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Volume 7 Issue 3

Peer Reviewed International Pharmaceutical Industry

Supporting the industry through communication

Thinking Digital Managing Compliance in the Connected Landscape Delivering Patient-Centric Support Services in Clinical Trials Better Ways to Handle Tablets Using IBCs The Evolution of Temperature-Controlled Transport How Innovation Overcomes the Biggest Challenges in Cold Chain Supply

Contents 06 Editor’s Letter REGULATORY & MARKETPLACE

International Pharmaceutical Industry

Supporting the industry through communication

DIRECTORS: Martin Wright Mark A. Barker EDITOR: Orsolya Balogh EDITORIAL ASSISTANT Frances Lee BOOK MANAGER: Anthony Stewart BUSINESS DEVELOPMENT: John Sympson DESIGN DIRECTOR: Fiona Cleland CIRCULATION MANAGER: Dorothy Brooks FINANCE DEPARTMENT: Martin Wright RESEARCH & CIRCULATION: Heather Bayran 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: 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 Winter 2015. 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. 2015 PHARMA PUBLICATIONS Volume 7 issue 3 - Autumn- 2015

08 Thinking Digital: Managing Compliance in the Connected Landscape Digital media dominates in the life sciences marketing arena. Today, traditional analogue promotional tactics are increasingly being displaced by new, dynamic and constantly evolving digital strategies. The shift has been driven by the mobilisation of technology and the rise of the internet, creating an increasingly ‘digitally native’ generation that is connected at all times by mobile and social platforms. David Bennett of Zinc Ahead explains how digital media supports life sciences. 12 Entering the Homestretch for ICD-10 Transition ICD-10 is the largest mandate in US healthcare history. It will require diligent, comprehensive actions to be fully prepared for the transition. Practices have until October 1 to successfully upload, test and implement ICD-10 codes, which will replace the ICD-9 code set. Whether healthcare firms are ready or not, the US government’s upcoming deadline stands firm. Hospitals and physician practices have been discussing ICD-10 for many years. Jeffrey Goldstein of Allscripts shares his thoughts on ICD-10 transition. 16 Sifting Through the Sourcing Options Outsourcing is now a widely accepted practice in the life sciences industry. However, choosing precisely which activities to entrust to an external supplier remains challenging. The standard methodologies are two-dimensional; therefore, they fail to address some key considerations. Here we present a new methodology that refines previous approaches and provides a rigorous framework for making such decisions. Dr Subrata K Bose of Kinpase deals with outsourcing in the life sciences industry. DRUG DISCOVERY, DEVELOPMENT & DELIVERY 26 Alzheimer’s Disease – Breakthrough Due Soon? Over recent weeks we seem to be waking up to news headlines suggesting the cure for Alzheimer’s disease (AD) is imminent. Why is there so much buzz about a cure for AD? How close is a cure? And just why has it been so difficult to see progress in AD treatments? This article by Susan McGoldrick of QCTR reviews the recent headline-grabbing news in AD clinical trials and looks at the results we can expect in the next couple of years. 32 Drug Metabolite Synthesis with Human Enzymes: How Can We Utilise Microbes to Make Authentic Human Metabolites? The characterisation of the metabolic fate of a new drug molecule is essential in the course of the drug discovery and development process. As a consequence, potential human drug metabolites must be available in amounts of at least a few milligrams of pure compound. Metabolite preparation can become a significant time and cost factor, if elaborate multi-step chemical syntheses become necessary. Dr techn. Margit Winkler at ACIB, Austrian Centre of Industrial Biotechnology, answers this question: how can we utilise microbes to make authentic human metabolites? CLINICAL RESEARCH 38 Comparator Sourcing – An Analytical Approach to Find Best Suited Sourcing Strategies Sourcing comparator drugs for clinical trials is a complex process, especially for branded drugs, and in many cases the selection process to find the best sourcing partner falls short of expectations. An analysis has shown that around 30-55% of comparator drugs are left unused at the end of the trial. This is due to issues such as disruptions in the supply chain, unexpected delays, incomplete paperwork, stock-out situations and regulatory hurdles. Mark Walls at Verastem Inc., Rahul Sodhi of Beroe Inc. and Dr Mihai Bragaru of Durbin PLC reflect on comparator sourcing. INTERNATIONAL PHARMACEUTICAL INDUSTRY 1


44 Delivering Patient-centric Support Services in Clinical Trials While patient safety is paramount in clinical trials, there are a number of additional key patient concerns, including recruitment, engagement, retention and compliance. Patients also require significant support throughout a trial for scheduling visits, visit/ medication reminders, completing diaries/questionnaires, emergency medical enquiries, technical device enquiries and simply questions related to their involvement in the trial. Julia Lakeland at PAREXEL shares her thoughts on patient-centric support services in clinical trials. 48 Orphan Drug Trials: Putting the Patient First Over recent years, there has been a notable increase in the number of orphan drugs being successfully brought to market. Here, Jennifer Peters of Greenphire speaks to International Pharmaceutical Industry about the orphan drugs market, the unique logistical challenges faced by organisations when conducting clinical trials for this type of drug, and how addressing payment processes and financial management strategies can overcome them. LABS 52 Rapid and Traditional Methods in the Contract Microbiology Laboratory In the world of contract testing, we are bound by regulatory guidelines and high client expectations. We perform the necessary safety and performance testing of pharmaceutical and medical device products that will be used by the general public. It is therefore vital that we work to prescribed guidelines, with our performance under constant review through audits by regulatory bodies and our clients. Lynne Murdoch at Wickham Laboratories Limited explains rapid and traditional methods in the contract microbiology laboratory. 58 Contact Killing on Copper Surfaces: From Lab to Application As evidence grows for the key role of the environment in the spread of infection, the selection of materials for hygiene-sensitive environments is moving up the agenda, and copper is leading the way with unmatched efficacy against headline-making pathogens. This article provides an update on the expanding evidence base – from laboratory experiments to clinical trials – and illustrates the growing adoption in healthcare and other sectors. Angela Vessey, of Copper Development Association, guides us from the laboratory to application, focusing on the usage of copper. LOGISTICS AND SUPPLY CHAIN 64 Healthcare’s Fountain of Youth The medical revolution is creating the prospect of much longer – and healthier – lives. But achieving the full benefits requires better logistics. Undeniably, aging populations, chronic diseases and ongoing constraints on public finances are presenting significant challenges to healthcare systems in Europe. Daniel Gagnon of UPS focuses on healthcare.

66 The Evolution of Temperature-Controlled Transport How Innovation Overcomes the Biggest Challenges in Cold Chain Supply Not all of the products you need to ship are created equal — and neither is their packaging. Today’s customers require precise processes and innovative tools capable of moving their shipments around the world within an increasingly narrow temperature range. Sue Lee at World Courier discusses the evolution of temperaturecontrolled transport.


Autumn 2015 Volume 7 Issue 3


Let‘s enter the future of aseptic filling. By protecting pharma vials securely in a nest during fill & finish as well as lyophilization, we enable pharma companies to achieve maximum flexibility and efficiency. What‘s your next milestone?

SCHOTT AG, Pharmaceutical Systems,

Contents MANUFACTURING 72 Pharmacopoeial Comparison of In-process & Finished Product Quality Control Tests for Parenterals: IP, BP & USP The present study deals with a brief overview of the comparative study of quality requirements for in-process and finished products quality control tests of the Indian Pharmacopeia (IP), British Pharmacopeia (BP) and United States Pharmacopeia (USP) for some conventional dosage forms. The concept of total quality control test refers to the process of striving to produce a quality product by a series of measures, requiring an organised effort in order to eliminate errors at every stage in the production. Shilpi Khattri, Balamuralidhara V. and T.M. Pramod Kumar, of JSS College of Pharmacy, explain. 84 Better Ways to Handle Tablets Using IBCs It is common to find intermediate bulk containers (IBCs) being used for handling powders and granules in solid dosage manufacturing processes, from initial dispensing through to tablet compression or capsule filling. The benefits of using IBCs for efficient and flexible materials handling at this stage of the process are widely appreciated and applied in modern facilities. Shaun Baker at Matcon Limited reflects on better ways to handle tablets using IBCs 90 Tooling Design – How Tooling Options Can Benefit Different Types of Pharmaceutical Formulations during Tablet Compression It can be a labour of love to get a tablet to market. With time and monetary investments made throughout the process from research to development and scale-up, one of the most challenging steps in the process can be the actual manufacture of the product. Issues range from tablet quality to equipment malfunction – all of which can result in downtime and delayed market deployment. Kevin Queensen and Bill Turner at Natoli explain how tooling options can benefit different types of pharmaceutical formulations during tablet compression.

114 Get It Right the First Time Tips on Maximising Efficiency in Blister Packaging Development For technical products across many industries, small details are often modified without customers perceiving significant visual or functional changes. Manufacturers of such products or devices implement these changes to save costs, simplify the manufacturing processes, or make a product more reliable. Typically, these alterations are relatively simple to introduce as there are no regulatory restrictions on them; so long as customers are still happy, no feathers are ruffled. Thomas Schwarz at Constantia Flexibles gives us insight to blister packaging development.

96 Automated Efficiency Making Pharmaceuticals More Energy-efficient with Industrial Automation Iconic imagery of smoke-bellowing chimneys silhouetted against illuminated skies is a traditional way of illustrating the Industrial Revolution as an idyllic era of industrial pride. Back then, health and safety were non-existent and ‘climate change’ meant nothing more than the changing of the seasons. This industrial era brought a lot of change – not only did it mark a turning point for global industry, but also meant the beginning of a dramatic change in the way humans impact the environment. Jonathan Wilkins of European Automation discusses automated efficiency.

118 Sterile, High-quality Components for Increased Patient Safety Quality-wise, the main focus in pharmaceutical manufacturing has been primarily on the drug product and its primary container. Many pharmaceutical and packaging manufacturers have placed emphasis on those materials in direct contact with the drug product itself, such as the glass vial, plastic syringe and elastomeric stopper or plunger. Additional packaging elements, such as caps and seals, have not been the primary focus. However, in recent years, regulatory guidelines have influenced the requirements for crimping processes significantly. Sylvia Marzotko at West Pharmaceutical Services, Inc. reports on the production of sterile, high-quality components for increased patient safety.


122 How to Tackle Counterfeiting; A Global Public Health Issue Today, counterfeit products can be found in every country and every sector of the global economy. According to international organisations like the World Health Organisation, counterfeiting concerns between 5% and 9% of global trade and approximately 10% of the global pharmaceutical market. It is estimated that 50% of drugs available on the internet are counterfeit, while this figure can reach up to 70% in some African or Eastern European countries. Ian Lemon of Essentra answers the question of how to tackle counterfeiting.

102 Packaging: Protecting Your Contents Biologic products such as vaccines and active pharmaceutical ingredients (APIs) are sensitive to potential contamination at multiple stages of the manufacturing process. Therefore, ensuring that the packaging or container conforms to the highest industry standards is of the utmost importance. Kacey Wiley Pouliot of Thermo Fisher Scientific shares her thoughts on packaging. 108 Where are Pharmaceutical Anti-counterfeiting Technologies Headed? Interpol estimates the annual turnover from pharmaceutical crime as USD 75 billion worldwide. In the US alone, the number of IPR-related seizures in the pharmaceutical and personal care industries amounts to USD 72,939,399 or 6% of the market share for FY2014. Improvements in technology, however, have allowed government officials, brand owners and experts in the field to curb this alarming trend. Within this editorial, Dr Fred Jordan of AlpVision answers the question; where are pharmaceutical anticounterfeiting technologies headed?


124 Nested Vials for Improved Lyophilisation Efficiency Lyophilisation vials are normally washed and sterilised prior to processing and filling, which requires the use of cleanrooms, washing machines and sterilisation tunnels — depending on the level of containment needed — to perform these tasks. However, to improve efficiency and to reduce time and costs, pre-washed and sterilised ready-to-use packaging materials may offer a solution and improve the overall process. Johannes Selch of ALUS, GEA, in collaboration with Gregor Deutschle of SCHOTT Pharmaceutical Packaging, discusses nested vials for improved lyophilisation efficiency.

Autumn 2015 Volume 7 Issue 3





Editor's Letter The global pharmaceuticals market is worth US$300 billion a year, a figure expected to rise to US$400 billion within three years. The 10 largest drugs companies control over onethird of this market, several with sales of more than US$10 billion a year and profit margins of about 30%. Six are based in the United States and four in Europe. It is predicted that North and South America, Europe and Japan will continue to account for a full 85% of the global pharmaceuticals market well into the 21st century. Companies currently spend one-third of all sales revenue on marketing their products - roughly twice what they spend on research and development. Digital media dominates in the life sciences marketing arena. Today, traditional analogue promotional tactics are increasingly being displaced by new, dynamic and constantly evolving digital strategies. The shift has been driven by the mobilisation of technology and the rise of the internet, creating an increasingly ‘digitally native’ generation that is connected at all times by mobile and social platforms. David Bennett at Zinc explains how digital media supports life sciences.

