed in aqueous conditions, demonstrating that blending zein with PCL stabilised the protein. Figure 2: Effect of long-term immersion in aqueous buffer on electrospun zein and zein/ PCL matrices. A) and B) show pure zein fibres before and after immersion, respectively. C) and D) show a 5:1 blend of zein and PCL under the same conditions.
Impressive results Single layers and triple layers (3L) of electrospun zein/PCL and PEVA/PCL matrices with incorporated Tet proved effective against the growth of meticillinresistant S. aureus. 3L matrices exhibited sustained release of Tet for longer periods of time (at least 14 days) and the effectiveness of the 3L Tet matrices were similar to the immediate-release positive controls used in antibacterial studies (commercially available Tet disks), even after a period of two weeks, showing that retaining a part of the loaded dose of the drug for sustained release did not lower the initial bacterial killing ability. As such, in our study we reported the first demonstrated controlled delivery of a clinically used antibiotic from electrospun 3L zein-based matrices. The amount and duration of Tet released was superior to previous reports for zein-based
electrospun scaffolds, which we consider to be due to the outer, drug-free layers acting as a diffusion barrier. Importantly, we have not only demonstrated that these matrices are capable of killing planktonic bacteria, we have also shown that they are able to prevent the formation of MRSA biofilms and kill the majority of bacteria in established biofilms. Future Developments Biofilms are a serious clinical problem and a causative factor in the failure of chronic wounds to respond to treatment. The smart wound dressing has been shown to break through the biological shield that biofilms provide to protect the bacteria within, and is able to kill bacteria such as MRSA. This development creates potential for this system to be taken further into an implantable device after surgery to prevent bacterial infection whilst degrading naturally over time. The design of the matrix could be tailored to include a number of different polymers and antibacterial drugs to tackle a range of clinical problems including burns, diabetic ulcers and wounds. There is also the potential for tissue engineering, where cells could be grown on the matrix and implanted into a biological defect, whilst simultaneously preventing infection. References 1. Alhusein, N., De Bank, P. A., Blagbrough, I. S. and Bolhuis, A. (2013). Killing bacteria within biofilms by sustained release of tetracycline from triple-layered electrospun micro/nanofibre matrices of polycaprolactone and poly(ethylene-co-vinyl acetate). Drug Delivery and Translational Research, 3 (6), pp. 531-541. 2. Ceri, H. et al. (1999). The Calgary Biofilm Device: new technology for rapid determination of antibiotic susceptibilities of bacterial biofilms. J Clin Microbiol 37:1771â€“1776
Dr Paul De Bank is a lecturer in Pharmaceutics within the Department of Pharmacy & Pharmacology at the University of Bath. Paul De Bank is also Co-Deputy Director of the Universityâ€™s Centre for Regenerative Medicine. Email: email@example.com Acknowledgments A number of researchers were involved in this project at Bath, including Miss Nour Alhusein (PhD student); Dr Ian Blagbrough (Senior Lecturer in Medicinal Chemistry and lead supervisor of Miss Alhusein); and Dr Albert Bohuis (Senior Lecturer in Microbiology). Paul De Bank worked on this editorial with University of Bath undergraduate science students Emily Mobley and Emily Pritchard.
Summer 2014 Volume 6 Issue 2
How to Eliminate Cleaning and Be Rewarded with Substantially Improved OEE Summary ‘Tumbling’ is a widely used way of dry powder blending in the oral solid dosage (OSD) manufacturing environment.
the IBC itself, and the other part is the clamping mechanism which picks up and rotates the IBC (figure 1).
The possible downside of using an IBC Blender is that there is more limitation in batch size, as the IBC needs to remain a transportable size. However, modern IBC blenders are available up to 3500 litres in volume, effectively holding a batch of 1200 - 1400 kg.
The aim of this article is to demonstrate how IBC blenders, when compared with other methods of dry powder blending, can significantly increase your blending capacity and reduce your manufacturing costs. Batch size selection criterion is challenged - can we get closer to a ‘batch to order’ philosophy?
Stationary blenders can be used for larger volumes, however in practice, due to room height limitations, sensible capacities do not usually go above 4000 litres gross volume.
Inline sampling is scrutinised - is it now unnecessary and overly expensive? And finally attention is paid to the actual transfer of the batch from the blender to the next process. How does an IBC container ensure that the uniformity of the carefully blended batch is not ‘lost in transition’? Introduction All dry blend operations rely on three basic blending mechanisms: 1. Convection – the overall transfer of lots from one place to another, forced by a rotating mixing element (ribbon blenders, conical screw blenders etc.) 2. Diffusion – a re-distribution of particles, a relative change of place in the blend (tumble blending) 3. Shear – the actual forced movement over slip planes (plough shear blenders etc.) Most blenders used are tumble blenders, either ‘stationary’ shell (V-cone, hexagonal, double cone etc.) or ‘mobile’ shell (IBC or drum blenders). The main reason for their popularity is that these blenders are quicker and easier to clean thanks to the absence of internal mixing elements. They therefore present less cross contamination risks. The Benefits of IBC Blending Intermediate bulk container (or IBC) blenders basically consist of two parts. One is the blending chamber, which is 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY
cleaning as there is no product transfer and associated risk of product exposure or contact.
Figure 1 This separation of chamber and mechanism is the most important difference between mobile shell and stationary shell blenders. It has striking benefits in terms of overall blending capacity and operational costs: •
• • •
IBC blenders do not have to be cleaned, not even at product change because as the IBC is the cleaning vessel, the cleaning can be done offline in a separate washing area. IBC blenders are loaded and unloaded very quickly (placement or removal of the IBC) which means that a high OEE for blending can be achieved. One blender can take multiple IBC sizes, therefore the blending ‘chamber’ can match the ordered batch size Modern IBC blenders can nowadays also process large batches (up to 1400 kg) Sampling can be done ‘off line’, not affecting the availability of the machine. The blender room does not require
What Drives the Requirement for Larger Batch Volumes? Regulatory bodies require specific sampling methods and quantities to analyse and validate that a blend is uniform. The cost of such sampling is significant and it makes sense to increase the batch size in order to reduce the ‘QC cost per kg’. However, with quality by design (QbD) efforts and strict control over the raw material properties, the need for blend sampling could become a thing of the past, or at least reduced. PAT methods such as the use of NIR spectroscopy might replace blend sampling altogether and in some applications it does already. Having said that, some companies have their own mandatory procedures which make sampling definitely not yet extinct. Efficiency of IBC Blending The following calculation (figure 2) demonstrates the difference between IBC and stationary blenders in a more quantitative way. The comparison is done on 1200 kg quantity of collected lots. The loading and unloading of the IBC blender is simply a matter of placing and removing the IBC. For the stationary blender, we have assumed the loading is done using a vacuum transfer system. The unloading is assumed to be by gravity, straight into a batch container. We have assumed cleaning is required after five batches and we estimate it takes three hours for the stationary blender Summer 2014 Volume 6 Issue 2
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and room to be cleaned. This means an average of 36 cleaning minutes per run. In this scenario, the overall blending capacity of the IBC blender is more than three times that of the stationary blender! What does this mean? From a capital investment point of view, a single IBC blender situated in a relatively small room produces the same number of blends
for example), a novel solution is now available. Matcon have designed a lubricant addition system, which will allow the addition to be loaded into the IBC without the need to open it. This way, the room will not need to be cleaned or the IBC to be transported back and forth to the dispensary. This further adds to the ‘lean’ approach of OSD manufacturing. How do you Prevent Segregation during
‘heap’ that will create more rolling effects over the top surface. Using an IBC Blender removes the transfer risk as the product remains in the IBC throughout the whole process. As for the discharge process, using a cone valve IBC ensures the powder flows under mass flow – the cone ‘holds back’ the batch in the centre and promotes flow from the sides, thus avoiding any rolling effects. This mass flow maintains the blend uniformity during the whole discharge process, particularly important when using direct compression. Concluding Cone Valve IBC Blenders (figure 1) have striking benefits over stationary blenders – they provide: •
Figure 3: Stationary Blender Segregation during discharge per time as three stationary blenders with consequently three cleanrooms and associated cleaning time. Although an individual IBC blender is normally more expensive than a similar sized stationary blender, the total investment to achieve a certain blending capacity is often lower. It also means less operator intervention, so reduced running costs. How do you Accommodate Multi-stage Blending? The concept of fully contained IBC blending is challenged when multi-stage blending is required. It would not be a good idea to open up the IBC inside the blender room, because that activity would contaminate the room. An approach is to bring the IBC back to the dispensing area to receive the addition. For adding a lubricant (a stearate
70 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Transfer? Sampling protocols and tools do get a lot of attention in order to avoid ‘disturbing’ of the batch and to ensure the samples form a representative image of the batch as a whole. Yet the actual transfer of the batch from the stationary blender to the next process step is where the batch is most likely to become ‘very disturbed’. That changes things considerably, and the batch is in danger of losing its mandatory degree of uniformity. The material has to flow out by gravity and possible rolling effects present a segregation risk that cannot be ignored. This happens typically when a batch discharge shows a funnel flow discharge pattern (figure 3). An additional negative effect occurs in the drum or IBC as the granules form a
• • • •
A much higher overall blending throughput, replacing 2-3 stationary blenders The ability to blend up to 1400 kg Reduced operational cost and high OEE Avoiding segregation (with cone valve technology) Optional Contained Lubricant addition system
It’s perfectly possible to reduce the number of blenders whilst trebling your blending throughput.
Wim Spook (BSc Engineering) is a professional powder handling specialist with extensive experience working in hygiene business environments for many years. He joined Matcon Ltd in 1997 as Sales Manager for Holland and Belgium, focusing on the food and pharmaceutical industries. In 2009, he became Pharmaceutical Business Development Director of Matcon Ltd UK. Email: email@example.com
Summer 2014 Volume 6 Issue 2
Your business partner for custom freeze-drying
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Cleanroom Injection Moulding Demand for cleanroom conditions in injection moulding packaging processes has expanded almost exponentially in recent years as growing numbers of medical and pharmaceutical manufacturers come to rely on the technology to meet the manufacturing requirements of the European Medical Devices Directive. As a result, it is becoming increasingly important that professionals in the medical and pharmaceutical industries have at least a basic understanding of the most important elements of cleanroom injection moulding, as well as how to avoid potential pitfalls. What is Cleanroom Injection Moulding? Injection moulding is a process that involves injecting molten plastic material into a cavity, or mould, so that this then takes the form of a container. One prolific use of the application is injection moulding label (IML) decoration, whereby a label is fitted inside the cavity prior to the plastic being injected. Hence, once the plastic material has been injected into the mould, and allowed to cool, the label effectively b e c o m e s amalgamated with the plastic container. The Importance of Controlling Static in Cleanroom Injection Moulding While injection moulding is highly effective for both labelling and packaging applications, users of the technology need to take into account the fact that static electricity can have an effect on contamination control by attracting dust and dirt that can have an adverse effect on the overall quality of a product. Businesses in a large number of sectors, including food and electronics manufacture and particularly medical and pharmaceutical, are forced to dispose of any products affected by dust or dirt, making it essential that they prevent this in order to avoid costly waste. This is why they perform injection moulding applications and packaging processes in contamination-free environments, hence the term “cleanroom moulding”.