An intermediate bulk container (IBC) is a large vessel that is used to store fluid and bulk materials or transport them. IBCs can be manufactured from many different materials, such as stainless steel, aluminium, mild steel, and exotic alloys. It is common to find IBCs being used for handling powders and granules in solid dosage manufacturing processes, from initial dispensing through to tablet compression or capsule filling. The benefits of using IBCs for efficient and flexible materials handling at this stage of the process are widely appreciated and applied in modern facilities. Shaun Baker at Matcon Limited reflects on better ways to handle tablets using IBCs. Whenever someone interacts with health services, they should always be treated with dignity, respect and compassion. These ‘experience standards’ are basic human rights that are enshrined in the NHS Constitution. Because we are all different, person-centred care is care that is tailored to the needs and aspirations of each individual, not standardised to their condition. While patient safety is paramount in clinical trials, there are a number of additional key patient concerns, including recruitment, engagement, retention and compliance. Patients also require significant support throughout a trial for scheduling visits, visit/medication reminders, completing diaries/questionnaires, emergency medical enquiries, technical device enquiries and simply questions related to their involvement in the trial. Julia Lakeland at Parexel shares

her thoughts on patient-centric support services in clinical trials. Temperature-controlled packaging is the latest design in packaging. This is essential when dealing with 'cold chain shipping' for companies who deal with perishable and temperature-sensitive product. Not all of the products you need to ship are created equal — and neither is their packaging. Today’s customers require precise processes and innovative tools capable of moving their shipments around the world within an increasingly narrow temperature range. Sue Lee at World Courier submits a white paper on the evolution of temperature-controlled transport. IPI welcomes CPHI/ICSE attendees in Madrid! Please visit our booth, 3A64, and meet our team!

Editorial Advisory Board Bakhyt Sarymsakova, Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

Jagdish Unni Vice President- Beroe Risk and Industry Delivery Lead- Healthcare, Beroe Inc.

Catherine Lund, Vice Chairman, OnQ Consulting

Jeffrey Litwin, M.D., F.A.C.C. Executive Vice President and Chief Medical Officer of ERT

Deborah A. Komlos, Senior Medical & Regulatory Writer, Thomson Reuters Diana L. Anderson, Ph.D president and CEO of D. Anderson & Company Franz Buchholzer, Director Regulatory Operations worldwide, PharmaNet development Group Francis Crawley. Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organization (WHO) Expert in ethics 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

Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma Jim James DeSantihas, Chief Executive Officer, PharmaVigilant Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation Maha Al-Farhan, Vice President, ClinArt International, Chair of the GCC Chapter of the ACRP Nermeen Varawalla, President & CEO, ECCRO – The Pan Emerging Country Contract Research Organisation

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmac 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

Autumn 2015 Volume 7 Issue 3

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Regulatory & Marketplace

Thinking Digital: Managing Compliance in the Connected Landscape Digital media dominates in the life sciences marketing arena. Today, traditional analogue promotional tactics are increasingly being displaced by new, dynamic and constantly evolving digital strategies. The shift has been driven by the mobilisation of technology and the rise of the internet, creating an increasingly ‘digitally native’ generation that is connected at all times by mobile and social platforms. The open availability of data on the internet, and the increase of patient dialogue on social media channels, have changed the way the public engages with the medical world around them, while driving expectations in the way the pharmaceutical industry must respond and deliver their communications to the world. Today, the patient demands more interactive, twoway dialogue with life science companies about the efficacy, heredity and quality of their products. The Industry Challenge This has led to a series of step changes in pharmaceutical marketing. First, as the marketplace has changed, companies must now seek to engage more fully and directly with the patient on digital channels; creating a wave of new challenges in managing effective, purposeful and above all strategic content marketing and outreach programmes. Additionally, managing compliance in this setting has become increasingly complex. The cadence of messaging has accelerated dramatically and the digital supply chain now also incorporates a wealth of relatively expensive rich media and multi-platform assets that must nevertheless continue to meet appropriate regulatory guidelines if they are to adhere to industry standards. Finally, the explosion in digital marketing is also coupled with an increased preference for international brand alignment and cost savings achieved through re-use. This has led to an increase in globalisation of campaigns, where marketing assets are now being shared, distributed and re-purposed widely across international locations, each with their own regulatory backdrop that may 8 INTERNATIONAL PHARMACEUTICAL INDUSTRY

ultimately change the legal requirements of the asset. The regulatory backdrop that influences the global life sciences environment continues to be necessarily stringent and complex, as governing bodies around the world work to ensure promotional content and claims distributed via digital platforms, such as websites, social media and apps, are subject to the appropriate local scrutiny and control. Recent industry figures have shown that a majority of marketing executives recognise that digital outreach to customers is a top-ten company priority. As such, the market challenge has moved on, and marketing materials and content now require a very different management process than they did ten years ago. Marketing and commercial professionals need to ingrain new tools and processes into their business model to meet this head on. Companies must seek to fully align digital and social marketing with their global business goals, and ensure that accelerated compliance capabilities are embedded at the heart of digital customer engagement and outreach programmes from the outset. By doing so, companies can manage to seamlessly integrate digital asset management into their workflows. This will, in turn, deliver significant ROI as the embedded time and resources invested in the development and approval of digital content will be significantly reduced. To realise the cost savings that effective digital asset management (DAM) can deliver, companies must first understand the digital supply chain fully. Ultimately, the principles of good digital asset management and librarianship need to be fully embraced to help deliver effective and timely marketing tactics that are not only engaging and creative, but also fully compliant. The Digital Supply Chain The digital supply chain encompasses multiple touch-points and includes all of the stakeholders and departments

involved with the creation, sharing and approval of digital content. It is important to remember that all departments that ‘touch’ a digital asset, at any stage in its lifecycle, will impact its potential time to market. Therefore, these departments will be an integral part of the digital asset management workflows from the onset of project delivery. This way all members will be unified and working towards an agreed set of objectives. The digital supply chain in a pharmamarketing setting is made up of the following: Marketers: The core delivery engine; marketers drive the project and act as a central information resource for other departments. Marketers will be the ones to set benchmarks for review and approval timeframes, and deliver all reporting and sharing. Commercial managers: Commercial managers act as facilitators and gatekeepers for any digital assets available for distribution, re-use and repurposing. Medical, legal and regulatory (MLR) team: Responsible for gold standard compliance review, ensuring all promotional assets meet the guidelines of the country and market intended for distribution. The MLR team will have the most input at review and approval, and their buy-in to digital asset management workflows is essential if processes are to remain smooth and efficient. Agency partners: Responsible for creative and design concepts that are completed following the briefing stage. It is useful for life science companies to work closely with their agency partners to ensure that compliance objectives are outlined clearly at the concept creation stage to ensure quality from the outset. Enabling a productive collaborative environment which effectively embraces and adds value to all of these functions Autumn 2015 Volume 7 Issue 3

Chapter Advertorial Title

Diamond Pharma Services has provided regulatory affairs and product development services to a diverse range of clients worldwide since 2005. The company takes pride in offering bespoke services to meet the needs of clients; from academics establishing start-up biotech companies to top 5 global pharmaceutical companies. The company was founded by Dr Maureen Graham, with the aim of providing an innovative and dedicated service to overcome the challenges faced by clients in their product development, and regulatory authority interactions at all stages of product lifecycle. A consultancy offering expertise in all areas from advanced therapies to generics is unique, with previous case studies proving the successful business model can provide the ideal outsourced solution within the areas of expertise. Quotes received from clients previously supported by Diamond: “The Diamond team provides a diligent and efficient outsourced regulatory affairs department.” “The support provided offers the perfect mix of strategic regulatory thinking and operational excellence that has enabled us to move our corporate regulatory function forward.” “Diamond came on board at a time of critical importance as we were gearing up towards the MAA submission and then continued to provide the guidance and support required to see us through to approval in Europe.” The support Diamond can offer culminated with recognition by the Organisation for Professionals in Regulatory Affairs in 2013, when Diamond BioPharm Ltd – the EU regulatory affairs division of Diamond Pharma Services - won the award for Innovation in Regulatory Affairs.

This October, Diamond BioPharm Ltd celebrates its 10th anniversary. Dr Maureen Graham, Managing Director, Diamond BioPharm Ltd, explains: “Over the course of the last 10 years, a number of challenges have presented themselves to the pharmaceutical and biotech industry. Diamond Pharma Services has sought to overcome these for our clients in order to ensure regulatory challenges and changes are met with innovation and compliance. Our team are able to draw on a wealth of experience and we continue to look to provide services that offer maximum value to our clients in the most efficient and cost-effective manner.” Diamond constantly strives to provide the services that companies are looking for. The recent regulatory affairs and product development support expansion into the USA has enabled cohesive interactions with regulatory authorities in the EU and USA, and has enabled Diamond clients to take forward a programme in one or both regions seamlessly. The incorporation of Diamond BioPharm’s subsidiary company, Diamond Pharma Services, Inc, as well as the hiring of Dr Nancy Markovitz (ex-FDA, Office of Cellular, Tissue and Gene Therapy) as Director, Regulatory Affairs has enabled Diamond to support global development programmes. Take-up for the service is proving highly successful for companies embarking on clinical development, particularly in the gene and cell therapy arena.

molecule and generic products, and he joins Diamond from his previous role as Director of European Quality Assurance at Glenmark Pharmaceuticals. For more information on these exciting new offerings and the existing services provided by the Diamond Pharma Services group, please visit our website, About Diamond Pharma Services Diamond Pharma Services is a leading technical and scientific consulting group of companies serving the biotechnology and pharmaceutical industry. Our emphasis is on the following areas: • • • •

Regulatory Affairs: From product concept to registration and beyond Product Development: Nonclinical, CMC and clinical aspects Pharmacovigilance: Clinical trial (Phase I-IV), post-marketing and QPPV services Compliance & Quality: GxP and QP services throughout the product lifecycle, from concept to market and beyond

Contact Lena Demetre Senior Business Development Manager E: ldemetre@diamondpharmaserivices. com T: +44 (0)7876 664543

More recently, Diamond Pharma Services group has re-launched its quality assurance provision with Diamond Compliance and Quality Limited. Following the retirement of the previous Managing Director, Diamond are pleased to confirm the appointment of Dr David Crome as Managing Director and Qualified Person. The relaunched company will enable a further period of growth and extension to the existing team. David brings over 35 years’ experience in innovative small INTERNATIONAL PHARMACEUTICAL INDUSTRY 9

Regulatory & Marketplace is central to effective acceleration of costeffective tactics and, most importantly, compliant materials. Managing Digital Assets in a Multichannel World Global life science companies have a tremendous opportunity to achieve more targeted brand alignment in such a collaborative environment by fully integrating a true digital asset management into their marketing workflows. This can be swiftly accomplished by using modern cloudbased software platforms, combined with specialised industry expertise in managing the compliant digital supply chain from creator to consumer. The typical objectives and outcomes from a structured digital supply chain project are:

A true DAM solution not only speeds up deployment to market by reducing iterations of review and approval, but will also facilitate dynamic content review of rich media video content by allowing reviewers to add commentary directly into the production suite, identifying precise timings where cuts or edits are needed. In this way a video-enhanced DAM can support a wide range of formats, helping MLR and production teams to quickly identify and agree on edits to video content in a ‘live’ manner. As a single source of truth, the DAM can also provide a quick shopping interface for assets for global affiliates to get a fast start on localised programmes whilst protecting and providing for appropriate intellectual and digital rights management. Finally the ROI is driven significantly by the reuse and re-purposing of content versus the need to generate brand new tactics.

1. A reduction in the overhead costs associated with the development and adaption of marketing tactics. This is important as marginal gains in cost savings at all stage of the digital supply chain will soon leverage significant ROI for the operating company. 2. An established and unified end-toend asset management ecosystem to manage and consolidate all assets across the supply chain. 3. High efficiency, quality and compliance in the development, approval, management and support of digital assets. 4. A decrease in the time and effort required for content to be approved, published and re-purposed through an approved operating model. 5. A collaborative environment where operations can enable and support the transformation of brand tactics into content that can be shared across multiple channels and markets.

Using Benchmarking for Measured Improvement Impact analysis of campaigns is a key driver for re-purposing and reuse of assets. KPIs and metrics can be monitored over time, so the marketing and commercial organisations can measure impact and respond in a timely fashion at digital speed.

A focus on these goals will guide the use of any software tools while ensuring the benefits for individual functions are holistic and implemented to support the total delivery of the asset.

Software solutions designed to meet the exact challenges as outlined above can assist the task force by providing secure access to assets at any stage of their development with clear and consistent methods for overseeing their review and approval. 10 INTERNATIONAL PHARMACEUTICAL INDUSTRY

This is where the Zinc MAPS Reporting Suite offers excellent value to a delivery task force. The enhanced reporting flexibility offered through this system will enable collaborators to: • • • • •

Pin commentary to a dashboard, and share with other users Expose all data metrics to be utilised in reporting Design reports that can be scheduled to run automatically and be emailed out by the system Filter standard reports Enable all users to build custom reports using any metrics Manage the audit trail through print, social and internet channels

In this way companies can seek not only to reduce cycle time, but also reduce the number of cycles that assets undergo before delivery to market and measure the percentage of sharing, from region to region, and across departments, re-purposing content where possible, ultimately making savings when volume of sharing is higher.

Digital is Now The relevance of digital marketing is only set to grow as companies across the globe are increasingly using digital media and social channels to engage with their audiences. It is clear that companies need to ensure they make big gains in their use of digital positioning to maximise their outreach and engagement programmes by delivering material consistently across multiple channels while making more personalised and targeted offers available online. As global regulatory bodies continue to tighten up their governance of the pharmaceutical marketing landscape, it is crucial for life science companies to invest now in their digital workflows so that fully complaint materials can be delivered on time and on budget. The only realistic solution to managing this effectively is to deploy a specialised industry digital supply chain solution that delivers effective and streamlined processes, leading to high quality digital content that is secure yet fully available to be re-purposed across the globe in a safe and compliant fashion. The added value of investing in a specialised solution will be the inclusion of targeted benchmarking and metrics. This will drive a more informed analysis of the effectiveness of a DAM system and its management task force, giving vital insights into ROI and, where required, areas for making improvements in delivery timeframes – ultimately leading to tighter compliance of all digital assets. To learn more about digital supply chain management in a life science setting, and how to approve and share digital assets effectively while gaining access to invaluable performance and benchmarking data, please contact Zinc Ahead via our website: David Bennett is president of Global Sales and Marketing at Zinc. David is a well-known international software business leader with 20 years’ experience as General Manager, Sales and Marketing leader and CEO in international software companies. David holds a business degree from the University of the West of England. Email: Autumn 2015 Volume 7 Issue 3

Meet us at de i w d l r o W I h P C in Madrid 15 October 13 –

Advancing Austrian life science // at the heart of Europe 2015 meet LISA at

BIO-Europe Spring Paris, 9.– 11.03 BioEquity Europe Vienna, 19.– 20.05 BIO International Convention Philadelphia, 15.– 18.06 Swiss Medtech Expo Luzern, 15.– 16.09 CPhI Worldwide Madrid, 13.– 15.10 BIO-Europe Munich, 02.– 04.11 Medica Duesseldorf, 16.– 19.11

Regulatory & Marketplace

Entering the Home Stretch for ICD-10 Transition ICD-10 is the largest mandate in US healthcare history. It will require diligent, comprehensive actions to be fully prepared for the transition. Practices have until October 1 to successfully upload, test and implement ICD-10 codes, which will replace the ICD-9 code set. Whether healthcare firms are ready or not, the US government’s upcoming deadline stands firm. Hospitals and physician practices have been discussing ICD-10 for many years. However, even with a one-year implementation delay, many are just realising that they are still not ready for the October 1 start date. As the implementation date nears, experts have expressed varying degrees of doubt about the long-term success of the updated disease classification codes. These include the belief that productivity across the board in healthcare organisations will plummet, leading to a loss of revenue.1 But is this so? Can the implementation of successful strategies lead to increased productivity and revenue? A significant number of inquiries have come from organisations that have considered ICD-10 to be an IT or HIM issue. When looking at the scope within a hospital or practice that ICD-10 encompasses, there are many areas that should be involved. Ignoring any of these areas can have a detrimental effect on ICD-10 readiness.

entire organisation, be it hospital, office practice, home health agency or any entity involved in direct patient care. One would think that ICD-10 education would not be an issue, but in reality, it is probably the most common problem facing the healthcare community. Specifically, the problems most frequently encountered are lack of education specific to a provider’s speciality and ongoing reinforcement of the requirement and training for best documentation practices within the organisation’s electronic health record (EHR) products. With the one-year delay in ICD-10 implementation, many organisations have openly stated that educational activities came to an abrupt halt. Now we are less than two months away from the October 1 deadline. Hospitals, clinics and ambulatory practices are looking to evaluate just how ready they are to move to ICD-10 and how best to address critical gaps in education and training.

Following the summer article, which covered the general approach to ICD10 and governance, this article looks at education and standardisation of documentation.

ICD-10 education is often not viewed as a priority, with the possible exception of nursing. Instead of aligning physician education to high-volume, high-value care, physician training is most often addressed with generic online or brief classroom sessions. Physicians, nurses, coders and billers were the groups that have suffered the most. But other areas clearly need to understand what is needed for ICD-10 – such as registration, patient access, case management, and social work – and they are no longer being trained in the fundamentals of the new coding system, either.

Educate Everyone, Early and Often According to Michael X. Repka, MD, MBA, American Academy of Ophthalmology medical director for governmental affairs, the transition to ICD-10 should be virtually seamless for practices that have EHR systems, but training for physicians and staff is critical.2 When conducting an ICD-10 readiness assessment, a major area of review is to evaluate the organisation’s educational programmes. All too often organisations provide education for just the clinical providers, but in fact, ICD10 education should extend across the

Any other areas that need to understand how ICD-10 operates have all but been ignored for education. They understand how this will impact not only their work, but it will also negatively affect collections through delays and denials. The effect on patient satisfaction and quality of care can be devastating. To be successful, every healthcare organisation must assess ICD-10 readiness and use the findings to create a meaningful education programme. It’s a critical area of responsibility for the governance team. This overlap between governance and education is a critical part of the path to


ICD-10 readiness. Document Consistently, with the Right Amount of Detail Concise, thorough and comprehensive documentation is not only essential, but it is the required basis for ICD-10, as well as value-based purchasing, bundled payments, pay for outcomes and managing episodes of care. Without solid documentation, hospitals and physicians alike will soon find themselves challenged to validate their work, which could lead to undervalued or denied payments. No one expects every doctor, nurse or therapist to document exactly like their colleagues. But within an organisation there should be clear guidelines in place that mandate how clinicians chart key components of the medical record. Lack of consistency in documentation takes on many forms. It can be a hospital that enables its clinicians to document both on paper and in an electronic medical record. Or it can manifest itself as relying on free text or dictated notes that do not follow a consistent format. But perhaps the biggest challenge facing hospitals and physicians alike is not providing the level of detail needed to justify selecting high-value codes. The Centers for Medicare and Medicaid (CMS) is well aware of this challenge. In 2006, CMS instituted Recovery Audit Program (RAC) audits for the sole purpose of seeking to recoup Medicare and Social Security overpayments. To put this into perspective, the 2013 CMS Report to Congress noted that the Medicare Fee for Service (FFS) Recovery Audit Program returned more than $3 billion to the Medicare Trust Fund.3 When looking at audit triggers and providers’ costs, hospitals note that medical necessity denials accounted for 96% of costly complex denials. Managing these audits can be expensive; 63% of all hospitals reported spending more than $10,000 managing the RAC process during the fourth quarter of 2012; 43% spent more than $25,000 and 13% spent over $100,000.4 While hospitals were able to overturn about two-thirds of appealed denials, Autumn 2015 Volume 7 Issue 3

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Regulatory & Marketplace only 40% of hospital denials went to appeal. While there is less published data regarding physician practices, it would not be surprising to see similar numbers for this segment of the medical community.5 Clearly documentation cannot, by itself, address all these woes, but coupled with strong governance and training on how to do effective documentation offers the best solution to avoiding these financial penalties. Wide variation in physician documentation processes within an organisation, department or service can complicate coding, prolong billing cycles and inhibit effective communication across providers and with the patient. The issue comes down to being able to consistently retrieve pertinent clinical information to support the ICD-10 code. If the documentation is there but hidden in some dark recess of the chart, then the chances of clinicians being able to retrieve it for coding is minimal, and the organisation risks under-coded charts, which loses money. At the other extreme is the situation where a physician selects a high-value code, but doesn’t chart the supporting documentation, thus overcoding the record. In either case, the outcome can pose a severe obstacle to the financial stability of the organisation. Perhaps most disturbing are the potential clinical effects of poor documentation. In a 2013 study that examined the financial impact of CDI, there are significant increases in length of stay, cost of care and re-admissions when documentation falls short of expectation for consistency and content.6 Summary The three pillars to ICD-10 success are the same with any enormous organisational change: governance, education and documentation. Only those organisations that have invested time and resources in governance, education and documentation are ready to move into ICD-10 pre go-live activities, such as testing and dual coding. Even for non-clinical staff, such as coders, the overwhelming majority admit they need to refresh the skills and knowledge they acquired in 2014, if they are to be a skilled resource in October 2015. One question remains: “What can 14 INTERNATIONAL PHARMACEUTICAL INDUSTRY

I do in the time before the deadline?” This is the most difficult question of all to answer. If an organisation is willing to make ICD-10 its primary task through to October, then there is a strong possibility it can achieve a sufficient amount of readiness. It is more likely to be ready to start on October 1 and continue to make improvements and enhancements on an ongoing basis. If, however, this same organisation continues to delay in developing a comprehensive assessment and remediation strategy, then October 1 may be only the start of a descent into a financial abyss from which there is no way out. ICD-10 readiness is a journey, but unless the fundamentals are in place, moving forward toward an October 1 launch is an uphill journey on a very steep slope. References 1. Kristen Lee, 2015. Experts predict bleak results after ICD-10 implementation date. (Internet) http://searchhealthit.techtarget. com/video/Experts-predictbleak-results-after-ICD-10implementation-date [Accessed 14/08/2015] 2. Ocular Surgery News, 2015. Transition to ICD-10 codes requires keen oversight, rigorous training. (Internet) http://www.healio. com/ophthalmology/practicemanagement/news/print/ocularsurgery-news/%7B8a509f60-ae364a40-ac44-7b81eed5e2f5%7D/ transition-to-icd-10-codes-requireskeen-oversight-rigorous-training [Accessed 14/08/2015] 3. Centers for Medicare and Medicaid Services. Recovery Auditing in Medicare for Fiscal Year 2013. (Internet) Research-Statistics-Data-andSystems/Monitoring-Programs/ Medicare-FFS-CompliancePrograms/Recovery-AuditProgram/Downloads/FY-2013Report-To-Congress.pdf [Accessed 10/08/2015] 4. Bob Herman, 2012. 25 Statistics on Hospitals and RAC Audits. (Internet) http://www.beckershospitalreview. com/finance/25-statistics-onhospitals-and-rac-audits.html [Accessed 10/08/2015] 5. Bob Herman, 2014. RACs recouped $3B for Medicare in 2013. (Internet) http://www.modernhealthcare.

com/article/20140929/ NEWS/309299939 [Accessed 10/08/2015] 6. Dianne L. Haas, 2013. Clinical Documentation Improvement: What Executives Need to Know and the Financial Impact of Neglect. (Internet) http://www. b e c k e r s h o s p i t a l r e v i e w. c o m / finance/clinical-documentationimprovement-what-executivesneed-to-know-and-the-financialimpact-of-neglect.html [Accessed 10/08/2015]

Jeffrey Goldstein is a Clinical Transformation Consultant at Allscripts and an internationallyrecognised consultant with over two decades of experience in senior administrative and clinical management for hospitals, ambulatory care centres and long-term care facilities as well as extensive consulting experience in both the provider and payer segments of the industry, with a focus on the medical management payer practice. He provides analytic and operational consulting expertise related to medical management, optimising the quality of healthcare, improving clinical efficiencies and integrating interdisciplinary evidence-based medicine programmes into an organisation. Jeff has been an active voice in the healthcare community on the importance of quality and efficiency. He has spoken on this subject before numerous professional meetings including the American College of Healthcare Executives (ACHE), the New York Association of Homes and Services for the Aging (NYAHSA) and the Gartner Group’s national conference on new technologies in healthcare. He has authored several white papers to guide the consumer in making educated, appropriate choices when selecting both a hospital and a physician. During his career, Jeff had worked with private and not-for-profit healthcare organisations in the US, the UK, Canada and Hong Kong. He has advised facilities ranging from rural community hospitals to academic medical centres to help them identify opportunities to improve care and then to guide them through the process of implementing the interdisciplinary changes needed to achieve their goals. Autumn 2015 Volume 7 Issue 3



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Regulatory & Marketplace

Sifting Through the Sourcing Options Outsourcing is now a widely accepted practice in the life sciences industry. However, choosing precisely which activities to entrust to an external supplier remains challenging. The standard methodologies are two-dimensional; therefore, they fail to address some key considerations. Here we present a new methodology that refines previous approaches and provides a rigorous framework for making such decisions. Outsourcing on the Increase A few decades ago, every life sciences company worth its name did everything itself. Today, most rely on a network of contract research organisations (CROs) to handle critical parts of the development process. In 2000, the market for the services of CROs was just $5.2 billion. By 2010, it was $23.2 billion1 – 34% of the estimated $68 billion spent on drug discovery and development that year.2 Demand for the services CROs provide is projected to rise by more than 20% by 2016 versus 2014 and, as Figure 1 shows, the bulk of the growth is expected to occur in the clinical area.3

Some of the biggest life sciences companies also outsource other tasks, including payroll management, buildings maintenance, data management, medical affairs and outcomes research. And our analysis suggests that many of them are exploring the potential for contracting out an even wider range of activities (see Figure 2).