72 INTERNATIONAL PHARMACEUTICAL INDUSTRY
sterile blister packaging is every bit as important as the product inside, since even the most minimal source of contamination will result in the item being rejected. In fact, the most frequent source of contamination within a cleanroom environment is actually the operative. Eyelashes, strands of hair and skin follicles are all capable of being attracted to the packaging’s surface by static charge, ultimately leading to the product’s rejection. While the food industry is concerned with brand protection, avoiding perishing and ensuring that a product’s image isn’t tarnished in the eye of the consumer, the medical and pharmaceutical sector is obviously more concerned with contamination control from a sanitary point of view. The presence of even the smallest amount of static charge can attract fibres and small specks of dust to products that need to be kept sterile, such as catheters, stents, scalpels, syringes and hypodermic needles. There are a series of eventualities that need to be taken into consideration when addressing the issue of static in the medical and pharmaceutical sectors. For instance, in the case of a number of small medical components, the accumulated static charge is actually greater than the weight of the product itself, which in turn can cause them to stick to the surface of the moulding components. If the moulding tool closes with the product still attached to the tool face, the product could be noticeably damaged and have to be thrown away. Another example can be observed during the packaging and storage phases. When a statically charged product is placed in a plastic bag following the moulding stage, there is a risk that the charge on the product will fail to neutralise for the length of time that it’s contained within the sealed plastic environment. As a consequence, the charge will cause the packaging to attract contamination onto its outside surface. Furthermore, once the plastic bag has been opened, an even higher degree of the contamination will be instantly drawn to the product. What some fail to realise is that the
For these reasons, there needs to be an awareness of the effects and repercussions static charges can have on both productivity and product quality, as well as a range of ionising solutions that meet the ever-increasing demands of the businesses operating within the medical sector. By employing pulsed DC static control equipment, a long-range ionising system removes and controls the static charges, while the product cools to meet ambient temperature. If air-assisted ionising systems are used in this process, a possible side-effect is that the airflow may redirect airborne contamination towards the mould’s surface. Pulsed DC has the ability to create an ionising field large enough to not require air assistance. For the sanitation-conscious medical and pharmaceutical industries, every possible step must be taken to eliminate possible sources of contamination. The use of injection moulding in packaging to prevent contamination and counterfeiting of sterile equipment and pharmaceuticals is one such step, but static elimination and control is a vital element of maintaining sterile conditions and it is important not to underestimate the savings it can deliver. Stewart Gordon-Smith is the Export Sales Engineer at Meech Static Eliminators Ltd. His principle responsibility is to develop sales of static electricity control equipment in new territories, including South America and the Middle East. Email: firstname.lastname@example.org
Summer 2014 Volume 6 Issue 2
The Rise and Rise of Prefillable Syringes
Prefillable syringes are fuelling one of the medical device industry`s fastest growing and most innovative markets. Cecilia Stroe, Managing Editor of IPI, takes you inside one of the most modern production facilities for ready-to-fill syringe systems and cartridges in the world. The plant is operated by Gerresheimer Group, a leading partner to the pharma and healthcare industry, and a global organisation with 11,000 employees and over 40 production facilities in Europe, North and South America and Asia. Located in North Rhine-Westphalia, Germany, the Bünde site has a production output of several hundred million syringes per year. Here, I am told, the production stops only twice a year, for a week or so, for maintenance. Night and day, incessantly, long glass tubes are cut to the required length using a thermal-shock technique. First a cutting wheel is used to score the intended break-point into the tube. At this point, the glass is cooled using a water mist and immediately heated with a flame, essentially causing thermal stresses to split the glass tube apart at the break point. The Gerresheimer Bünde facility has around 800 employees and represents the Gerresheimer Group`s competence centre for ready-to-fill glass syringes. From here, glass ready-to-fill (RTF) syringes are supplied to pharma and biotech customers around the world to be filled with pharmaceuticals. The company has a comprehensive portofolio of sterile and non-sterile syringe systems. The RTF syringe systems, for instance, are supplied to customers in a complete ready-to-fill state, which means washed, siliconised, pre-assembled with the closure cap, packed in nest and tubs, and sterilised. “This cuts out a whole chain of elaborate process steps for pharma manufacturers. Therefore, customers can start filling product straightaway, saving a lot of time and money”, points out Carlo Reato, Senior Vice President Global Syringe Systems, Gerresheimer Bünde. There is a huge demand for prefilled syringes, and that has pushed the rate of development forward. In the
74 INTERNATIONAL PHARMACEUTICAL INDUSTRY
prefilled syringe industry, the product development is revolving around their design, properties and accessories. In Bunde, the fourth production line for RTF syringes is currently being commissioned in the new production bay. Meanwhile, key process improvements include the avoidance of glass-glass and glass-metal contact through the use of pick-and-place robots and segment transport systems, optimised washing and siliconisation processes, and more effective camerabased quality inspections. During the manufacturing process, each and every syringe is inspected several times, by cameras, sensors, computers and the human eye. “Our employees have special responsibility for ensuring that no patient suffers harm as a result of a defective syringe,” emphasises Reato. All these measures improve the syringes` “modus operandi” during the filling process, and their general function. According to Carlo Reato, “the main challenge is the human factor. That`s why we have quality control, to ensure only the best gets to the market. We are responsible for every component, not only for the glass. The supply chain is key. A prefilled syringe can be stored for 5 years on a shelf, but when it is used it has to work.” The Right Syringe for Every Application Injections work faster and more effectively than oral medications. The medication goes directly to where is needed and its effect isn`t weakened by the digestive system. Vaccines and other medications are filled into glass syringes because glass is inert and impermeable. That`s why it is perfect for the long-term storage of medications. In the field of primary packaging for injectable medication, glass is still the “gold standard”, says Claudia Petersen, Global Director Marketing & Development Tubular Glass Syringes and Business, Gerresheimer Bünde. Glass is inert, it is less reactive, and has better barrier properties than most plastics, i.e. glass is impermeable to gases such as vapour or oxygen. Many of the familiar plastic syringes are made from inexpensive polyethylene/
polypropylene. These are disposable syringes that draw up the medication before it is injected into the patient, so the medication only comes into contact with the syringe very briefly and cannot be stored in it. Conversely, makes clear Petersen, medications in glass syringes are suitable for long-term storage over several years. The advantage of glass prefillable syringes is that there is no need for the step of taking the medication from a bottle prior to application. “This can be critical for emergency situations, where time is of the essence. Additionally, this eliminates sources of error due to drawing the wrong amount of medication from the bottle, so patients are given the exact dosage they need. The general rule applies: one syringe equals one dose.” Primary packaging products, syringes come in direct contact with the medication, and that`s exactly why absolute care must be taken when manufacturing them. As Claudia Petersen explains, the syringe has to be perfectly clean because even the tiniest amount of contamination could alter the medication; it has to be also absolutely intact; it cannot have cracks; and must be firmly sealed. The desired mechanical properties of the syringe are achieved by siliconising the syringe barrel, explains Petersen. “The silicone coating plays an important role in reducing the forces that are necessary to move the plunger head. However, the silicone coating cannot be too thick, otherwise there would be too much free silicone oil inside the syringe. The objective is to optimally match the syringe with the type and viscosity of the medical silicone used and the plunger`s head properties.” Diving nozzles for silicone application can considerably improve the evenness of the coating across the entire length of the syringe body. If the active ingredient in the pharmaceutical drug needs a lowsilicone primary packaging, the silicone coating can alternatively be baked on. This process involves the use of very low quantities of silicone oil and chemically bonding it to the glass surface.