Why Outsource? The reasons for growth in outsourcing are straightforward. The life sciences industries are under huge pressure to become more productive. In the blockbuster era, the leading research firms had money and resources to spare. Today, the commercial climate is quite different; every dollar must be spent as wisely as possible.

Figure 2: The biggest life sciences companies are outsourcing an expanding range of activities. Source: Kinapse. Many life sciences companies therefore hope to save money by using specialists who can call on greater know-how, better processes or scale (sheer numbers of resources as well as geographic footprint) to provide certain services more efficiently and economically. Others want to make their organisations more flexible to manage peaks and troughs in demand, spread their risk or focus on value-adding activities, instead of having to worry about activities that, although important, aren’t core to their business.

Figure 1: The CRO market is growing rapidly. Source: SCRIP Insights. Yet others want to get access to new skills, since even the biggest and best companies cannot be equally good at 16 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2015 Volume 7 Issue 3

Chapter Title


Regulatory & Marketplace everything. Clinical testing is now a very complex process, for example. The number of trial protocols has increased dramatically,4 as has the number of countries in which trials are conducted.5 Few drug makers can therefore manage the entire process and infrastructure alone and, even if they can, they possibly cannot do so as rapidly as a competent CRO. On average, CROs can reduce clinical testing times by as much as 30%.6 In short, the main motives for outsourcing have to do with speed, cost and expertise. But they are not mutually exclusive; many companies have more than one goal. From Tactical to Strategic The nature of the relationship between the client and service provider has evolved, as the life sciences industries switch from tactical to strategic outsourcing. Previously, most companies saw external suppliers as temporary labour hired to meet peaks in demand. But one recent survey demonstrates how much attitudes towards CROs have advanced. Only 21% of respondents said they still outsource on a short-term, ad hoc basis, whereas 67% form long-term partnerships with a few carefully chosen alliances. The remainder do everything in-house.7 Our research confirms and expands on these findings. It shows that the multinationals are expanding the depth and breadth of their links with CROs. Many of them are switching from functional-service outsourcing (where a supplier performs a single activity across multiple studies) to full-service outsourcing (where a supplier performs most, or all, of the activities involved in a study). They are also changing the commercial models they use, with output-based pricing contracts and full cost transparency. A few companies are entering into gainsharing agreements and paying the CROs they employ, when the volume of work falls below a predetermined level in return for access to key skills familiar with the way the sponsor company works (‘on demand skilled resourcing’). Such long-term strategic partnerships have advantages for both sides. They enable the outsourcing company to tap into the knowledge of its external suppliers more easily, as well as facilitating crossfunctional collaboration because there are fewer organisations to coordinate. They also help the service provider plan 18 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 2: The biggest life sciences companies are outsourcing an expanding range of activities ahead and make strategic investments into the partnership. To sum up, then, strategic outsourcing is replacing tactical outsourcing rapidly and CROs are beginning to play a bigger role than ever in the value chain. Choosing the right strategic partner has therefore assumed greater importance. The Heart of the Dilemma Many life sciences companies still struggle to select the right activities to outsource. That is sometimes because emphasis is focussed too much on what will save most money, regardless of the impact on their ability to compete in the longer term. Sponsors sometimes make outsourcing decisions on a piecemeal basis; using different selection techniques – often inherited from earlier acquisitions – in different parts of the business; or simply assume that an external service provider must be better, when that’s not necessarily true. Also, companies do not always use a collaborative approach involving business partners (e.g., procurement) and service providers to formulate outsourcing strategies. Rigorous analysis is therefore essential both to establish the business case for outsourcing, and to justify that decision outside the boardroom. Announcing that a company plans to outsource an activity to a service provider can potentially generate weeks of hostile media coverage and industrial action. The question is how best to perform that analysis. The Standard Methodologies Various frameworks have been devised for determining which activities to outsource. In effect, they fall into two categories: those founded on transaction cost economics, where the aim is to cut a company’s costs by creating the most

efficient governance structure; and those founded on the resource-based view, where the aim is to enhance a company’s competitive advantage by outsourcing any non-core processes that it doesn’t perform in a distinctive way. Critics of the first approach argue that it emphasises costs at the expense of strategic considerations. The prevailing frameworks therefore lean towards the resource-based view. They ask two questions. Is the activity concerned a source of strategic advantage? And how well does the company perform that activity, compared with its peers? Where no strategic advantage arises from doing something internally and the company doesn’t do it particularly well, an activity is regarded as suitable for outsourcing (see Figure 3).8 Unfortunately, the conventional capability frameworks have some limitations. First, they require a company to identify activities that constitute a source of strategic advantage. Harvard Business School Professor Clayton M. Christensen notes that it is quite possible for two companies in the same industry to see completely opposite factors as strategically advantageous.9 Christensen cites the example of power-tool makers Black & Decker and Makita. The former spent much of the 1980s consolidating its manufacturing in a few global centres to counteract the market gains made by its Japanese rival. Meanwhile, the latter was moving towards manufacturing in smaller-scale local facilities around the world.10 Second, in such frameworks it is implicit that every activity can be classified as ‘core’ (i.e., a source of strategic advantage) or ‘non-core’ (i.e., commoditised); while in practice, some Autumn 2015 Volume 7 Issue 3

Regulatory & Marketplace activities fall in between.11 Many clinical operations procedures are not performed in a distinctive fashion that creates a strategic advantage; for example, many clinical operations procedures are not performed distinctively and therefore do not provide a strategic advantage, but are nonetheless essential. The biggest weakness of the standard capability frameworks, though, is arguably their failure to address the financial implications of outsourcing. They ignore the maturity of the service industry concerned, which influences both its competence to perform an activity and the associated transaction costs (e.g., the cost of finding a supplier, negotiating terms, writing the contract and monitoring its performance). And they take no account of the potential savings.

are given a numerical value and weighted as appropriate. This framework has various advantages. It uses objective as well as subjective criteria to measure the strategic significance of each activity. It evaluates supply-side risks and costs, by distinguishing between activities that are routinely outsourced (where the processes suppliers are mature) and those that are rarely outsourced (where suppliers may have no expertise). It also assesses the financial ramifications, including any

factors that could reduce the scope for savings (such as requiring a supplier to perform a task in a place where labour is expensive). Putting the Framework into Practice So how is the framework applied? There are four key steps. Map all activities The first step is to map every activity in a given function and prepare an exhaustive list. Clinical project management is not just one activity, for example; it is

Our Methodology The Kinapse outsourcing framework aims to rectify these omissions by using a hybrid approach that captures all the information required to make a robust outsourcing decision and represents it three-dimensionally (see Figure 4). The first dimension (on the primary y-axis) measures an activity’s strategic added value – by which we mean its strategic impact, value-creating potential and the level of risk it carries. This dimension comprises two factors: the extent to which an activity is deemed a source of strategic advantage (internal surveys can be used) and the extent to which other companies in the same industry outsource it (based on external research). Both factors are measured on a scale of 1 to 5 and weighted.

Figure 3: Conventional capability frameworks use two criteria to make the outsourcing decision. Source: Richard C. Insinga and Michael J. Werle, ‘Linking Outsourcing to Business Strategy’.

The second dimension (on the x-axis) measures how well the company performs that activity. Internal surveys and metrics (such as the time taken to reach project milestones and number of critical audit findings) are used to make this assessment. Each activity is then ranked on a numerical scale representing the range from very good to very poor. The third dimension (on the secondary y-axis) combines two further measures: the degree of experience and skill exhibited by the service industry to which the activity would be outsourced in performing that particular activity; and the potential for saving costs by outsourcing it. Again, these two factors 20 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 4: The Kinapse framework assesses activities based on 1) the extent to which an activity is deemed as a source of strategic advantage, 2) the extent to which other companies in the same industry outsource it, 3) how well the company performs that activity, 4) the degree of experience and skill exhibited by the service industry in performing that activity, and 5) the potential for saving costs by outsourcing. Source: Kinapse. Autumn 2015 Volume 7 Issue 3

Chapter Title

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Regulatory & Marketplace a set of activities, including milestone planning, milestone tracking, budget and resource forecasting, budget and resource tracking and site budgeting and contracting. Some of these activities may be suitable for outsourcing, while others should be kept in-house. So they must be independently assessed. Rate each activity against key parameters The next step is to rate each activity against each of the parameters in the framework on a scale of 1 to 5, and weight the two composite measures on the primary and secondary y-axes as required. Where, say, a company’s main aim is to focus on more strategic activities, the competence of the service industry is likely to be more important than the scope for cost savings. Plot each activity on the framework and identify the best sourcing strategy Thereafter, a company can plot each activity on the framework, using the ratings to identify the quadrant in which it belongs – and thus the most appropriate strategy for sourcing it. The company depicted in Figure 5 has, for example, decided that budget and resource forecasting and tracking are strategically valuable activities at which it excels, so these are the activities that should remain in-house. It also considers milestone planning and the preparation of reports and analysis plans strategically important and, since it is weak in these areas, it knows that it needs to improve its internal resources. Conversely, the company regards site budgeting and contracting as strategically insignificant activities in which it is weak, so these are activities that should definitely be outsourced. And even though its milestone tracking skills are much stronger, this is also an activity with little strategic value, which may be worth outsourcing as well. In most cases, determining which quadrant an activity falls within is enough to indicate the best course of action. However, occasionally, the situation is not quite so clear-cut. For instance, if a strategically important activity is performed badly in-house but there are some very capable suppliers who could do the same task much better. The company will have to decide whether it wants to outsource the activity or retain it and upgrade its own skills. 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 5: The quadrant an activity falls within shows how that activity should be sourced. Source: Kinapse.

Figure 6: Potential candidates for outsourcing in a typical pharma company’s R&D function. Source: Kinapse.

Figure 7: Potential candidates for internal sourcing in a typical pharma company’s R&D function. Source: Kinapse. Alternatively, if an activity is both strategically insignificant and poorly performed by the company concerned, and there also are very few suppliers who could do it well, the company can either search for a competent – and possibly expensive – supplier, or invest in improving its internal facilities, and the choice may not be an easy one.

Moreover, it may sometimes make sense to bundle up related activities and outsource them as a package. Where a company plans to outsource the vast majority of activities in a particular function, for example, outsourcing the remaining few activities in that function may be preferable to splitting them up and keeping them in-house. Similarly, it Autumn 2015 Volume 7 Issue 3



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Regulatory & Marketplace may make more sense to bundle activities belonging to two or more similar functions, such as pharmacovigilance and regulatory, and outsource them together. Validate sourcing strategy The final stage in the process is to validate the resulting map and establish the commercial and legal feasibility of the sourcing strategy for each activity. This should include checking the availability of required capabilities within and outside the existing supplier list. The existing supplier list should be updated to ensure that it has the best available CROs identified in the analysis. Kinapse Approach in a Typical Sourcing Strategy Project When supporting a typical pharma company’s R&D function with its sourcing strategy, Kinapse begins by preparing an exhaustive list of activities under all of its sub functions such as clinical operations, clinical development, medical affairs, regulatory affairs, etc. These activities are then rated with inputs from key stakeholders (collected through workshops or interviews) and then mapped onto Kinapse framework. The resulting map feeds into key sourcing recommendations which are reviewed and agreed with the client. In its vast experience of working on numerous sourcing strategy projects, Kinapse has typically seen the following R&D activities emerge as potential candidates for outsourcing and internal sourcing. As can be seen in figures 6 and 7, the Kinapse framework is a very flexible tool that can be used to evaluate an entire function to its greatest details such as its sub functions and activities. Conclusion In short, the methodology we have outlined above refines and enhances the existing decision-making frameworks. It provides a sound strategic and quantitative basis for making sourcing decisions. It is also a powerful tool for assessing a company’s performance, evaluating its strengths and weaknesses and identifying any areas where it needs to improve.


 References 1. SCRIP Insights, ‘The CRO Market to 2016’ (March 2011). 2. Ben Hirschler, ‘Drug R&D spending fell in 2010, and heading lower’, Reuters (26 June 2011), http://www. pharmaceuticals-rdidUSL6E7HO1BL20110626 3. SCRIP Insights, op. cit. 4. The Tufts Center for the Study of Drug Development reports that, between 1999 and 2005, the average length of a clinical trial increased by 74%, while the average number of routine procedures per trial increased by 65% and the average workload increased by 67%. For more information, see‘ Protocol Design Trends and their Effect on Clinical Trial Performance’, RAJ Pharma (May 2008), pp. 315-316, www/2816Getz.pdf. 5. S. W. Glickman, J. G. McHutchison et al., ‘Ethical and scientific implications of the globalization of clinical research’, New England Journal of Medicine 360 (19 February 2009): 816-23. 6. Alison Sahoo, The Future of R&D Outsourcing: Investigating development hurdles, key challenges & strategies to optimize CRO relationships, Business Insights (2010), p. 58. 7. Economist Intelligence Unit, ‘Finding Alignment: Opportunities and Obstacles in the Pharma/CRO Relationship’ (2012), pp. 10-11. 8. Richard C. Insinga and Michael J. Werle, ‘Linking Outsourcing to Business Strategy’, The Academy of Management Executive, Vol. 14. No. 4 (November 2000): 58-70. 9. Clayton M. Christensen, ‘The Past and Future of Competitive Advantage’, MIT Sloan Management Review (Winter 2001): 105-109. 10. Ibid. 11. Farok J. Contractor, Vikas Sumar et al., ‘Reconceptualizing the Firm in a World of Outsourcing and Offshoring: The Organizational and Geographic Location of High-Value Company Functions’, Journal of Management Studies, Vol. 47, Issue 2 (December 2010): 1417-1433.

Jonathan Peachey is Head of Client Partnerships. Jonathan has over 20 years industry experience, leading drug development programs and delivering business and IT transformations across Pharma R&D. Previous employers include: IBM, PwC Consulting, and GSK, BMS and Pfizer Clinical Development. Commending Kinapse for its dedication to the life sciences industry, and its ability, as a company, to deliver – even exceed expectations, Jonathan says he admires the intellectual and professional skills he sees in every member of the Kinapse team. He says: “When clients can speak positively about us – that’s the greatest compliment to have.” Email: Dr Subrata K Bose, Kinapse Senior Manager Ankita Sharma, Kinapse Consultant. Dr Andy Black, Kinapse Chief Executive Officer. Dr Alastair Benbow, Kinapse Chief Medical Officer. Matthew Mcloughlin, Head of Advisory Services. Email: matthew.mcloughlin@ Dr Stuart Donald, Advisory Services.



George Botsakos, Vice President, Advisory Services and Head of Kinapse US. Email: george.botsakos@kinapse. com Dr Nicholas Chairman.



Autumn 2015 Volume 7 Issue 3

Drug Discovery, Development & Delivery

Alzheimer’s Disease – Breakthrough Due Soon? Over recent weeks we seem to be waking up to news headlines suggesting the cure for Alzheimer’s disease (AD) is imminent. Why is there so much buzz about a cure for AD? How close is a cure? And just why has it been so difficult to see progress in AD treatments? This article reviews the recent headline-grabbing news in AD clinical trials and looks at the results we can expect in the next couple of years.

and their functioning in daily life, and ultimately shortening their life.

The most recent headlines (July 2015) came from the Alzheimer’s Association International Congress (AAIC) in Washington DC, USA. Headlines such as ‘Alzheimer’s drug … could slow patient’s decline’ were made following an announcement from Eli Lilly on its monoclonal antibody directed towards increasing the clearance of β-amyloid plaques. In addition, Biogen announced additional results from its much-heralded Prime study with aducanumab, also a monoclonal antibody targeting β-amyloid plaques. Other result announcements were made by Anavex, Axovant Therapeutics and Roche, among others. The Eli Lilly results became the top story on the BBC news on the evening of 22nd July 2015, and the interim results of Biogen’s Prime study led to a front-page cover in the USA’s Fortune magazine. Why are these clinical trial results leading to such widespread mainstream news coverage?

Drugs Approved To Date The USA and EU have approved five drugs to treat the symptoms of AD; four cholinesterase inhibitors and memantine, an NMDA receptor antagonist that was approved in 2003. These drugs help with improving the memory-loss symptoms, but they do not alter the course of the disease and eventually they stop working as the disease progresses. Despite this limited efficacy, Aricept, the most popular of the cholinesterase inhibitors, had peak sales of 2.4 billion in 2010.2 There are no drugs approved at all as treatments for the other forms of dementia.

AD is becoming a more common cause of death, and whilst deaths from breast and prostate cancers, stroke, heart disease and HIV are declining, deaths attributed to AD are increasing. AD is now the sixth-leading cause of death in the US.1

There is a growing recognition of the burden this disease places on patients, their carers, and society as a whole. In the US, payments for care are estimated to be $200 billion.3 Given the large numbers of people affected and the massive burden

placed on them, combined with no new treatments for over a decade and no treatment offering any hope of altering the exorable progress of the disease, it is unsurprising that any positive news is being heralded with a fanfare and frontpage headlines. Disease-modifying Therapies – the Antiamyloid Drugs After the relative success of the symptomatic treatments for AD, attention moved to seeking treatments that altered the underlying pathology of the disease. Amyloid became the target of choice for many companies. Amyloid precursor protein (APP) is a protein found widely throughout the body. The amyloid hypothesis is that a fault with the processing of amyloid precursor protein (APP) in the brain leads to the production of a short fragment of APP known as beta-amyloid (or Aβ). The theory is that the over-production of Aβ leads to a build-up of this sticky protein fragment in the brain that triggers the disruption and destruction of nerve cells that causes Alzheimer's disease. The accumulated clumps of Aβ are known as amyloid plaques. The hypothesis is thus that there is a fault with the over-production of Aβ or with the mechanism that usually clears it from the brain, or possibly both.4

Firstly Some Background Alzheimer’s disease (AD) is the most common form of dementia. Other types of dementia are vascular dementia, the second most common form of dementia, affecting an estimated 16% of dementia patients, followed by less common forms such as Lewy bodies dementia and frontotemporal dementia, including Pick’s disease. In the UK there are around 850,000 people with dementia, and around 60% will have AD (520,000). In the USA there are 5.4 million people living with AD. Estimates put the number of worldwide AD patients at 44 million. Disease progression varies and can be as short as five years or as long as 20 years of insidious decline, during which symptoms relentlessly worsen, robbing a person of their memory, their independence 26 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Source: Autumn 2015 Volume 7 Issue 3

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Drug Discovery, Development & Delivery The rationale of exclusively targeting Aβ remains disputed, especially by those who feel that the tau tangles are a better target. Significantly, at end stages of AD, patients will have both amyloid plaques and tau tangles in their brain. Whether removing, blocking or reducing these is going to be beneficial and, if so, what the optimal time is for doing so, all remain as yet unanswered by the research community. However despite a raft of negative clinical trials targeting this mechanism of action, Aβ still remains a popular target. It has been noted that, ‘Anti-Aβ therapies have dominated AD clinical trials in recent years, with 70 of 146 (combined small molecules and immunotherapies) compounds being directed against Aβ compared with 13 compounds addressing taurelated mechanisms and 62 compounds assessing neuroprotective approaches.’5 Companies Targetting Amyloid Solanezumab is a monoclonal antibody aiming to clear Aβ. Eli Lilly ran two large Phase III trials of solanezumab in mild to moderate AD patients (EXPEDITION 1 and EXPEDITION 2). A combined total of 2052 patients were enrolled in the two studies. Neither study showed a benefit of solanezumab on either of the coprimary endpoints, however in patients in mild AD, a cognitive benefit was seen that was not witnessed in moderate patients. Based on this result and because there was also a positive result on plasma and CSF levels of Aβ that were consistent


with target engagement of soluble brain amyloid by solanzumab,6 Lilly announced it was commencing a third trial, EXPEDITION 3, recruiting 2100 patients with mild AD and a positive biomarker for Aβ. The results announced at the AAIC conference that caused the headline news, came from the open label extension in mild AD patients from the EXPEDITION 1 and EXPEDITION 2 trials. The results of this indicated that solanezumab could slow the rate of decline by around 30%. All eyes now will be on the results of EXPEDITION 3, due in the second half of 2016. Biogen announced positive interim results from their Phase Ib study of Aducanumab in patients with prodromal or mild AD (PRIME) on 20 March 2015. This interim analysis of 166 patients for a year’s treatment showed a dose- and time-dependent reduction of Aβ and a statistically significant slowing of clinical decline on the cognitive endpoints. On the basis of these results, Biogen announced it was commencing two Phase III trials in a total of 2700 patients with early AD (ENGAGE and EMERGE – 1350 patients each). Top-line results from ENGAGE and EMERGE studies are expected in 2017. At the AAIC, additional data was presented on one of the doses in the PRIME study which showed a reduction in Aβ levels. The change in cognition, however, was not statistically significant for this dose. Anticipation remains high, however, for the Phase III trials.

Companies Targetting Tau There are fewer companies targeting tau as a therapeutic intervention and generally they are at an earlier stage of development than the anti-amyloid drugs. One company at Phase III is TauRx, a privately-owned Singaporean company which has three large trials ongoing, two in AD and one in frontotemporal dementia. Results from these trials are expected in Q2 2016. Aceneuron is also targeting tau, however it is aiming its lead development programme at rare tauopathies, in particular progressive supranuclear palsy, where a Phase I is due to start later this year. Other companies in Phase I include Axon Neurosciences and AC Immune, with the latter working on a vaccine and a recently-announced licence deal with Jansen. So although relatively few in number and generally at an earlier stage of development, the tau-targetting companies are growing in number and also starting to secure large pharma deals that until recently were the preserve of the Aβ companies. Large Number of Clinical Trial ‘Failures’ From 2002 to 2012, 244 compounds have been tested in clinical trials in AD patients, of which one was approved for marketing, an attrition rate of 99.6%.7 The attrition rate for oncology trials is 81%. Why is there such a monumentally high failure rate in AD clinical trials? Cummings et al. attribute trial failure to be based on one of three elements; lack of efficacy, excessive side-effects or

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Drug Discovery, Development & Delivery challenges in trial execution. Of particular note is the role trial execution can play in AD clinical trials. ‘Trial-conduct failure is suggested by a lack of decline in the placebo group, no effect in an activetreatment comparator arm of the study, or excessive measurement variability.’7 The Challenge in Measuring Cognition There is a growing recognition of the role trial execution plays in AD clinical trials. In particular, the measurement of cognition, often the primary endpoint, is generally reliant on subjective measures of cognitive performance. For example the ADAS-Cog is a mixture of memory tests and doctors’ rating of impairment. Inconsistencies in conducting these measures – within sites, by multiple staff members applying slightly different rules, and between sites, where different sites apply the rating scales in a different manner – can cause so much variety that any positive signal is ‘drowned’ by the variability. How many times this has occurred is almost impossible to calculate and it is a rare sponsor that wants to invest in investigating why a trial has failed; however, one publication looked at phenserine and the reasons for the failed trial that led to the abandonment of the development of the drug. Phenserine was being developed as the ‘next generation acetyl cholinesterase inhibitor’ as a treatment for the symptoms of AD. A Phase II trial was completed in 72 AD patients and following these results, two Phase III registration trials were conducted, one enrolling 375 and the other enrolling 450 mild to moderate AD patients. The results for these two trials were negative. A detailed review of the data from one of these trials led the reviewers to conclude that there were statistically significant relationships in the trial between outcomes at sites and levels of variance such that ‘We conclude that phenserine was abandoned, at least in part, due to a clinical trial invalidated by relationships among its methods and outcomes’.8 To minimise the risk of further trial failures, strategies for enhancing the success of trials such as improved administration and monitoring of cognitive rating scales, enhanced training on these rating scales, together with better patient-selection approaches are warranted. The Challenge of Early Intervention Even if the trial conduct is exemplary, there can remain a lack of efficacy and the reason for this should be investigated. 30 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It now appears to be well-accepted that the anti-amyloid agents need to be used earlier in the disease process and that perhaps some of the many failures are attributable to being used at too late a stage in the disease. The fact remains that in the absence of reliable biomarkers, the diagnosis of AD remains an art rather than a hard science. There is no diagnostic test that can definitively diagnose AD; instead, the clinician has to use his clinical judgement in assessing the patient’s symptoms. The Challenge of Ensuring Your Drug is Meeting its Target With growing understanding of the biology of AD and the considerable work that has been undertaken on AD biomarkers, the role of ensuring that your drug is hitting its intended target has grown. Biogen and Eli Lilly have taken steps to ensure that only patients with amyloid are included in the study and they will be measuring the biological response of their drug on amyloid as well as the cognitive and functional endpoints. We are not there yet with being able to have a surrogate biomarker endpoint as primary in AD, however with the recognition of the limitations of the subjective cognitive rating scales then this is a much-needed advance. Still Plenty of Opportunity for Companies Working in this Field. There have been a large number of trial failures and the investment community are understandably cautious about another AD blockbuster. However, the need is enormous and if any good is to come from these clinical trial failures, then let it be to learn from past mistakes, focus on trial execution, focus on measuring your target and ensure patient selection matches the mode of action of your drug. If early intervention, which has become the hallmark of good cancer treatment, is to be replicated in AD, then the tools to confidently perform an early diagnosis, along with the tools to reliably measure cognition, are seriously needed. With an estimated 44 million AD sufferers worldwide, the market for AD treatments is immense. So, an AD breakthrough soon? Perhaps not too soon … but there is hope …