Summer 2014 Volume 6 Issue 2
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The outside of the needle is also siliconised so that it hurts less when the needle penetrates the skin. Then, needles have to be sterilised: they undergo a treatment with ethylene oxide gas, which kills almost all living micro-organisms, achieving microbe reduction by a factor of at least 10-6. Furthermore, in order to prevent contamination with the microbes in the first place, the syringes are manufactured in special cleanrooms and rinsed with a pharmaceutical water known as WFI. Sterilisation samples of each batch are then taken and tested for endotoxins. Only when all tests have been passed, the batch is approved and delivered to the customer. â€œWe wash, we siliconise, we do what was [formerly] done by the customer. We took on this responsibility. Quality starts in the design stage, but we have to keep in mind throughout the entire manufacturing process that every single syringe is a patient,â€? says Carlo Reato. Glass Meets Plastic Medical and technological progress is a very powerful prefilled syringe innovation driver. New biotech drugs and a range of new ophthalmic drugs require primary packaging manufactured to rigorous standards. But the properties of biotech drugs pose special challenges to pharma manufacturers. They are so expensive that unnecessary overfill has to be avoided and extremely precise dosage is essential. There are only a few companies in the 76 INTERNATIONAL PHARMACEUTICAL INDUSTRY
world to offer their customers both glass and COP syringes, and Gerresheimer is one of them. In addition to the RTF syringes, the company portofolio includes the ClearJect brand of COP syringes, which are manufactured in Japan by Taisei Kako. Several years ago, a plastic called cyclic olefin polimer, or COP, was introduced in the prefillable syringe segment in addition to glass. Cyclical olefins are considered an interesting alternative to glass due to their special properties: COP has high barrier properties against water vapour and oxygen, which means that the content of the syringe is effectively protected. It is also transparent, therefore making easy to check the content for clouding, particulate and other defects. COP syringes are used as primary packaging for biotech drugs, highly susceptible to external influences. The aim of medical device development in regard to the user profile is either to make the device less dependent on the abilities of the user, or to make the device fit the abilities (or disabilities) of the user better. As a result, many pre-filled syringes are now being integrated in autoinjectors, and cartridges are being used in pens. Safety devices to prevent needle injuries further increase the complexity of the basic syringe system. Autoinjectors reduce the cost of chronic disease treatment and eliminate the need for patients to visit their doctor on a daily basis. They ensure the safe
and precise dosage of self-administered medication, also eliminating the psychological barriers surrounding the invasive process of injecting because the needle isn`t visible before the device is used. But the syringe and device have to be tailored to one another to maximise dosage precision. Gerresheimer has under development an interface for the integration of glass syringes in autoinjectors. As Peter Wallrabe, Managing Director Medical Device Design, explains, Gx G-Fix works without complex two-component injection-moulded parts or sophisticated assembly processes. Attached to the syringe shoulder, the plastic standard adapter provides a precisely defined interface to the device. It has been designed to be assembled in conjunction with ready-to-fill syringe processing at the syringe manufacturer`s facility. Device integration and RNS positioning with the adapter can be used individually or in combination in the autoinjector. Autoinjectors with GX G-Fix are suitable for plastic as well as glass syringes, and can be used for a variety of drugs (especially adequate for high-viscosity medicines like monoclonal antibodies, where the spring force and therefore risk of glass breakage is particularly high). And no changes to the customer filling station are required. Editors Review By Cecilia Stroe Summer 2014 Volume 6 Issue 2
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The Hidden Challenges of Pharmaceutical Serialisation In the almost 40 years since counterfeiting of pharmaceutical products was recognised as a problem by the World Health Organization (WHO), the industry has waged a constant battle against increasingly sophisticated and organised counterfeiters, with drug packaging serving as one of its foremost defences. The true extent of the counterfeiting is unknown, since no global study has ever been carried out, but according to WHO estimates, up to 15% of all medicines are counterfeit and there was a recorded rise of 92% in seizures of falsified medicines between 2005-2011. The problem varies in severity around the world. In some areas of Africa and the Far East, up to 30% of all medicines sold are counterfeit, while estimates of around 1% are the norm in EU Member States. However, the huge growth in sales of drugs over the internet means that national and trading area borders are increasingly irrelevant. This is a global problem and legislatures around the world are taking action to protect patients. In Asia, Europe, South America and the USA, governments are drafting legislation that will make life that bit harder for the counterfeiters. While each of these schemes has its own particular characteristics, a fundamental premise of each is item-level serialisation - that is, assigning a unique identity to each unit of sale, typically a single pack. In much the same way as a car is assigned an identity number and registration plate at the point of manufacture, drugs will be required to have a unique, machinereadable code that can be used at any given point in the supply chain to help to verify its authenticity. All activities related to drug serialisation that are evolving in different countries are backed by the overarching global initiative managed under the auspices of the WHO. It set up the International Medical Products AntiCounterfeiting Taskforce (IMPACT) which
78 INTERNATIONAL PHARMACEUTICAL INDUSTRY
developed principles and elements for national legislation against counterfeit medical products. Be it the EU Falsified Medicines Directive (FMD), Brazil’s ANVISA, Argentina’s ANMAT, South Korea’s MHW, China’s SFDA, or the recently announced senate bill (Drug Quality and Security Bill) in the USA, manufacturers subject to any of these schemes are now engaged in a race against time to implement serialisation ahead of the deadline. This applies to all products supplied into the respective territories and not just to locally-produced drugs or indigenous manufacturers. Taking the EU FMD as an example, the timeline for compliance is three years after the forthcoming publication of the Delegated Acts in each of the EU28 countries. For all but three of these countries, the date for full compliance is expected to be 2017. The Directive applies to all branches of the industry, including research-based manufacturers, generics producers, contract packers, parallel traders’ importers, wholesalers and distributors. Simply put, any organisation intending to supply Prescription Only Medicine (POM) and some Over-The-Counter (OTC) products into the EU which after that date will not be able to do so unless full compliance can be demonstrated. There is a view, apparently relatively widely-held, that the challenge of itemlevel serialisation does not extend beyond the confines of the packaging hall. This may stem from the fact that the most obvious expression is on-pack information in the form of a code, which has of course been required for both legislative and GMP purposes for many years. However, serialisation is a significant shift in that data will be unique to each pack rather than to each batch. This has huge knock-on effects beyond the installation of new equipment, namely, on the need for increased staff investment
and stakeholder engagement. To characterise it as an engineering issue is therefore to grossly underestimate its consequences, which touch virtually every business function in pharmaceutical manufacturing. This white paper looks at the challenges encountered during serialisation trials by the ‘early adopters’ and provides guidance on strategies to overcome them. Most trials were undertaken at a time before any legislative imperative or global standards and although these trials have not gone the full extent of serialisation and aggregation, the lessons learnt may prove invaluable. It is worth noting at the outset that the first challenge of serialisation is the fact there is not a ‘one size fits all’ solution. No one supplier will be able to handle all the requirements, from the coding and marking technology to the data handling. Even reportedly ‘turn-key’ or ‘end-to-end’ solutions will inevitably be comprised of multiple vendors working in collaboration. Technology For packaging manufacturers, the updating of lines and installation of serialisation-capable coding equipment may seem like a project much like any other, with predictable timelines and considerations such as where the coding and inspection equipment will be located and how it will be integrated. This may be true to some extent, but it is an assumption that merely scratches the surface: trials have shown that installing and commissioning serialisation-ready equipment is markedly more complex. There is also likely to be a debate about which coding technology is best suited to serialisation. By now manufacturers should be well aware that older technology such as hot foil or embossing is now far beyond its expiry date. Serialisation-capable alternatives might include thermal ink jet (TIJ), laser or thermal transfer overprint (TTO). Variables such as substrates, speeds and
Summer 2014 Volume 6 Issue 2
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pack design might need to be factored in, as does any company-specific preference based on legacy technology, plant location and experience. Whatever the equipment choice, manufacturers should certainly not be delaying their serialisation projects while waiting for clarification of all the finer details of whichever legislative scheme (or schemes) applies to them. There is sufficient detail and guidance already available for the industry to make informed decisions about how to achieve unique pack identification. With the exception of China (which is looking at the option of linear barcodes), the model is a combination of a 2D data matrix code and human readable text. Thermal ink jet and laser are good choices, as because codes need to be verified as well as applied, print quality is a critical factor. Furthermore, although data matrix codes are designed with inherent redundancy, the scrutiny of text by vision systems is less forgiving, so high levels of consistency need to be achieved in order to avoid rejection. While the lower resolution of CIJ is more than sufficient for alphanumeric data, it is not recommended where small, high-density codes need to be applied and verified, leaving thermal ink jet and laser as the systems of choice. Laser offers significantly lower running costs because the only consumables are the filter bags for the extractor and may therefore be the preferred route in instances where throughputs (and hence potential ink consumption) are high; laser marking is also indelible and therefore a good choice for cold chain products. Thermal ink jet offers a clarity and density of marking combined with a lower initial capital outlay and may therefore be a better option for other applications. Both offer the speed and quality of marking required in a high-speed serialisation environment and both are capable of meeting the requirements of all pharmaceutical traceability schemes in operation or planned around the world, which will certainly be a consideration for manufacturers supplying multiple regions from a single plant. With any ink-based marking system, the quality of the end result relies as much upon the choice of ink as it does 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY
on the capabilities of the printer and the type of product packaging. The advent of serialisation, and the associated volumes of data required to be applied to each pack, has spurred new developments in multi-substrate inks for TIJ printers, which offer fast drying times (essential to prevent smearing where tamper-evident labels are applied as part of a highspeed packaging operation), optimised clarity to minimise the incidence of false rejects produced by machine vision systems, and enhanced light-fastness so that the code contrast remains high from the point of production, to dispense and beyond. Data According to IBM, we now generate 2.5 quintillion bytes of data every day – to the extent that 90% of the data in the world today has been created in the last two years alone. Those who have experimented with serialisation thus far are well aware of just how much data it can create, and the challenges associated with storing and maintaining the integrity of that data for the required period of time. The volume of data generated by serialisation derives principally from the fact that each item now consists of two parts – a physical asset and a data asset – and that the association between the two must remain linked from the moment a unique identity is assigned to a pack right through to the moment it reaches the patient. Delve deeper and it quickly becomes clear that this simple fact alone will require a modal shift in the manufacturing mindset, with each pack effectively a unique batch of one. Reconciliation, which has until now been a line-side task completed once per batch, will in future need to extend right through the supply chain and be open to interrogation for the life of the product and beyond. The outcome here is that product data must be uploaded to a national or supranational systems infrastructure against which product IDs will be verified at the point of sale or dispensing. This in turn raises the question of data aggregation (the establishment of hierarchical relationships at each stage of the packaging process). While some of the schemes in play include aggregation as a requirement, others do not. However, it would seem to be a logical extension of item-level serialisation, enabling,
for example, the data for each pack in each case, and each bundle on a particular pallet to be retrieved with a single scan. It is therefore a requirement which manufacturers would do well to accommodate, even if not implemented from the outset. The same principles apply to equipment capabilities for aggregation as they do for serialisation: printers need to have on-board capability to apply unique information to each aggregated ‘unit’. Establishing hierarchical associations between the unit-of-sale packs in a bundle, bundles in a case, cases in a pallet and so on enables any party authorised to handle product in its journey through the supply chain to interrogate, with a single scan, precisely which items the batch contains. While speed is not such a significant requirement in code application at aggregation stage, quality and legibility most certainly are: as stated above, a pallet code is effectively the key to the unique data associated with every single item on that pallet, and the consequences of a failed scan are therefore significant. As at item level, users have a choice of technologies, the principal ones being print and apply labelling machines or, for printing direct onto the packaging, large character continuous ink jet systems which offer a label-free solution. There is currently no protocol for uploading data to a central repository and to date, it remains unclear how data will need to be supplied to regulators, and what the obligations are on the manufacturer to replicate and retain that information and for how long. The strategy will vary from one company to the next but the planning process needs to start now, before the deluge begins. Re-designing Packaging Protocols One of the questions thrown up by serialisation is whether a machinereadable code is artwork or data. Until now, any pre-printed code, such as a GTIN, would have been treated as artwork by some; however, since it will now form part of the product identity, there is an extremely strong case for reclassifying all codes as data and storing them accordingly. The need to maintain a unique data asset in parallel with each physical pack will place restrictions on the way Summer 2014 Volume 6 Issue 2