References 1. 2012 Alzheimer’s disease facts and figures 2. general/2013/08/23/the-pastpresent-and-future-of-alzheimerstreatmen.aspx 3. 3 2012 Alzheimer’s disease facts and figures downloads/facts_figures_2012.pdf 4. Ayesha Khan ‘The amyloid hypothesis and potential treatments for Alzheimer’s disease’ http://www. documents_info.php?documentID=383&pageNumber=6 5. Jeffrey L Cummings, Travis Morstorf and Kate Zhong ‘Alzheimer’s disease drug-development pipeline: few candidates, frequent failures’ Alzheimer's Research & Therapy 2014, 6:37 6. Rachel S Doody et al. ‘Phase 3 trials of Solanezumab for Mild to Moderate Alzheimer’s disease’ N Eng J Med 2014 370:311-3321 7. Jeffrey L Cummings, Travis Morstorf and Kate Zhong ‘Alzheimer’s disease drug-development pipeline: few candidates, frequent failures’ Alzheimer's Research & Therapy 2014, 6:37 8. Robert E Becker and Nigel H Greig ‘Was Phenserine a Failure or Were Investigators Misled by Methods?’ Current Alzheimer Research 2012 9 1174- 1181

Susan McGoldrick is an experienced pharmaceutical executive with experience in various roles within the pharma industry including a small pharma company developing a treatment for Huntington’s disease and founding and running a CRO specialising in CNS disorders. Susan now advises The CNS Company on clinical trial issues in CNS disorders. Email:susan_k_mcgoldrick@ Autumn 2015 Volume 7 Issue 3



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Drug Discovery, Development & Delivery Drug Metabolite Synthesis with Human Enzymes: How Can We Utilise Microbes to Make Authentic Human Metabolites? The characterisation of the metabolic fate of a new drug molecule is essential in the course of the drug discovery and development process. As a consequence, potential human drug metabolites must be available in amounts of at least a few milligrams of pure compound. Metabolite preparation can become a significant time and cost factor, if elaborate multi-step chemical syntheses become necessary. This applies especially for chemo-, regioand stereoselective oxidations, which hold a prominent share of the human body’s repertoire of metabolic reactions. Employing whole-cell biocatalysts (recombinant microorganisms furnished with human enzymes) constitutes an elegant one-step alternative to organic synthesis to produce the required compounds in sufficient amounts. Detailed characterisation of metabolic pathways necessitates the availability of potential drug metabolites for structure elucidation and as analytical references. Furthermore, with the introduction of the MIST (Metabolites in Safety Testing) guidelines by the US Food and Drug Administration in 2008, all metabolites present at >10% of the parent compound in the human metabolism have to be subjected to the elucidation of their toxicological properties1. In this context two questions arise: Which drug metabolites are formed in the human body and how can these compounds be produced in sufficient amounts? In human Phase I drug metabolism, drug molecules are typically metabolised into more polar metabolites of the parent compound in order to functionalise them to facilitate their excretion. In this context, enzymatic oxidations, reductions, hydrolysis, cyclisations/decyclisations or dealkylations may take place, depending on the chemical structure of the drug. The largest number of these reactions is ascribed to the action of cytochrome P450 monooxygenases but also human flavin monooxygenases, aldehyde oxidase, xanthine oxidoreductase, alcohol dehydrogenases, aldehyde dehydrogenases, monoamineoxidases, esterases, amidases and epoxide hydrolases act on particular compounds (Figure 1). These enzymes can also 32 INTERNATIONAL PHARMACEUTICAL INDUSTRY

act in sequence on a compound.

purified, which saves time and costs. In addition, the half-life of enzyme activity can be prolonged because the cell acts as a protective shield against e.g. shear forces and organic solvents. As many industrially relevant reactions rely on cofactors, whole cells constitute an attractive strategy to regenerate these costly compounds by exploiting the cell metabolism.2 The focus of this communication is the use of E. coli as the host organism for the expression of human drug metabolising enzymes and its use as the cell factory for the supply of the necessary co-substrates for the biotransformation of active pharmaceutical ingredients.

Figure 1. Schematic representation of the enzymes involved in Phase I drug metabolism

Cytochrome P450 Monooxygenases (CYPs) In humans, cytochrome P450 monooxygenases constitute the major system for the clearance of drug molecules. These enzymes are membraneassociated heme-iron proteins that rely on the presence of a cytochrome P450 reductase and oxidise their substrates at the expense of molecular oxygen and NADPH. Whereas the incorporation of an oxygen atom into a complex organic structure is one of the most challenging reactions in organic chemistry, this is the main task of CYPs: they activate oxygen and are able to introduce atomic oxygen into allylic positions, double bonds, or even into non-activated C–H bonds. The typical reaction is a hydroxylation, but epoxidation, sulfoxidation, or dealkylation reactions have also been well described.

Chemical preparation of authentic drug metabolites often requires multiple steps including several functional group protection and deprotection steps. To circumvent this problem, our aim was the generation of scalable mimics of single steps of the Phase I metabolism reactions in vitro. Heterologously expressed human enzymes in a ready-to-use biocatalyst such as E. coli can be used as smart tools for the one-step synthesis of particular metabolites, on the one hand to probe a deconvolved human metabolism in vitro, and on the other hand to produce the metabolites in sufficient amounts for structure elucidation and toxicity studies. The over-expression of complex – and in particular membrane-associated enzymes – is, however, still a bottleneck in biotechnology. The membranes' capacities in widely used microbial expression hosts are limited and the presence of excessive amounts of a particular, recombinant protein may destroy membrane functionality, and therefore cell viability. The common understanding is that this is particularly problematic in E. coli, but less of a problem, e.g. in yeasts, which provide intrinsically more membrane space. The use of whole-cell catalysts is beneficial in many aspects. The enzyme performing the actual biotransformation does not need to be isolated and

A large number of cytochrome P450 monooxygenases are known to date and they are found in various different tissues, although the majority of Phase I metabolic reactions have been ascribed to occur in liver tissue. Mammalian liver P450 monooxygenases have been found to exhibit extremely wide substrate specificities. Some of the most important cytochrome P450 isoenzymes are CYP3A4 and CYP2D6 among the plethora of isoforms, and the polymorphism of these enzymes additionally complicates the generation of valid scientific results3. Although human cytochrome P450 Autumn 2015 Volume 7 Issue 3

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Drug Discovery, Development & Delivery monooxygenases seem to be ideal biocatalysts for the preparation of metabolites of active pharmaceutical ingredients, they are not only characterised by their functional complexity but also by low activity and stability and inhibition phenomena. The heterologous expression of multicomponent (and partly membraneassociated) systems is by far not trivial and this may be a reason for the relatively low number of published synthetic applications of human cytochrome P450 monooxygenases. One example in which a metabolite was synthesised on the preparative scale was the dealkylation of Amodiaquine – an agent against malaria. In this case, a modified CYP2C8 was co-expressed with a P450 reductase in E. coli JM109 at low levels of dissolved oxygen during biomass production. The reaction proceeded in a total of five 2L flasks in the presence of excess disodium citrate and 12.5 mol% of NADP+. Within 32h, 93% of the substrate were N-deethylated and the product was isolated and purified (Scheme 1 top)4. A similar biocatalyst expressing CYP3A4 was used to convert AAG561, a drug that was in development for the treatment of anxiety and depression. In this case, the enzyme acted on three different sites of the molecule and catalysed N-depropylation, N-dealkylation of the (cyclopropanyl) methyl substituent and hydroxylation. In addition, the enzyme produced metabolites with combinations of these reactions. From this product spectrum, three metabolites were isolated in amounts between 2.1mg and 13.6mg and their structure elucidated by HPLCMS and NMR (Scheme 1 bottom)4.

Scheme 1: Examples of the preparative use of E. coli whole cell biocatalysts coexpressing human Cytochrome P450 monooxygenases and P450 reductase. 34 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Top: CYP2C8 catalysed metabolisation of Amodiaquine; Bottom: CYP3A4 catalysed N-depropylation, N-dealkylation of the (cyclopropanyl)methyl substituent and hydroxylation of AAG561. Flavin Monooxygenases (FMOs) Flavin monooxygenases are membraneassociated flavin-containing enzymes that catalyse substrate oxidation at the expense of NADPH and molecular oxygen. Particularly amines and sulfurcontaining substrates are oxidised by these enzymes to the corresponding N-oxides, nitrones, oximes, sulfoxides or sulfones. Like in the case of human cytochrome P450 monooxygenases, FMOs exhibit overlapping substrate specificities. Six human FMO isoforms have been described to date (hFMO1-hFMO6) and they are expressed in different human tissues. hFMO3 is the most abundant non-CYP metabolizing enzyme variant in the adult human liver whereas hFMO1 is found in fetal liver and the human lung. The majority of hFMO2 alleles (hFMO2*2) yield inactive protein due to a premature stop codon and hFMO6 genes appear to be non-functionally transcribed5. hFMO5 is also found at high levels in the human liver, but the function of this isoform has not yet been fully understood and is subject of current studies. In comparison to human CYPs, flavin monooxygenase enzymes are less complex as they are self-sufficient in the catalytic cycle and only require the presence of sufficient amounts of NADPH and oxygen but not additional proteins in particular amounts. Human FMO3 and 5 are surprisingly well expressed as active proteins in E. coli and the preparation of these biocatalysts on scale is possible by standard means. As one selected example, 100 mg of Moclobemide, an antidepressant acting by monoamine oxidase A inhibition, was converted to 65mg of the N-oxide in a simple whole cell biotransformation with hFMO3 expressed in E. coli BL21. The biocatalyst had been frozen and thawed and the reaction proceeded in shake flasks in the presence of citrate, catalytic amounts of NADP+ and air. The product Moclobemide-N-oxide represents one of the human metabolites of this drug (Scheme 2, top)5.

In contrast to FMO3, the isoenzyme FMO2*1 showed a significantly lower expression level in E. coli under identical conditions. Nevertheless is the biomass a valuable biocatalyst, as demonstrated by the selective oxidation of trifluoperazine, an antipsychotic drug. Although five soft nucleophiles are potential oxidation sites, only the 1N position of the piperazine ring was oxidized. This metabolite, again an authentic human metabolite, is not accessible by chemical oxidation with neither hydrogen peroxide nor Na+ -periodate which afforded mixtures of different products (Scheme 2, bottom)6.