packaging operations might traditionally have operated: if a pack is rejected or otherwise removed, how is it removed from the database and what strategies are in place to ensure that the integrity of serialisation regimes is uncompromised by such events? How will rework of false reject products be managed in the future? The concerns for manufacturers of both research-based and non-researchbased pharmaceuticals are self-evident. Although daunting, there are positives to the creation of such a database: engineers on the packaging hall floor will have access to the database, and if there are issues on a line, the database can be used to pinpoint certain packs, when they were produced, and if they caused any problems. This will drive up standards and may create leaner production lines. A New Status Quo in Operating Efficiency According to the early adopters of serialisation, the engineering challenge lies in returning to ‘business as usual’ in terms of operating efficiency. Although manufacturers are no doubt anticipating an impact, it is crucial to be aware early on that the effect is considerable. One company reported serialisation at 300 units per minute as comfortable, 400 to 450 per minute achievable but not fully robust, and 500 per minute and beyond still a real technical challenge. Anecdotal evidence also suggests that the reject/re-work level in the early stages can be as much as 10%, far above what is normally acceptable. This reduces over time, with rates well below 1% being achievable, but it takes commitment, effort and engineering know-how. In many cases, reject bins in the packaging halls simply are not big enough; this might seem like an almost trivial concern but if a full reject bin results in an unplanned line stoppage, then it is a point that needs addressing. The best possible foundation for robust serialisation is uninterrupted production: it will quickly become apparent that unplanned stoppages due to below-par line performance cause significant and unacceptable headaches in a serialised environment. The causes will need to be identified and addressed as a matter of urgency if acceptable operating efficiencies are to be achieved. Good practice, such as planned and preemptive maintenance to ensure lines are fit for serialisation ahead of time, will www.ipimedia.com
ensure that businesses can concentrate on the more significant and less familiar challenges as the deadline approaches. Investment in Staff The challenges demonstrated in this paper so far will largely need to be addressed and solved by engineers. Manufacturers need to ensure that their staff members are confident in dealing with issues that are not currently in their remit. Investment in training, therefore, is crucial. Budgets should be assigned now to get engineers trained and ready to help get lines back to ‘business as usual’ as quickly as possible. Implementing serialisation highlights any flaws on a packaging line. Issues taking longer to resolve can cut quite significantly into overall equipment effectiveness and profit margins. Training will limit the time it takes to overcome problems, and though it may seem an unnecessary expense, it can up morale during a challenging period, lead to new best practice and drive up standards across the organisation. Stakeholders Trials to date have shown that overcoming the challenges detailed so far becomes a lot easier with stakeholder buy-in. But as production, regulatory compliance and quality assurance personnel know, this is not always as easy to attain. Many stakeholders believe serialisation to be a purely engineering challenge, but this seriously underestimates its impact right across the business. Project engineering new equipment into existing lines is the essential first step confined to the packaging hall, but beyond that the critical success factor is senior stakeholder engagement to establish a robust serialisation infrastructure. The engineering challenge of recognising that each physical pack has an associated data asset, and that association must remain intact throughout the supply chain, is easier to overcome with support from the top. As a result, manufacturing managers need to be in constant communication with stakeholders to ensure buy-in way ahead of the deadline. This case is strengthened considerably by the widespread view that serialisation will be a key element of future brand protection schemes. The impending legislative imperative aside, serialisation has the potential to improve the supplier-patient relationship across
the industry. Patients will also be able to verify the authenticity of their medicines, increasing trust in the brand and the manufacturer. That confidence might well lead to improved patient compliance, resulting in better outcomes. Business Benefits Implementing such a significant change in a relatively short timescale and in an industry as highly-regulated as pharmaceuticals is a daunting prospect and it is therefore no surprise that much of the focus currently is on problems and challenges. At the most basic level, many are approaching serialisation projects with caution and asking what the regulations mean for their business. This, inevitably, leads to a ‘wait and see’ approach, before investing in new plant and equipment. The trick, in many ways, is to be more visionary. By taking a front-foot approach, manufacturers and packers can have their say in defining standards and formulating the regulations at an early stage. At a company level, by adopting a robust approach to the new regulations, companies can get ahead of the curve through improved response to counterfeiting incidences, reducing their prevalence and the risk of contamination. It also works to enhance the safety profile of marketed products, with the unique on-pack data serving as a guarantee of authenticity and quality. Although this might seem a distant prospect right now, serialisation ultimately offers the opportunity to really drive down business costs. By improving operating efficiencies, reducing inventory losses, improving the rate of returns, recalls and the chargeback process, and providing all-round visibility of the supply chain, the pharmaceutical business can substantially improve its outlook, in terms of efficiency, profitability and brand image. Craig Stobie has worked for Domino for over 18 years in technical, operations service and commercial roles. Craig has a broad view of the legislative and commercial pressures facing the healthcare sectors and is well versed in current and impending global legislation. Email: firstname.lastname@example.org INTERNATIONAL PHARMACEUTICAL INDUSTRY 81
Parenteral Packaging: Raw Material Substitution and Procurement Impact Abstract / Business Case 1. Introduction: The industry of glass primary packaging is seeing a rapid shift towards usage of plastic substitutes for specific end uses such as biotech drug packaging, prefilled syringes etc. The main reason for the shift is the characteristic of glass as a raw material (flaking and delamination) and its failure to safeguard the product formulations inside, leading to recalls. 2. Main: This white paper deals with the underlying facts related to the issue of glass substitution. The seriousness of the issue at hand is discussed with apt industry examples and facts. The main substitute (COC/COP) has been discussed with industry examples such as that of Schott’s (a glass packaging supplier) TOPPAC plastic vials. Global insights pertaining to this trend, and a comparison of glass over plastic to find out qualitatively which is the better suited material in the future is provided in the paper. Going further, the white paper provides explanation of the reason for the shift to plastic from glass, taking into consideration the cost of recalls and total cost of ownership. And finally, the impact substitution has over procurement factors such as raw material sourcing, industry integration, and manufacturing of packaging. 3. Recommendation: For a company which has invested time and money in the research and development of an innovator drug, the decision concerning the right kind of material for the package and the right volume of dosage is of paramount importance. As the company has already invested millions, maybe billions, to reach this stage, a wrong decision will lead to recalls, which is a costly affair. It is for this reason that pharmaceutical packaging buyers spare no effort and money to source the right kind of packaging material best suited for their drugs. To avoid the issues with glass and its 82 INTERNATIONAL PHARMACEUTICAL INDUSTRY
characteristics, companies must follow a two-pronged approach: The glass to plastic shift decision: The company, while deciding upon the best raw material for this drug packaging, needs to take into consideration the time period of storage of the drug, the complexity of the delivery format and the risk associated while choosing plastic over glass. Increase collaborations during raw material sourcing and final packaging: The buyers, who, after R&D, opt for COC/COP as their packaging material need to initiate collaborations with the COC/COP resin manufacturers so that they can work together to form the best packaging raw material for their product. From a supplier point of view, the supplier who has decided to provide COC/COP packaging as a part of their product portfolio needs to source special machinery which is aimed to use COC/ COP as its feed stock. Is it Really that Serious? The essential purpose of a packaging material is to ensure the security of its contents. But when the package itself reacts with the contents, creating detrimental effects and costly recall issues, the purpose of using that material is defeated. For centuries, glass has been the primary packaging raw material for the pharmaceutical packaging and parenteral packaging industry, however, this dominant primary packaging raw material is being replaced by plastic, slowly but surely. This substitution shift, though costly, is being driven by the high demands from biotech drugs which require advanced technologies in package forming. Another important reason for the substitution of glass is the need for alternative packaging materials due to the problems that glass has, such as delamination and tungsten residues. Traditionally, Type I glass is the established packaging raw material for the parenteral industry. However in the context of new biotechnological drugs, borosilicate glass or Type I glass has a high interacting possibility dependent upon the acidity of the product packaged inside. Added
to this pitfall for glass packaging, is the fact that glass flakes may peel off over a period of time, causing the composition of the product packaging inside to react with the package walls, thereby leading to massive drug recalls. Some of the recalls that have happened due to delamination are Baxter’s recall of Hylenex, Sandoz’s recall of Methotrexate, Amgen’s recall of Epogen and Procrit etc. – and the list keeps on growing. Prefillable packaging formats, with a growth rate of 11% till 2014, will be the area where most of the substitution will take place. Proof of this substitution trend is the fact that out of the total number of prefilled syringes manufactured, 2030% of them are made out of plastic raw material substitutes. COC/COP- The Strongest Competitors to Glass as Raw Material Substitutes The high cost of transition to plastic from established glass processes and lack of incentive in terms of drug formulation innovation discouraged the majority of producers of parenteral products from initiating the shift until now. But with the industry evolving with new and demanding types of protein formulations, innovative materials such as cyclic olefin copolymers (COC) and cyclic olefin polymers (COP) are being utilised more often. One of the pioneers in the utilisation of COC and COP materials for glass primary packaging is Schott glass, which is the world’s largest pharmaceutical primary packaging provider, with a clear 30% market share of the glass primary packaging industry, and is third in line for prefilled syringes after Becton Dickinson and Gerresheimer. Let us delve deeper in to this industry example, for better understanding of the substitution trend. The TOPPAC COC vials (2ml to 200ml) manufactured by Schott as one of their product portfolio have found increasing acceptance in the industry for pharmaceutical primary packaging. Schott claims that its new COC vials are suitable for liquid filling and lyophilisation Summer 2014 Volume 6 Issue 2
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and lower interaction rates, which in turn improve the shelf-life of the product packaged. “COC polymer offers a few important advantages. Glass has been a well-tried and accepted material for parenteral packaging by the pharmaceutical industry for decades, but depending on the drug and its application, it has also certain limitations. In these cases COC polymer can offer a very good alternative,” says Schott product manager Wolfgang Streu. Some of the areas where Schott uses their COC vials are ophthalmic medicine, oncology and veterinary medicine. Still Not Convinced? Well, Let’s Go Global. COC has become very well accepted as a substitute to glass and normal plastics due to two main factors, viz. the innovation opportunities it provides in terms of design during the forming process for prefilled syringes, and the lightweight savings it provides as compared to its glass counterparts. Some of the companies which have started using COC as a raw material are Gerresheimer, Alcan packaging and Schering. Even the global packaging giant Amcor has warmed up to COC as a substitute to glass and traditional plastic by using this material in its chlorine-free thermoformable coextruded COC/PP blister packs.
be highly break-resistant. But it doesn’t end there. pH resistance of COC/COP plastic has higher values, and plastic doesn’t leach, i.e. there is no flaking of plastic over a period of time as there is in glass. One more important factor that is characteristic to plastic is its drainability i.e. the product doesn’t stick to the walls when coming out. However plastic does have its own share of cons, a major one being the permeability of the COC/COP material towards gas and vapour. Coatings and additives which decrease the gaseous permeability of the COC/COP package are some of the areas where companies
The largest substitution in primary containers has been in Asia, especially Japan. Japan has always had a good spending trend in terms of R&D, and until now remains the only country in Asia to have produced innovator drugs, with the rest of Asia focusing on generics. Along with this, the capability and capacity to accept disruptive technologies ensure that Japan as a country is at the forefront of all futuristic technology applications. Almost 60-70% of the prefilled syringes used in Japan are made out of plastic, especially, COC/COP. The Daikyo Crystal Zenith with its improved thermo mechanical properties, ease of precision moulding, sterilisation and improved moisture barriers, is a COP that has seen good acceptance in Japan.
using substitute materials are trying to innovate. Some comparisons are as follows
Let us Understand why Plastic is being Considered Over Glass For a layman, the first property of plastic when pitted against glass is the fact that packaging made out of plastic will
Let us look at this issue objectively. For a company which has a major stake in manufacturing and sale of a biotech drug, a significant amount of capital is invested right from the start of the project.