Scheme 2: Examples of the preparative use of E. coli whole cell biocatalysts expressing human Flavin monooxygenase enzymes. Top: FMO3 catalyzed metabolization of Moclobemide; Bottom: FMO2*1 catalyzed chemoand regioselective metabolization of Trifluoperazine. Aldehyde oxidase (AOX1) and Xanthine Oxidase (XO) Both enzymes, AO and XOR, are molybdo-flavoenzymes, and are characterized not only by the presence of a molybdenum cofactor (MoCo) but also by a flavin in the active site as well as two 2Fe/2S redox centers. The overall protein structure and function of the two relatively large and complex enzymes is very similar. The natural and name-giving substrates of XOR are hypoxanthine and xanthine, however, a wide variety of heterocyclic compounds have been reported as substrates (e.g. purines, pyridines, pyrazine). Human AOX1 catalyzes the oxidation of a broad spectrum of aldehydes and aromatic azaheterocycles. In contrast to human CYPs and FMOs, XOR and AOX1 are not membraneassociated but cytosolic proteins. Human xanthine oxidoreductase is mostly found in the small intestine and in the liver, in relatively high amounts, but also in human milk. XOR exists in two forms, as Autumn 2015 Volume 7 Issue 3

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Drug Discovery, Development & Delivery a dehydrogenase (XDH) and an oxidase (XO), as an effect of post-translational modification. Aldehyde oxidase is expressed in the liver and has been shown to be important for the activation of several N-heterocyclic prodrugs. The heterologous expression of AOX1 and XO is challenging in classical proand even eukaryotic expression hosts due to the particular requirements of correct formation and incorporation of the MoCo cofactor. Nevertheless, both AOX1 and XOR were functionally expressed in an E. coli deletion strain (TP1000), and under well-optimised expression conditions, the expression also succeeded in a standard E. coli BL21 strain. Although the expression levels were extremely low for both enzymes, the biotransformation conditions can be optimised to reach good conversions within short times. For example Famciclovir - an antiviral drug with activity against herpes - was completely oxidised in vitro in a wave reactor within only 3h using whole cells of E. coli expressing human AOX1. Therefore, the cells were first cultivated under non-oxygen-limited conditions and a high lactose feed, and subsequently a very concentrated and well-aerated whole cell suspension was used at neutral pH and relatively low temperature. Finally, the product was isolated and purified to yield 223 mg (82%) of the metabolite diacetylpenciclovir (Scheme 3, top)7. Similarly, human xanthine oxidase was utilised for the oxidation of quinazoline to 4-quinazolinone. In this case, the optimisation of cultivation conditions revealed that highest levels of productivity can be achieved in the absence of

inducing agents (Scheme 3, bottom). Scheme 3: Examples of the preparative use of E. coli whole cell biocatalysts expressing human aldehyde oxidase (AOX1) and xanthin oxidase (XO) enzymes. Top: AOX1 catalysed metabolisation of Famciclovir; Bottom: XO catalysed oxidation of quinazoline. The biocatalytic synthesis via whole cell biotransformations allows the preparation of drug metabolites in a single step and perfectly complements chemical metabolite synthesis in cases where low or wrong selectivities demand elaborate chemical routes. References 1. Smith DA, Obach RS: Re V iews Metabolites in Safety Testing ( MIST ): Considerations of Mechanisms of Toxicity with Dose , Abundance , and Duration of Treatment. Chem Res Toxicol 2009, 22:267–279. 2. Duetz WA, Van Beilen JB, Witholt B: Using proteins in their natural environment: potential and limitations of microbial wholecell hydroxylations in applied biocatalysis. Curr Opin Biotechnol 2001, 12:419–425. 3. Evans WE, Relling M V: Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999, 286:487–91. 4. Hanlon SP, Friedberg T, Wolf R, Ghisalba O, Kittelmann M: Recombinant Yeast and Bacteria that Express Human P450s: Bioreactors for Drug Discovery, Development, and Biotechnology. In Mod Biooxidation Enzym React Appl. Edited by Schmid RD, Urlacher VB. Weinheim, Germany: Wiley-

VCH Verlag GmbH & Co. KGaA; 2007:233–252. 5. Hanlon SP, Camattari A, Abad S, Glieder A, Kittelmann M, Lütz S, Wirz B, Winkler M: Expression of recombinant human flavin monooxygenase and moclobemideN-oxide synthesis on multi-mg scale. Chem Commun 2012, 48:6001. 6. Geier M, Bachler T, Hanlon SP, Eggimann FK, Kittelmann M, Weber H, Lütz S, Wirz B, Winkler M: Human FMO2-based microbial wholecell catalysts for drug metabolite synthesis. Microb Cell Fact 2015, 14:82. 7. Rodrigues D, Kittelmann M, Eggimann F, Bachler T, Abad S, Camattari A, Glieder A, Winkler M, Lütz S: Production of Recombinant Human Aldehyde Oxidase in Escherichia coli and Optimization of Its Application for the Preparative Synthesis of Oxidized Drug Metabolites. ChemCatChem 2014, 6:1028–1042. Acknowledgements: This work has received funding from the European Union (EU) project ROBOX (grant agreement nº 635734) under the EU‘s Horizon 2020 Programme Research and Innovation actions H2020-LEIT BIO-2014-1 and has been supported by the Federal Ministry of Science, Research and Economy (BMWFW), the Federal Ministry of Traffic, Innovation and Technology (bmvit), the Styrian Business Promotion Agency SFG, the Standortagentur Tirol, the Government of Lower Austria and ZIT - Technology Agency of the City of Vienna through the COMET-Funding Program managed by the Austrian Research Promotion Agency FFG.

Dr. Margit Winkler has 12 years experience in biocatalysis, is a Senior Researcher at the Austrian Center of Industrial Biotechnology and currently holds an EliseRichter-fellowship at Graz University of technology. She studied Technical Chemistry, did a PhD in Organic Chemistry at TUGraz, Austria and had a Schrödinger fellowship as a PostDoc in StAndrews, UK. Email: 36 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2015 Volume 7 Issue 3






Clinical Research Comparator Sourcing – An Analytical Approach to Find Best-suited Sourcing Strategies Abstract Sourcing comparator drugs for clinical trials is a complex process, especially for branded drugs, and in many cases the selection process to find the best sourcing partner falls short of expectations. An analysis has shown that around 30-55% of comparator drugs are left unused at the end of the trial. This is due to issues such as disruptions in the supply chain, unexpected delays, incomplete paperwork, stock-out situations and regulatory hurdles. Selecting an appropriate sourcing partner can mitigate the above issues, and for this to be successful a tailored approach per project is required. For example, in the US, engaging with an authorised distributor, such as McKesson, can be a viable option for sourcing very large quantities of branded comparator drugs, while in the EU region, engaging with a specialist is preferred. For emerging markets, generic drugs can be sourced from nearby areas with assistance from partnered CRO. Comprehensive insight into the above parameters is a key differentiator between a successful and unsuccessful commercial launch. This paper analyses the significant parameters and a matrix is created that would support a supply manager in the assessment, understanding, and selection of the right comparator sourcing vendors in different scenarios. Introduction Comparator clinical studies are gaining momentum year-on-year due to a reduction in innovations across the global R&D pipeline. Acquiring the comparator drugs these studies require and having them at the right clinical sites at the right time is still a significant difficulty for most sponsors. According to an observation from Tufts Institute in 2012-13, the amount of comparator drugs left unused from studies by global pharma companies, after the trial, was approximately 30-55%. This is due to the fact that sponsors are unable to acquire either batch forms such as CoA, CoE and pedigree documents, or storage data details on time. Another major issue is the unexpected unavailability of branded or innovative drugs that leads to an insecure 38 INTERNATIONAL PHARMACEUTICAL INDUSTRY

or risky supply chain, ultimately having a negative effect on these expensive comparator clinical studies. In addition, clinical trials increasingly require a broad international scope, resulting in further complexities to sourcing strategies. Studies have shown that more than 50% of the management of comparator drugs is outsourced, and this figure is only expected to increase, as more pharmaceutical companies release resources to carry out core functions. As a result, companies are looking at effective strategies to enable them to improve R&D productivity, with the selection of a strategic supplier being a necessity. To achieve this, an in-depth analysis of all KPIs is necessary, in order to fully understand the market dynamics and supplier landscape. Type of Suppliers Innovators or manufacturers are a feasible option if both sponsor and innovator are a part of the TransCelerate Biopharma consortium or if they have mutual agreements for supplying the drugs (which is rare and difficult). Specialists, such as Durbin, Myoderm and Clinigen, are the second preferred version for comparator sourcing. These specialists are a significant part of the overall supply chain, due to their experience in managing the supply chain for top-tier pharma companies. CTS vendors such as Bilcare, Catalent and Fisher Clinical are a third option for comparator sourcing. These organisations will have some knowledge of comparator sourcing, but will normally utilise a network of specialist vendors and wholesalers to procure the comparators. Authorised distributors are suppliers for commercial drugs distribution worldwide and include McKesson, Cardinal Health and AmerisourceBergen. Comparator sourcing is a very small part (~0.1-0.5%) of their overall drug distribution business, and therefore this route is preferable for small studies or for the supply of easy-toaccess medication, especially in the US. Major Concern Areas for Category

Managers in Global Pharma Companies The increase of comparator studies in emerging markets, post 2009-10, has created many challenges for category managers in the global pharma industry. Following an assessment of the current status of the clinical trial supply market, several parameters, essential to a successful and effective clinical trial, were identified and are as follows: Assurance of supplies: Securing the required volume of comparator drugs can be very challenging, especially for branded drugs. Each of these four specialists has its advantages and disadvantages as a supplier of comparator drugs. Assurance of continuous supply by each supplier type varies with the drug category, origin and destination country, as well as any regulations involved. Generally, sponsors aim to secure the required comparator drugs before any ‘risk’ arises in the market, usually as a result of low stock availability. This strategy is useful for small molecule drugs with long expiry dates. However, this is not always feasible for branded biologics that risk becoming denatured, either due to short expiry dates or inappropriate handling of the drug in the supply chain. Therefore, and especially for biologics, it is important to have a good supply chain strategy and a specialist partner that has the expertise required. Securing required documents: These documents include batch forms such as CoA, CoE, pedigree documents and storage data details. Tufts found that one of the biggest reasons for comparators to remain unused at the end of a trial is the supplier’s inability to secure and provide the right documents. In some cases, the innovator or wholesalers do not provide the storage data for the comparator drugs, whereas in other cases specialists may not be able to secure pedigree documents from their sourcing channels on time. Anonymity: The need to remain anonymous or off-radar may be highly Autumn 2015 Volume 7 Issue 3

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Clinical Research significant for a sponsor for two reasons. First, to avoid potential supply scarcity situation in the market by innovator pharma company. Second, to avoid unwanted risk of price escalation, also called speculative pricing, for required comparator drugs by a number of suppliers. Reliable distribution system: Timelines involved in the distribution of comparator drugs are very significant. A sponsor, in most cases, needs to involve a distribution partner to deliver comparator drug supplies to trial sites. Authorised distributors, as well as specialists, do not directly provide the distribution services and in this scenario it becomes indispensable to understand the logistics provider’s global reach and network for effectively managing logistics. Specialist vendors with their own warehouses in both the EU and the US will have a distinct advantage in this area. Management of comparator sourcing: This includes not only the distribution but also the planning and execution of assured comparator supplies for global multicentre clinical trials (GMCTs). For example, if a particular branded drug cannot be shipped from the US to Europe, then the vendor needs to identify the reliable channels in the EU or other geographies, for securing the required volume of these drugs. In the case of biosimilars, it may become a bigger issue, as securing supplies from locations too remote from the specialist’s supplier base becomes more difficult, particularly proper auditing of the supply chain, securing the required documentation, and an assured supply chain. Therefore it is preferred for the supplier to have at least one location in each major region (EU and US).

Table 1 Strategic supplier engagement and selection has become imperative, as comparator trials increasingly become a significant part of pharmaceutical companies’ R&D budget. There is a need to shift from tactical supplier selection to strategic partnerships with best-suited vendors. For example, an authorised distributor may be a reliable partner for small-volume or less complex comparator studies in the US, but a specialist supplier would be needed in Europe. It is clear that securing different types of drugs in different geographies may require alternative sourcing strategies, which is a very dynamic and complex process. To make this process clearer and easier to comprehend, the first step is to understand the category it falls into. This can be achieved with the help of a matrix that takes into consideration all levels of complexities for sourcing these drugs.