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For instance, for a biotech drug without RNA Interference technology (a costly technology to accelerate the pace of discovery biology) takes about 14 years to reach its preclinical phase. It is during this 14-year time period the effective method of drug delivery is optimised and decided. For a biotech drug with small volumes, the most common delivery format would be a prefilled syringe. A decision concerning the right kind of material for the package and the right volume of dosage is of paramount importance at this stage. As the company has already invested millions, maybe billions, to reach this stage, a wrong decision will lead to
recalls, which is not only inconvenient but may cause complete bankruptcy. It is for this reason that pharmaceutical packaging buyers spare no effort and money to source the right kind of packaging material best suited for their drugs. Traditionally, PFS made out of COC/ COP polymers cost around 20-25% Summer 2014 Volume 6 Issue 2
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more than the normal package material that is glass. However from a total cost of ownership view, the prefilled syringes made out of COC will have better cost savings on the basis of reduced costs of recalls and increased throughput and cost saving from design flexibility. Along with this there are added benefits, such as those accrued by using plastic as a raw material, e.g. reduced delamination, light weighting, etc. With the improvement in technology, new and cost efficient COC/ COP are being developed which will not only provide all the best properties of glass but also that of polypropylene. A very good example of such a product would be the Zeonex(r)/ZEONOR(r) COC which: • • • •
Costs 1/4 to 1/10 of the price of glass syringes with luer lock assemblies Highly shatter-resistant Less than 50% weight than that of the glass counterparts, thereby improving freight and shipping costs Improved design opportunities through injection moulding technologies
This not only proves that plastic as a substitute is not just a trend being noticed in some instances, but also is here to stay and provide benefits to the pharmaceutical and healthcare companies, as well as packaging suppliers. A Raw Material Substitution Will Lead to Industry Movement, Won’t It? Improving opportunities of sourcing plastic for parenteral packaging and level of innovations in the industry provide pharmaceutical companies with ample opportunities to source the best packaging material for their parenteral product. The current industry norm is to develop long-term supplier contracts and involve the supplier in the overall R&D of the product developed, so that the optimised drug delivery format and the dosage is decided in consensus. This way the pharmaceutical companies can not only mitigate the risk of recalls due to wrong package, but also can capitalise upon the combined R&D capabilities of both partners. The following representation provides insights to the impact of the substitution on the procurement of packaging for parenteral products. To Conclude: The shift from glass to plastic may be 86 INTERNATIONAL PHARMACEUTICAL INDUSTRY
slow, but is going to happen, and that is evident through the industry movements in the parenteral packaging sector. For normal or standard drugs a complete shift to plastic is not feasible, especially if the drug has become generic and mature. However, with sophisticated drugs and delivery technologies being developed, the packaging formats need to evolve. “Glass has been around for many years and will continue to be a suitable material for drug containment for many years to come. However, as newer and more sophisticated drug products and delivery technologies are developed, containment systems must evolve,” says Graham Reynolds, Vice-President of Marketing and Innovation of Pharmaceutical Delivery Systems at West. COC/COP are now finding an increased usage as substitutes for glass in special conditions where the issues with glass, such as delamination and tungsten residues, can lead to costly recalls. Pharmaceutical companies need to understand their product formulation and decide upon the best package material to improve shelf-life of the product. To do this, the companies have to involve suppliers in their sourcing strategies, especially at the product development stage. Currently, it can be said that glass and plastic are moving parallel to each other, and major companies are trying to improve the properties of these materials through surface coating and barrier technologies; however the industry cannot ignore the immediate delamination threat that glass has as a packaging material, and hence must move towards plastic, especially for demands from large molecule biotech drugs.
References • Plastic Shows Benefits in Parenteral Packaging by Jennifer Markarian • Trending Towards Plastic by Graham Reynolds • Glass breakage, delamination and compatibility with biologics have boosted interest in novel materials in pharma packaging By Fran DeGrazio and Diane Paskiet • TRENDS IN PHARMACEUTICAL PRIMARY PACKAGING FOR INJECTABLES by Claudia Petersen, Director of Business Development at Gerresheimer Bünde • Cyclo olefinic copolymers make medical progress by By David Vink • NEW CYCLIC OLEFINS By Jan H. Schut • h t t p : / / l i f e s c i e n c e l e a d e r m a g . epubxp.com/i/140470/13(Life Science Leader) M. Abhiraj, is a Domain Lead working with Beroe Inc. a global provider of customized procurement services specializing in sourcing, supply chain visibility, financial risk analysis and environmental impact to Fortune 500
organizations. M.Abhiraj specializes in tracking the pharmaceutical Primary packaging (Rigid) industry. He has worked on multiple projects for many Fortune 500 clients involving categories such as Rigid and flexible packaging in the end use markets such as pharmaceuticals and Consumer packaged goods M.Abhiraj has earned his degree B-Tech Biotech (IASE University) with MBA in Marketing (Christ University).
Summer 2014 Volume 6 Issue 2
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New Technologies in the Fight Against a Global Pandemic The number of people suffering from diabetes is increasing rapidly worldwide. In parallel, the global market for insulin therapies is growing at a much higher rate than total sales of prescription drugs. For people with diabetes who are dependent on insulin, pen systems that can be equipped with insulin cartridges and injection needles have long since surpassed all other injection systems. For the safe filling of insulin cartridges, manufacturers offer new technologies that ensure high output, low product loss, and optimal patient protection. Diabetes mellitus is the first noninfectious disease that has taken on the magnitude of a pandemic. The growing number of young people with diabetes is especially worrisome, as it increases the burden on health systems through diabetes-related long-term effects. Nevertheless, diabetes research has made great progress in recent years. The once-deadly disease has become one that is chronic. Thanks to new, targeted therapies and application technologies for insulin administration, people who are suffering from diabetes today have the same life expectancy as their peers. The current figures are frightening, however: 382 million people worldwide suffer from diabetes. It is estimated that the number will increase to 592 million by 20351. Most people with diabetes – about 80 per cent – live in countries with medium to low income, with an increasing percentage in the so-called emerging economies.
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Forms of Diabetes In type 1 diabetes, the body’s own immune cells are directed against the insulin-producing beta cells of the islets of Langerhans in the pancreas. This happens very often already in childhood. What triggers this misguided immune response is still not scientifically clarified to its full extent. Due to the resulting insulin deficiency, insulin therapy is always necessary for treatment of type 1 diabetes. In contrast, experts now agree that the modern lifestyle is the main cause of type 2 diabetes. This type accounts for about 90 per cent of all present cases. Obesity and lack of exercise lead to a resistance to the insulin hormone, preventing it from working properly on the cell membranes and from transporting glucose into the cells. The result is increased blood glucose concentration, which often goes unrecognised for many years. All approaches to diabetes therapy have always been aimed at controlling blood sugar levels and preventing large fluctuations down (hypoglycemia) or up (hyperglycemia). In the 1920s, researchers Frederick Banting and Charles Best were able to extract insulin and successfully treat a young patient with it for the first time2. A disease that had been fatal up to that point suddenly became manageable. Today, insulin is obtained from bacteria using biotech methods and brought to the market as human insulin. Since 1996, modified insulins have also been approved. Referred to as insulin analogs, they work particularly quickly or uniformly.
Changing Diabetes Therapies and Delivery Methods Technical innovations since the 1980s have made domestic self-monitoring of blood glucose possible – an important advance for the calculation of the insulin dose, giving back some flexibility in everyday life to patients. Insulin pens were developed for more ease of delivery. The pens are used as multiple application systems with pre-filled insulin cartridges3. For diabetes patients the independent administration of insulin is now a lot easier. Due to their shape, the pens can not only be transported more conveniently, they can also be applied “en route” without attracting attention. Patients are able to better adapt the therapy to their own rhythm of life. Another milestone was the development of insulin pumps, which continuously and flexibly provide diabetes type I patients with short-acting insulin. While needle-free injection systems do not yet have great penetration in the market, several developments promise further improvements in the quality of life of diabetes patients. One such example is inhalable insulin. Although the first commercial trials from around 2006 initially failed, a comeback may be imminent: The U.S. Food and Drug Administration (FDA) is presently reviewing the inhalation formulation of an American pharmaceutical manufacturer4. Further studies are currently underway, including ones on the development of orally administered insulin5. Safety of the Product and Patient Due to the worldwide increase in the number of people suffering from diabetes and constant improvements in therapy and delivery methods, the global market for insulin is growing continuously, along with the market for pens and other injection aids. Currently pens are the most widely used system for insulin injection, mainly due to their ease of use and relatively inexpensive production. The insulin pens are loaded with cartridges. The cartridge is a glass cylinder which is closed on the front end by an aluminum cap with a puncture membrane. The rear end of the cartridge is closed with a rubber stopper. For diabetes patients, easy and safe handling of the pens is the most important Summer 2014 Volume 6 Issue 2
Our comprehensive offering: RTF速 syringe systems | High-quality ready-to-fill syringes | Innovative accessories | Proprietary baked-on siliconization
packaging, the industry demands ever greater flexibility. That is why modern plants and lines are compatible with all current filling technologies and partly also equipped with combi filling stations for several packaging types, such as cartridges, vials, and injection bottles or syringes.
criterion. Insulin manufacturers in turn must pay particular attention to sterile filling and to the integrity of the materials used. Product safety is the highest priority for pharmaceutical manufacturers. For this reason, the pharmaceutical industry looks to reduce manual intervention during the production process as much as possible. Modern barrier technology completely seals off products, processes, equipment, and operators from each other. Restricted access barrier systems (RABS) ensure effective separation in the sterile room. Insulin manufacturers also increasingly rely on the use of isolators, which ensure higher product quality at lower cost compared to conventional cleanrooms. Market Growth Requires High Output Cost pressure is omnipresent in the highly competitive insulin market. As it is not possible to establish a high price for insulin preparations, manufacturers can generate profits only through volume. Although insulin pumps are
even easier to use compared to pens, their higher production costs made it impossible for them to prevail globally. In addition to the cost factor, the growing number of diabetes patients in the emerging economies has driven major insulin manufacturers to expand their production to more and more locations worldwide. That is why machines for the processing of cartridges for insulin pens are increasingly used particularly in the so-called “pharmerging” markets such as India, Brazil, and China. The criteria by which manufacturers choose their machines are high output, high availability, and reproducible precision in insulin production. Filling and closing machines for cartridges with a capacity of up to 600 units per minute are now considered state-of-the-art and are already installed in the market in large numbers. Filling lines integrated in isolator systems run continuously for 21 days in some cases, thus ensuring maximum productivity. In terms of filling systems and processing of the
Focusing on Glass Integrity The process a cartridge runs through includes many steps: washing, siliconising, sterilising, filling and closing in the isolator device, inspection, and tray loading. The cartridge is exposed to different temperatures, pressures, and movements during these processes, all of which it must withstand unscathed. The higher the speed of a filling and closing machine, the more the manufacturing process subjects the glass to physical stress. This can cause damage to the glass, such as cracks, chips, or fractures. The product loss caused by these defects results in higher costs for pharmaceutical producers, which machine manufacturers are counteracting with new solutions for gentle processing. The primary objective of these innovations is to minimise contact between glass containers. During loading of the cleaning machine, for instance, the cartridges are loaded onto the conveyor belt in just one row and then transported in rows. Stainless steel containers, referred to as “transport pucks”, ensure smooth transportation from the washing station through the sterilising tunnel by preventing glass-to-glass contact. This is particularly important for the processing of dual-chamber cartridges, as they may be even more fragile due to the internal bypass. Adjusting the Physical Stress During the sterilisation process, the glass is exposed to an enormous heat influence. The high temperature leads to expansion of the glass mass in the tunnel. This can be compensated by a conveyor belt with flexible lateral support, which widens immediately after the tunnel entrance. To protect the cartridges from damage from tipping over, they are transported to the inlet of the filling machine in bulk, where a star wheel separates them again. The angle of the star wheel must be designed precisely, facilitating seamless loading of the receiving pockets in the star wheel with cartridges. Robotic feeding and removal of cartridges can provide further reduction in physical stress. Cosmetic
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Summer 2014 Volume 6 Issue 2
system. But the near future already promises the introduction of further insulin formulations and new, improved insulin pens. The artificial production of the insulin hormone – from the first extraction in the twenties until the introduction of the first long-acting insulin analog in 2000 – is a success story unparalleled in medicine. Although prevention and avoidance of long-term consequences must always be top priority, advances in treatment provide people affected by diabetes with the hope of further, significant improvement in their quality of life.
glass defects are evidence of damaged packaging, which may also break on the way to the patient or be contaminated with particles after the filling and closing process. Above all, however, exact and correct closure of the cartridges is essential for safe drug administration, where 100 per cent inspection plays an important role. With the “static division” (SD) technology, light is projected through the liquid onto an optical sensor, which allows differentiation between moving particles and static objects. Automatic camera-based systems in turn detect both particles and cosmetic defects. While the containers are rotated by more than 360 degrees, cameras take high-resolution images. By comparing these images, the system is also able to identify particles adhering to the walls or defects in the cap crimping. Precise Filling for Safe Dosing
The filling of insulin products into a cartridge must meet special requirements. On the one hand, insulin suspensions often require filling with a homogeneous level of active ingredients. On the other hand, full and bubble-free filling should be ensured without overfilling. This demands a two-step filling process, in which 80 www.ipimedia.com
per cent of the maximum quantity is dosed into the cartridge in the first step. In a second station, the remainder is filled to the full point by laser-scanning the cartridge neck. The laser sensor switches off the dosing when the fluid meniscus reaches the laser beam. Suspensions require constant homogenisation of the product template and often also require that mixing bodies (sterile glass balls) are added to the cartridge. This enables the patient to perform simple homogenisation of the suspension by shaking prior to application. The glass ball feeding is also monitored using sensors. Research for a Better Quality of Life Even at an early developmental stage of insulin preparations, safe filling of cartridges is top priority for the subjects in clinical trials. Insulin producers, therefore, have a great need for manual and semi-automated test machines for product development. New, highly flexible laboratory modules are primarily used in early clinical phases. It is particularly important that these machines can be equipped with different filling technologies and allow the filling parameters to be easily transferred to production systems via scale-up at a later point. Inspection is equally important during product development: manual inspection systems, supported by cameras where required, quickly and accurately inspect empty and full glass containers for particles in the liquid or for cosmetic defects. It is still uncertain when alternatives to injecting insulin will prevail. For the time being, insulin pens are set to maintain their status as the preferred application
References 1. h t t p : / / w w w . i d f . o r g / diabetesatlasMerkel, Howard: How a Boy Became the First to Beat Back Diabetes, http://www.pbs. org/newshour/rundown/how-adying-boy-became-the-first-to-beatdiabetes/, January 2013. 2. Freissmuth, Jérôme: Developments of Drug Delivery Devices are Increasingly Focused on Patients’ Needs, www.chemanager-online. com/en, April 2013. 3. White, Ronald D.: MannKind is seeking approval for diabetes inhaler system by spring, http:// articles.latimes.com/2013/ dec/08/business/la-fi-stockspotlight-mannkind-20131209, December 2013. 4. Yaturu, Subshashini: Insulin therapies: current and future trends at dawn, http://www.ncbi.nlm.nih. gov/pmc/articles/PMC3596776/, February 2013.
Johannes Rauschnabel, PhD, is Chief Pharma Expert at Bosch Packaging Technology. He is a graduated Chemist from EberhardKarls-University Tuebingen and has more than 25 years of experience in research and development and 15 years in the pharmaceutical industry as a product manager for Barrier Systems and as Director Process Engineering. Johannes Rauschnabel is a frequent speaker at conferences, a lecturer at University of Hohenheim, and an author of multiple scientific papers and patents. Email: johannes.rauschnabel@bosch. com INTERNATIONAL PHARMACEUTICAL INDUSTRY 91
Influence of Primary Components on Parenteral Delivery Systems, Biologic Therapies and Patient Outcome Introduction: Development of therapeutic proteins has been on the rise for a variety of disease conditions. The administration of parenteral biologics relies on interconnected attributes associated with compatibility of delivery components to the safety and efficacy of the final product. It is essential to characterise individual components in contact with a biologic to understand the risks to the delivery system as a whole and the effect on patient outcome. Selecting an appropriate delivery system for these therapies is critically important. The quality of the components within a delivery system also has a significant impact on the development efficiency and the time to market. There are unique regulatory expectations as well as physical and chemical aspects that need to be considered when choosing components for a delivery system. Adequate information on user needs is necessary to design a delivery device suitable for intended use. Quality considerations are important throughout each phase of the pharmaceutical lifecycle to assure fitness for intended use relevant to patients. Alignment of the delivery device with the biologic manufacture, storage and distribution processes is a key element for bringing a product to market. The development of delivery systems to accommodate therapeutic proteins compared to small molecule drugs presents unique challenges. The fragile nature of proteins and delivery of high volumes with complex matrices necessitates a holistic understanding of primary components used in injectable delivery systems. There are multiple device components that may have direct, indirect or intermittent contact with a biologic that can interfere with the safety and dosing of the biologic. The degree and type of assessments for each component are not equal due to risk associated with each application. The compatibility and performance of the combination of all components are critical to the overall function of the delivery system. The role of each component of the delivery system should be understood to allow 92 INTERNATIONAL PHARMACEUTICAL INDUSTRY
for applicable evaluations to provide patient-relevant data. This paper will first discuss material compatibility issues with a focus on biologics. A summary of the regulatory landscape will then put into perspective expectations for injectable delivery systems. Finally, a review of components used in injectable devices and factors for building in quality during development phases will be considered. Compatibility of Materials in Contact with Biologics Components of the manufacturing process, storage and delivery devices can leach detrimental substances, affecting the quality and safety of the final product. The concern for a chemical leaching from a component and interacting with a protein is high due to: i) possible instability of protein conformations, degradation, oxidation or aggregation; ii) the large size and extensive surface area with high frequency of interactive sites; iii) relatively high volumes and concentrations administered; and iii) the abundance of both hydrophilic and hydrophobic sites, which can be more efficient in solubilising leachables from device/manufacturing components1. Managing and mitigating the risk for device component leaching and interacting with a drug/biologic is contingent upon: •
Obtaining a systematic chemical characterisation of the individual critical components of the delivery system. Identifying the chemical species present in the components with potential to migrate and their transport properties in a given environment over the product lifecycle. Observing which chemicals in the component diffuse and migrate to the product contact surface and leach/solubilise or interact with excipients/active ingredients, shift pH, destabilise proteins, and/or form particles or other impurities. Detecting incompatibly of the components with the drug/biologic product due to migrating substances
impacting its physical/functional properties, degradation potential, surface absorptivity/adsorptivity. Realising the impact on patient safety and overall quality attributes of the drug/biologic product to enable preventative mitigation strategies.
Chemical entities that can be released from a pharmaceutical packaging/ delivery system, known as extractables, can be discovered under laboratory conditions2. The outcome of an extractable study will allow identification and quantification of potential leachables to guide development and validation of leachables methods. Data from extractables studies can be correlated to leachable data leading to control points as needed. Strategies for conducting controlled extractable studies to identify potential leachables with consideration of safety thresholds are described in detailed by the Product Quality Research Institute (PQRI) Leachable and Extractable Working Group; additionally United States Pharmacopeia Convention (USP) has recently published chapters on the subject.3,4 Extractable profiles will typically reveal a greater number of organic extractables compared to inorganic; however, it is not the number of extractables, rather the impact of leaching and the migrating species that can cause harm to the patient. Component processing, sterilisation, assembly, system configurations, age, storage and lot to lot variation will influence the outcome of the extractable profile. It is necessary to obtain knowledge of the final system to correlate extractables with leachables and assess impact to product quality and patient safety. Choosing materials that will not leach is not a practical goal; often leachables are detected, especially at low levels, over time. Qualification of leachables in a final product is dynamic and will depend upon certain elements, such as: ascertaining the critical components for assessment, the route of administration, dosage form/excipients, total daily intake of a leachable, toxicological end points, specific biologic Summer 2014 Volume 6 Issue 2
attributes and recognising appropriate limits for quality and safety. Comprehensive characterisation of component chemistry is accomplished using exaggerated solvents, but it is equally as important to consider the media unique to the biologic. Multiple and orthogonal analytical methods should be robust to detect potential leachables; however, target compounds of concern at the appropriate sensitivity for the delivery system are necessary in some cases. For example, proteins are particularly sensitive to metals, and significant interactions can occur between proteins and metal ions compromising product quality. Many protein-metal complexes have an important role in biological systems; the inadvertent contamination of biotherapeutics products with metal ions can have a critical impact on the stability of these products. Trace levels of metal ions can cause degradation via different mechanisms, such as protein oxidation, fragmentation, aggregation or the formation of insoluble particles.5,6 The stability of proteins in the presence of metals should be proven throughout the intended shelf-life. Examples of potential and actual metal leachables have been observed in final drug/biologic products and include: manganese, iron, zinc and barium, which can be present in glass formulations. These metals have been shown to leach and increase after steam sterilization.7,8 Visible particulates were formed when barium leached from glass vials and reacted with sulphate. Tungsten oxide is known to migrate from glass prefilled syringes from the needle insertion process, triggering protein aggregation9. Additionally, several recalls associated with glass lamella (flakes) have occurred. 10 Metals can be extracted from rubber and plastic formulations as well as glass, but organic extractable species are predominant in polymers. These substances arise from catalysts, curing agents, antioxidants, plasticisers, process aids, colourants, fillers and the degradation products of these compounds. The selection of appropriate components to have direct or indirect contact with biologics requires careful consideration built on knowledge of the material chemistry and assessment of risks for leachables to demonstrate systems suitable for use with biologic 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY
products and which are safe for delivery to the patient. Multicomponent systems will have unique extractable profiles for each component, yet the same extractable may be common to several components in the system; consequently, the worst case leachable profile will need to take into account accumulation of common substances. There are a multitude of components to be considered for extractables testing, and not all will have the same probability of migrating or severity of risk to the final product. The occurrence of a chemical species migrating from device components and/ or leaching into the biologic product requires knowledge of the component chemistry, as well as length/time of exposure to a contact media, the temperature, pressure, area of exposure and proximity of the component to the final product. Assessing the risk of device components interacting with biologics should begin early in the pharmaceutical development process and be grounded in the understanding of chemistry based on data from extraction studies. Product compatibility testing should be performed to assess the effects of container closure system materials and all leachables on product quality.11 Injectable Delivery Devices and the Regulatory Landscape Pharmaceutical delivery systems are regulated according to current good manufacturing practices (cGMP), but requirements vary depending on the application. The United States (US) regulatory provisions are intended to ensure that the drug, biologic or device is not adulterated, and the product possesses adequate strength, quality, identity and purity of a drug or biological product; compliance with performance standards is necessary for devices.12,13,14, The European Union (EU) legislation is supported by a series of guidelines (Eudralex) aimed at ensuring a high level of protection of public health and safety. The rules governing GMP for medicinal products can be found in Volume 4.15 Updates to cGMP in the US and EU address, specifically, quality aspects by managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.16,17 Specific requirements for container closure systems for finished pharmaceuticals verses devices are promulgated in US Code of Federal Regulation Title 21 (21 CFR).18 The United States Food and
Drug Administration (FDA) framework for manufacturing quality drug products is further outlined in guidance based on the International Conference on Harmonization (ICH) advocating Quality by Design (QbD).19,20,21 The US FDA Centers for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) enforce regulations for drugs and biologics while devices fall under the Center for Device and Radiological Health (CDRH). The regulatory pathway for a drug delivery device can fall into any of these centres or some combination thereof. While the mission of all three FDA centres is the protection of public health, the types of risk assessments for delivery devices depend upon the intended use. The Office of Combination Products (OCP) issues the classification of medical products and the jurisdiction is assigned to a lead centre based on the device primary mode of action (PMOA).22 Guidelines by the European Commission (EC) similarly regulate drugdelivery devices integral to medicinal substances.23 General approaches for qualifying injectable delivery systems for biologics can be ascertained from key guidance documents related to: i) technical considerations for injectors;24 ii) immunogenicity assessment for proteins;11 iii) submission information for container closure systems for drugs/ biologics25 and iv) ISO 10993 evaluation of medical devices.26 Supplemental guidance documents are incorporated by reference within these four key documents. There are many common elements in these recommendations, but the regulatory classification and intended use will guide the rationale for identifying critical components and the degree and type of assessment needed to establish suitability of delivery/device components. Primary Components of Injectable Delivery Devices Injectable delivery devices for parenteral products are designed to be used by healthcare practitioners and for patient self-administration. Injector devices span a wide range of applications that can be designed for single or multiple use, and can be disposable or reusable. The delivery systems are designed to meet a specific application based on the user needs that are defined by a quality target profile. Each individual component of the device contributes to Summer 2014 Volume 6 Issue 2
Sartorius Stedim Biotech Launches New Single-use Bag Family Flexsafe Sartorius Stedim Biotech, a leading global supplier of the biopharmaceutical industry, is introducing a brand-new, scalable range of single-use bags. Its completely new developed product family, Flexsafe, enables the implementation of singleuse bioprocessing throughout all steps of drug manufacture, from process development to production, both upstream and downstream – all using just the one innovative polyethylene film. The innovative concept of the Flexsafe family addresses key industry requirements for future-proof single-use manufacturing of commercial vaccines and drugs.
entire lifecycle of modern biological treatments from clinical development to commercial supply many years after launch. Users can gain assurance that their initial extractable and leachable qualification work and data remain valid every time they operate their single-use Flexsafe bioprocess. Assurance of supply, one of the most important aspects for manufacturers, is guaranteed as a result of long-term contracts with suppliers and business continuity plans with defined safety stocks and global manufacturing capabilities, including resin manufacturing. “Flexsafe represents a completely new generation of single-use bags. They offer our customers consistent cell growth as well as extraordinary robustness and flexibility. In addition, a sustainable supply chain and consistent film throughout the entire manufacturing process is guaranteed. Every single one of these benefits sets a new benchmark. Being unique in all of them makes us very proud,” stated Stefan Schlack, Senior Vice President Marketing and Product Management at Sartorius Stedim Biotech.
Flexsafe is based on a multilayer, proprietary polyethylene (PE) film, called S80, and has been developed in close collaboration with resin and film suppliers. A standardised cell growth assay has been used to optimise film formulation, to determine the operating ranges for extrusion, welding and gamma-irradiation processes, and to establish specifications and process controls. Flexsafe ensures excellent and reproducible cell growth behaviour of the most sensitive cell lines. The optimisation of the resin formulation, the complete control of raw materials, the extrusion process and the bag assembly guarantee lot-tolot consistent cell growth performance. With its robust 400μmthick PE film, Flexsafe is the strongest and most flexible bag currently on the market. The bags enable safe and easy-to-use operation, even in the most demanding applications such as liquid shipping and large-scale stirred bioreactors. Furthermore, batch-to-batch consistent extractables and leachables profiles support drug manufacturers throughout the
Sartorius Stedim Biotech is launching Flexsafe RM bags (1L-200L) and small bags for validation purposes first. Bags for single use bioreactors BIOSTAT STR (50-2000L) and additional applications such as storage, mixing, and shipping freeze and thaw will be rolled out step by step. A profile of Sartorius Stedim Biotech Sartorius Stedim Biotech is a leading provider of cuttingedge equipment and services for the development, quality assurance and production processes of the biopharmaceutical industry. Its integrated solutions covering fermentation, cell cultivation, filtration, purification, fluid management and lab technologies are supporting the biopharmaceutical industry around the world to develop and produce drugs safely, timeously and economically. Sartorius Stedim Biotech focuses on single-use technologies and value-added services to meet the rapidly changing technology requirements of the industry it serves. Strongly rooted in the scientific community and closely allied with customers and technology partners, the company is dedicated to its philosophy of “turning science into solutions.” Headquartered in Aubagne, France, Sartorius Stedim Biotech is listed on the Eurolist of Euronext Paris. With its own manufacturing and R&D sites in Europe, North America and Asia and a global network of sales companies, Sartorius Stedim Biotech enjoys a worldwide presence. Its key manufacturing and R&D site is in Germany. The company employs approx. 3300 people, and in 2013 earned sales revenue of 588.4 million euros. For more information visit www.sartorius.com
the overall performance and quality output. The primary components in direct contact with the finished biologic must be composed of compatible and stable materials. Components made from these materials must fit together to maintain an integral seal and should not adversely interact with final product. Optimising the interface of the primary container with the delivery system is another critical feature to enable an accurate dose with minimal discomfort. A typical parenteral delivery device uses either a prefilled syringe or cartridge system to contain and protect the final product until ready for use, which may be daily or a one-time acute treatment. The components of an injection system will have unique characteristics depending on performance expectations. Figure 1 is an example of primary components used in injectable delivery systems and their typical materials of construction. This table is illustrative and not intended to be all inclusive of current or future materials and components. The elastomeric plunger is a critical
Figure 1 Primary Components Used in Injectable Delivery Systems
component of the injection device that can be directly correlated to product administration and patient safety. The plunger within a prefilled syringe or cartridge serves as a primary seal for the container closure system and protects the final biologic product from contaminants that can adversely impact safety or stability during the respective shelf-life. The dimension of the plunger is a key input for achieving required quality attributes relevant to a positive patient outcome. Evidence of a desired dimensional design, with an integral seal between the barrel and plunger ribs, can be observed using finite element analysis (FEA) as shown in Figure 3. The potential for leachables can also be mitigated with lamination of the plunger (Figure 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY
2) product contact surface, and at the same time provide necessary lubricity to facilitate consistent glide force. The plunger has a major influence on the protection and delivery of biologics as there are several risks to identify and mitigate that are associated with the chemical, physical and functional Figure 2
attributes of an injectable delivery device27. The lined seal for cartridge systems functions similarly to that of the stopper-seal feature common to vials, which Figure 3 FEA of Rib also has the primary function Design of maintaining an integral container closure system and ensuring product quality. The lined seal is also in direct contact with the drug product; therefore a thorough assessment of chemical compatibility is required. The potential for leachables can also be mitigated with lamination of the lined seal product contact surface. Depending on the intended use of the biologic product and delivery device, the need for a multi-puncture compatible lined seal may be required. In this case, the rubber formulation re-sealability would be a critical attribute to assess during development. The critical quality attributes for a syringe barrel include chemical compatibility, strength and stability over the drug productâ€™s shelf-life. The materials of construction are an important consideration as this is the largest surface area of product contact. There are two distinct material options, plastic or glass, each with unique performance attributes. The surface chemistry of glass can change over time under certain conditions, which can lead to delamination (flaking) of the surface. Residual stress in glass can result
in microscopic cracks that can lead to fractures or breakage of the container. Dissolution of metal ions is another hazard for certain proteins. A biologic formulation will have a significant impact on the potential for chemical interaction and physical performance. Barrel materials such as cyclic olefin polymers can offer an alternative to risks associated with glass, but permeability can be a concern with certain grades of materials. The functional and chemical features of the barrel materials must be proven with respect to protein stability and delivery throughout the product lifecycle. The needle shield and tip cap for syringe systems are primary components to ensure an integral delivery system. These components protect the product and provide safety from inadvertent needle sticks. Depending on patient needs and dexterity, the needle shield pull-off force is a critical feature to optimise. To ensure ease of use and proper delivery, the force to remove the needle shield cannot exceed the forces that the patient can overcome comfortably. Factors such as the rubber formulation or the need for lubricity influence optimal pull-off forces. All primary components of a given delivery system have unique design inputs, but the properties are interrelated to the other components in the final system. The quality attributes of each individual component, once defined and controlled, will have a great influence on the delivery to the patient. Components to Enable Delivery Systems to Meet Needs of Patients Effective dosing and a positive patient experience are achieved through qualifying components of a delivery system for intended use. The patient and caregiver needs encompass a broad range of critical attributes and design features unique to each component. The overall dynamics of the primary packaging components within secondary delivery devices such as auto-injectors or electronic wearable injectors are a complex assembly of multiple components with discrete interactions. Examples of this are illustrated in Figure 4, namely a self-dose device, autoinjector, electronic wearable injector and prefilled syringe. The choice of container materials and designs for an injection device must consider multiple aspects related to Summer 2014 Volume 6 Issue 2
biologic compatibility with the material, filling, assembly, storage, shipping and patient administration. In the end, the patient outcome will be the measure of a successful treatment. The criticality of the primary components to the injectable device cannot be underestimated. It is beyond the scope of this article to convey all of the required design inputs and data to be acquired to identify critical attributes, process parameters and control points. Major component quality attributes are recognised in Table I relative to the final delivery device and patient need. The medical treatment can only be realised when the patient adheres to the dosing regime. This experience can be enhanced through proper design with quality materials used in delivery devices. The culmination of the user needs can, for a delivery system, be recognised immediately based on the injectability of the pharmaceutical product. Each component will need to show evidence of performance based on the various design inputs. Injectablity centres around the plunger performance within the delivery system. Features that impact the performance of the plunger within a delivery device include method of sterilisation, type of rubber formulation, type (and amount) of lubricious agent and age of the plunger. A critical design feature is for the Component Design Features
Consistent Dimensions Machinable Sterilisable Mechanical Strength Lubricous Biocompatibility Tight Tolerances Surface Compatibility Physical/Chemical Stability
plunger to glide consistently down the length of the barrel with ease. Parameters to consider will depend on such factors as viscosity of the drug product, force required to move the plunger, component materials of construction, design of the barrel and needle geometry. Viscosity of the drug formulation is a critical input for the force required for plunger breakloose force and the load required to sustain the movement of the plunger to expel the contents of the syringe or the dynamic glide force. Parameters of injectability include pressure or force required for injection, evenness of flow and freedom from clogging.28 Take, for example, risk for optimal breakloose and glide force on sterilisation methods and shelf-life stability. A breakloose and glide force study was conducted to evaluate functionality of plungers over time. A chlorobutyl 1mL long syringe plunger was sterilised by two different methods (steam autoclave and gamma irradiation) and tested at 0 and 12 months. The 12-month break-free glide force data as illustrated in Figure 5 showed the force nearly doubled for the gamma-sterilised plunger. Breakloose and glide force can be facilitated with increased levels of lubrication, but this may not be the best solution to this problem. Silicone, commonly used to lubricate plungers and glass syringe barrels, has been implicated
Final System Requirement Integral Fit Physically Stable Functional Through Shelf-Life Fill-Finish Compatible Withstand Extreme Environments Resist Breakage/ Damage Optimal Breakloose/Glide Force Ease of Needle Shield Pull Force Verified Injection Force/Depth Minimized Particles, Drug/Biologic Adsorption and Instability Non- Toxic: Control Potential Leachables
Patient Adherence Convenient Patient Compliance Container Closure Integrity Ease of Use Accurate Dosing Minimal Steps Steady Injection Reliable Safe
Table I Component Quality Attributes and Impact to Patient
Figure 5 Breakfree (breakloose) and Glide Force Data
in the induction of protein aggregation.29 Risks posed by silicone can be mitigated by using the right combination of components. In cases where proteins are highly sensitivity to silicone, cyclic olefin polymers coupled with a fluoropolymerlaminated plunger can be an alternative to applying high levels of silicone for optimal delivery. Stability of proteins in primary containers over the productâ€™s shelf-life is a concern, due to potential incompatibility of these types of molecules with various contact surfaces and potential interactions with leachables. Prolonged exposure of these leachables can also increase the potential for various forms of protein degradation, including conformational changes, reduced activity and increased immunogenicity30. The choice of primary components for a delivery system will depend on the fit, performance, compatibility with the specific biologic and conditions of use. The functional and chemical features of the syringe components must be proven with respect to protein stability and delivery throughout the product lifecycle. The output of the final design should meet patient requirements to allow safe and effective administration of biologics to the patient throughout the expiry period. Conclusion The components and materials used in systems to contain and deliver biologics can impact the final biologic product and ultimately affect patient outcome. The ability to deliver biologics effectively relies on proper quality and selection of individual components comprising the delivery devices. Each component poses various benefits and risks to balance for each specific application. It is advisable to conduct relevant studies for compatibility and functionality during development and over time for all primary components. A great deal of uncertainty may exist around the final dosage form and its manufacturing processes early in development, but appropriate control INTERNATIONAL PHARMACEUTICAL INDUSTRY 97
strategies can mitigate or eliminate calculated risks. Optimal delivery systems can only be achieved by acquiring timely and appropriate scientific evidence to verify the quality target product profile. This is consistent with regulatory recommendations for QbD approaches to enable delivery system suitability, efficiency and control of manufacturing processes. Holistic assessments of primary components for prospective prefilled syringe and cartridge systems for device applications are practical and vital for building quality into biopharmaceutical products and investing in a positive patient outcome. References 1. Ingrid Markovic, Ph.D. Expert Review Scientist, PQRI Workshop on Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products (PODP), Bethesda, MD, February 2011, www. pqri.org. 2. U.S. Pharmacopeia Convention (USP), <1663> Extractables Associated with Pharmaceutical Packaging Systems,PF 39 (5) Sept-Oct. 2013 www.usp.org. 3. Product Quality Research Institute (PQRI), Leachables and Extractables Working Group. Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products. Product Quality Research Institute: Arlington, VA, 2006. 4. U.S. Pharmacopeia Convention (USP), <1664> Leachables Associated with Pharmaceutical Packaging Systems,PF 39 (5) Sept-Oct. 2013, www.usp.org. 5. Markovic, I., “Challenges associated with extractables and/or leachables substances in therapeutic biologic protein products.” American Pharmaceutical Review, 2006. 9(6): p. 20-27. 6. Shuxia Zhou Lavinia Lewis, Ph.D.; Satish K. Singh, Ph.D., “Metal Leachables in Therapeutic Biologic Products: Origin, Impact and Detection,” American Pharmaceutical Review, May 01, 2010. 7. Fliszar, K.A.; Walker, D.; Allain, L., “Profiling of metals ions leached from pharmaceutical packaging materials.” PDA J Pharm Sci Technol. 60(6): 337 – 342 (2006). 8. Bohrer, D.; Cicero do Nascimento, P.; Binotto, R.; Becker, E., “Influence of the glass packing on the contamination of pharmaceutical products by aluminum. Part III. Interaction container-chemicals during the heating for sterilization.” J. Trace Elem Med Biol. 17(2): 107-115 (2003). 9. Liu, W.; Swift, R.; Torraca, G.; NashedSamuel, Y.; Wen, Z.-Q.; Jiang, Y.; Vance, A.; Mire-Sluis, A.; Freund, E.; Davis, J.; Narhi, L., “Root Cause Analysis of Tungsten-Induced Protein Aggregation in Pre-filled Syringes.” PDA J. Pharm. Sci. Technol. 2010, 64 (1), 11-19. 98 INTERNATIONAL PHARMACEUTICAL INDUSTRY
10. U.S. Department of Health and Human Services, Food and Drug Administration, American Regent Initiates Voluntary Nationwide Recall of Calcium Gluconate Injection, USP, 10%, 100 mL Pharmacy Bulk Package Due to Particulates, July 18, 2011, http://www.fda.gov/Safety/ Recalls/ucm263531.htm, 11. U.S. Department of Health and Human Services, Food and Drug Administration, Guidance for Industry Immunogenicity Assessment for Therapeutic Protein Products, CDER, CBER, February 2013, www.fda.gov. 12. U.S. Code of Federal Regulation Title 21 (CFR 21) Food and Drug Administration Part 210 & 211 GMP Subchapter C-drugs: general www.gpo.gov. 13. U.S. Code of Federal Regulation Title 21 (CFR 21) Food and Drug Administration Part 600, Biological Products General, www.gpo.gov. 14. U.S. Code of Federal Regulation Title 21 (CFR 21) Food and Drug Administration Part 820 Quality System Regulations, www.gpo.gov. 15. European Commission, EU Legislation, EudraLex - Volume 4 Good manufacturing practice (GMP) Guidelines; http:// ec.europa.eu/health/documents/ eudralex/index_en.htm 16. Arnold & Porter LLP, A reference guide to Food and Drug Administration Safety and Innovation Act Enhancing the Safety and Quality of the Drug Supply Chain (FDASIA §711), July 2012, www. arnoldporter.com. 17. European Commission Health and Consumers Directorate- Draft General, Medicinal Products – Quality, Safety And Efficacy Brussels, 6 February 2014, http://ec.europa.eu/h ealth/files/ gmp/2014-02_pc_draft_gmp_annex. pdf, 18. U.S. Code of Federal Regulation Title 21 (CFR 21) Food and Drug Administration Part 211.94 – container/closures for finished drug products, www.gpo.gov. 19. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), Pharmaceutical Development Q8(R2) 2009 www.ich.org. 20. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Quality Risk Management Q9, 2005, www.ich.org. 21. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Pharmaceutical Quality System Q10, 2008, www.ich.org. 22. U.S. Code of Federal Regulation Title 21 (CFR 21) Food and Drug Administration, Part 3 Product Jurisdiction, www.gpo.gov 23. European Commission DG Enterprise and Industry; Borderline products, drugdelivery products and medical devices incorporating, as an integral part, an ancillary medicinal substance or an ancillary human blood derivative; http://
ec.europa.eu/health/medical-devices/ files/meddev/213_rev_3-12_2009_ en.pdf U.S. Department of Health and Human Services, Food and Drug Administration, Guidance for Industry, Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with, Drugs and Biological Products, 2009, www.fda.gov. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER). Guidance for Industry - Container Closure Systems for Packaging Human Drugs and Biologics, 1999, www.fda.gov. International Organization for Standardization, ISO 10993 - Biological Evaluation of Medical Devices Package, www.iso.org. DeGrazio F., PDA Container Closure Components and Systems Workshop, Assuring Drug Product Quality and Patient Safety Through the Application of QbD, Bethesda, Maryland, 2013. Francesco Cilurzo, et al., Injectability Evaluation: An Open Issue, AAPS PharmSciTech. 2011 June; (Published online 2011 May 7). Sel Jones L.S.; Kaufmann A.; Middaugh C.R., “Silicone oil induced aggregation of proteins.” J Pharm Sci. 2005 Apr;94(4):918-27. Advait Badkar, “Development of Biotechnology Products in Pre-filled Syringes: Technical Considerations and Approaches,” AAPS Pharm SciTech. Jun 2011; 12(2): 564–572. Published online May 4, 2011
All photos courtesy of West Pharmaceutical Services, Inc. unless otherwise noted.
Ms. Diane Paskiet, Director, Scientific Affairs at West Pharmaceutical Services, Inc. has more than 20 years of experience in polymer analysis relating to product failures, deformualtion and migration studies. Currently, Ms. Paskiet is serving a fiveyear term on the United States Pharmacopeia (USP) Packaging, Storage and Distribution Expert Committee and is Chair of the PQRI Parenteral and Ophthalmic Drug Product (PODP) Leachables and Extractables Working Group. She has authored national and international papers on the subject of leachables and extractables and is a faculty member of the PDA Training Institute. Email: firstname.lastname@example.org Support author: Simon Côté Senior Technical Support Engineer, Global R&D and TCS.
Summer 2014 Volume 6 Issue 2
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Summer 2014 Volume 6 Issue 2
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