Comparator Sourcing Strategy Portfolio Matrix An overview of all major KPIs involved in the clinical trial supply can be extremely beneficial for pharma companies when finalising a strategic supply chain vendor. Following the analysis of these factors, a matrix to understand supplier landscape and capabilities for different scenarios has been created below:

The overall comparator sourcing strategy represents the output of an analysis using the following factors: •

Category Impact: Evaluation of supply risk and complexity in regard to business impact

In-house infrastructure: Many suppliers do not have in-house warehouses or clinical depots for managing comparator drugs on either side of the Atlantic. The EU and North America together hold more than 80% of overall comparator studies, and in this scenario it becomes necessary for a sourcing partner to have its own directly managed warehouse or clinical depot in each territory, thus reducing many of the risks associated in securing and storing comparator drugs. A detailed analysis across the different source types is displayed in the table below: 40 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Fig. 1 Flowchart for comparator sourcing strategy portfolio matrix Autumn 2015 Volume 7 Issue 3


Clinical Research • •

Value Opportunity: Evaluation of value opportunity in terms of difficulty of implementation Supplier Preference: Attractiveness for supplier in relation to relative value of business


approximately 20 different factors (KPIs) for analysis. Relative Value for Business This category provides a close description of the level of impact the current service can have on a client’s business. For example, the overall spend on comparator studies is very small compared to overall R&D budget, despite the category being

Fig. 2 Complexity Analysis The grid provides a holistic view of the level of complexity and risks that the supplier selection can have on the respective category. The complexity level is directly related to the chances of error in the overall clinical trial supply chain. This supply chain consists of three parameters: supply risk, difficulty of implementation of project, and business attractiveness of service or product to the market. This is broken down into


critical to the overall success of pharma companies. Additionally, while selecting suppliers, it is essential to acknowledge that different supplier types can provide different benefits, depending on your needs. The x-axis consists of three parameters: category business impact, value opportunity for client business, and relative value for business opportunity. This is further broken down in over 14

different factors (KPIs). **Complexity consists of both internal (controllable) and external (uncontrollable) factors, and so companies should drive maximum value for a business from a particular level of complexity. Advantages of using the matrix include: • Region-based overview of supplier landscape and effective supplier engagement strategy • Supplier ranking for particular types of comparator drugs in various regions • Determining the best sourcing channels, to ensure comparators are at the right place at the right time • Determining the buyer power, i.e. client’s power, with respect to market • Determining the best-suited suppliers, supplier power and supplier strategies • Business and strategic opportunities available with client • Understanding the need, if any, for a shift to gain more advantage • Understanding what is required in order to gain more business value for a particular level of complexity in the overall supply chain To demonstrate the analysis, a selection was performed to identify a favoured supplier. For this purpose a

Autumn 2015 Volume 7 Issue 3

Clinical Research case study was used, where a large pharma company wanted to understand supplier capability for sourcing branded comparators in the EU. All the factors (KPIs) were analysed and given a rating

detailed analysis between supplier and sourcing type has been shown in the below table.

Disclaimer: Beroe does not promote any company in anyway through this engagement. They have been used solely as a co-author to add value to the content of this whitepaper based on their analysis.

Table 2 between 0 and 10 (0 being no impact and 10 being the highest impact), based on industry analysis. Outcome analysis: • In the EU there is risk associated when working with authorised distributors due to factors such as strict regulatory requirements, supply chain risks and fewer supplier switching opportunities. • Specialists provide higher benefits for the category (higher business value) as well as less complexity in the supply chain process. The significant risk arises in the need to work across multiple countries, each with different regulations. Even a small issue of compliance could affect the trial, and as a result the selection and management of the supply chain is of prime concern for the effective execution of such studies. For branded comparator drugs, an effective strategy would be to work with a specialist or CTS vendor, to outsource the required drugs. The vendors must have substantial experience in the successful management of comparator drugs sourcing for large pharmaceutical companies. These vendors can also provide added value opportunities such as the management of unused comparator drugs after trials are completed. It is clear that securing comparator drugs internationally may require different sourcing strategies, which is a dynamic and complex process. A

Primary Sources: Survey conducted by Beroe with industry experts

Conclusion Based on the authors’ expertise and available market information, several factors that influence the clinical trial supply chain were identified. Following the analysis of over 30 factors, it has become clear that the field of comparator sourcing is complex and there is no simple answer to how a supply manager can identify the best partner. Further research is required to fully understand key strategies for comparator sourcing, supplier selection, risk mitigation, assurance of supplies and regulatory requirements. This analysis provides a clear framework among various types of suppliers for comparator drugs, suggesting a variety of strategies for a number of scenarios. Different types of vendors are required according to particular requirements of the study, such as geographic location, local regulations, and the type of products sourced. Secondary Sources: 1. h t t p : / / w w w. p h a r m e x e c . c o m / tracking-trial-cost-drivers-impactcomparator-drugs-and-co-therapies ?id=&sk=&date=&pageID=3, visited on 10 August 2015. 2. h t t p : / / w w w . edisoninvestmentresearch. com/?ACT=18&ID=11003, visited on 10 August 2015. 3., visited on 10 Aug 2015.

Dr. Mihai Bragaru, Business Development Specialist, Durbin PLC. Dr. Mihai Bragaru is a specialist in CTS & Supplier management, with over 5 years’ experience in pharmaceutical industry. He has a PhD in Medical Sciences and his papers are cited by over 50 authors in the last 4 years. Dr. Bragaru is currently managing the global supply network for the Durbin Group. Email: Mark Walls is currently the Director, Clinical Supply at Verastem, Inc. where he is responsible for overseeing the clinical supply processes for all of Verastem’s clinical programs. This includes providing clinical supply forecasts to CMC and upper management, design of all global clinical trial material labels and oversight of translation and approval and management and oversight of all clinical supply contract vendors. Email: Rahul Sodhi is currently a Senior Research Analyst in – Pharma R&D Beroe Inc. with 3+ years of work experience. His specialization includes understanding and analysing the strategic sourcing opportunities in Pharma R&D value chain. He is a thought leader with various publications in pharma magazines and journals. He has completed his Bachelor’s from National Institute of Technology, Jalandhar (India) in biotechnology background. Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 43

Clinical Research Delivering Patient-centric Support Services in Clinical Trials While patient safety is paramount in clinical trials, there are a number of additional key patient concerns, including recruitment, engagement, retention and compliance. Patients also require significant support throughout a trial for scheduling visits, visit/ medication reminders, completing diaries/questionnaires, emergency medical enquiries, technical device enquiries and simply questions related to their involvement in the trial. The Challenges of Supporting Patients Throughout the Clinical Trial Throughout the stages of a clinical trial, however, this essential patient support presents a number of challenges. Recruitment, engagement and retention starts with ensuring that the pool of patients available to recruit is accurate and up to date. Whether a patient is part of a waiting pool for registration or is an active participant, continued engagement is critical to ensure accuracy of patient information. For example, throughout the life cycle of the clinical trial, there may be changes in a patient’s contact details or personal situation. The clinical trial network is complicated, consisting of multiple vendors and interested parties. Over the course of time, patients’ information can become out of date. Depending upon the enrolment or ‘matching’ criteria, patients may be sat in a ‘waiting pool’ for registration for some time. During the study, clinical outcome assessments (COA) can be recorded infrequently with many months between each visit. Studies, particularly those at the peri/post-approval Phase (IIIb/ IV) can run for many years. These time lags in recruitment and engagement can easily lead to a loss of patient interest, impacting accuracy of the COA or even patient withdrawal. Keeping in regular contact with patients from the registration waiting pool stage until the end of the study is essential to maintain or raise retention and compliance rates. Once actively enrolled in the clinical trial, patients typically contact their participating centre for support regarding their study involvement. Today, a number of different solutions/ devices are employed to capture study 44 INTERNATIONAL PHARMACEUTICAL INDUSTRY

data directly from patients; and in many situations, the study doctor may not have the technical expertise to sufficiently resolve the patient’s question/issue or may not be available when the query arises. While the helpdesk of clinical trial technology providers is able to provide technical support, it may not be capable of handling enquiries direct from patients or may lack the clinical/medical expertise to address all concerns. As a result, the patient may need to inquire from various vendors/helpdesks and/or their study doctor to obtain the assistance needed. Patients can sometimes be left feeling vulnerable and uncertain on the best action to take, and the risks associated with this multi-layered support could lead to patients’ withdrawal or disenchantment with the clinical trial. These risks have the potential to not only impact the outcome of the study but could also adversely impact the patient’s health. Considering these potential negative consequences from the complexities of patient support, it is imperative that patient enquiries are handled promptly, effectively and accurately. Another key consideration is that even though a patient may contact a helpdesk for one reason, the underlying cause for their enquiry could be different. The person receiving this information has a social responsibility to act upon it and take the necessary course of action. To illustrate this, let’s look at a particular scenario: A patient contacts a helpdesk regarding a non-functioning eCOA (electronic clinical outcome assessment) device. As part of the discussion, the patient advises that he/she took a fall and the screen has cracked, making the reading unrecognisable. In the ideal situation, the helpdesk advisor receiving this information would ensure they can respond effectively to both elements of this problem. Firstly, the patient has taken a fall – there needs to be a defined set of questions asked to ascertain the patient’s current wellbeing, and any necessary medical escalation triggered; and the incident must be reported as an adverse event. Secondly, a replacement device needs to be issued and the faulty device returned. A defined process with the

distributor should be established to ensure that a replacement is sent immediately and this process is clearly communicated to the patient. This scenario must be given urgent priority and all necessary actions given immediate attention. It’s clear that in the above scenario, a helpdesk equipped to only respond to technical issues is not sufficient and could lead to the incident being unrecorded in the study and the patient’s medical needs unattended. Global Trials Require Local Support With the ever-expanding global reach of clinical trials, patient access to local support is vital. For the helpdesk, understanding and abiding by the differing local country regulations, and an appreciation of the local language and culture, need careful consideration and planning. Patient data collection, ethics approval processes, safe harbour and storage of patient data all present challenges to research sites who find their resources increasingly stretched in order to keep up with the changing needs of clinical trials. Now that we have explored some of the challenges with providing support to patients in clinical trials in both regular engagement to maintain interest and to answer queries, what can and is being done in the biopharmaceutical industry to address these issues? The Patient-centric Contact Centre Envision a patient-centric contact centre providing 24 hour/7 days a week/365 days a year, multi-lingual, global coverage as the single point of contact for clinical trial support. This solution eliminates confusion over who to contact in which circumstance and provides the benefits of global reach with local language capabilities. The Role of the Implementation Team and the Patient Contact Card In this situation, a dedicated implementation team is responsible for establishing tailored patient support solutions across all stages of the trial – recruitment, engagement, retention and eCOA, ensuring that all of the challenges Autumn 2015 Volume 7 Issue 3

Clinical Research

Figure 1 – Universal patient contact card outlined previously are addressed. This implementation team works in collaboration with the client (sponsor/ CRO – clinical research organisation) to fully understand the complete study support requirements – including all aspects of patient support, whether clinical, medical, logistical or technical.

An implementation team will also ensure that patient contact cards are available and provide patients and participating clinical personnel with all the information they need about the support services in a neat, compact and readily-available package. The patient contact card should have a universal design to ensure that the

contact centre can easily direct the patient, or in the case of the patient presenting themselves at a hospital or clinic other than the study centre, the treating healthcare professional, to the necessary information to assist with queries about the patient’s participation in the study.

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Clinical Research Essential Requirements for a Robust, Effective Contact Centre Responding to enquiries from patients requires a very different approach to handling enquiries from healthcare practitioners. The call volume fluctuates dramatically depending on the ongoing patient activities, including, for example: if the trial is actively recruiting, if the advertising campaign has launched, when eCOA responses are expected, if there has been a recent medical publication launched. A patient-centric contact centre will ensure that their contact agents are knowledgeable and empathetic at all times and that they also have a framework in place that can anticipate, plan and accommodate these changing demands of the clinical trial. Patient engagement is paramount at all times. Establishing this framework provides patients with reassurance that there is someone available to help them, and it serves as a reminder for compliance with eCOA events. Through targeted questioning, it enables that key information about the successes and failures of the trial’s progression are captured, documented and responded to. The patient-centric contact centre should be a global operation, with infrastructure for phone (with toll-free local numbers), web and email enquiries. Where the contact agents do not have local language expertise, translation services should be employed to ensure patients in all geographies are effectively supported. The contact centre should be enabled with resilient technology as well, with multi-redundancy, to assure full service is continuous, even in the case of a global catastrophe. Additionally, patient data confidentiality regulations must be fully complied with at all times and patient agreement must be obtained to ensure these calls do not become considered “nuisance” calls. A patient-centric contact centre should provide regular and up-to-date training to all contact agents and these training records should be readily available for client inspection. Performance monitoring and review of agent score cards is an essential component of high quality service. Ideally, a patient-centric contact centre should have immediate access to a global clinical network to record and resolve the unexpected. Clinical research organisations (CROs) are well placed to 46 INTERNATIONAL PHARMACEUTICAL INDUSTRY

provide this capability to a patient-centric contact centre. CROs also have access to local experts who can advise on medical enquiries and share detailed knowledge of therapeutic areas, associated local regulations, patient confidentiality rules and device shipments. The Growth of Patient-centricity in Clinical Trials and its Impact on the Contact Centre Patients have always been central to clinical trials, but the increasing use of ‘patient-centricity’ as a focus for how clinical trials are being designed has more recently been driven by scientific and technological developments. This includes personalised medicine, eCOA devices and apps, and ‘wearables’ that capture biometric data. Even more, ‘direct to patient’ studies are gaining popularity where it’s possible for patients to take drugs or use devices in their own homes and then submit outcomes directly to the sponsor/CRO. These developments will only increase the importance of the patient-centric contact centre in providing support to patients in using new technologies, addressing any issues with the shipment and return of drugs or ancillary supplies, ensuring eCOA compliance, answering queries about the trial they previously would have asked the study centre staff, and as a place to turn for any concerns and needed assistance. Summary Provision of support for patients needs careful consideration throughout all stages of a clinical trial – from recruitment to close. Study centres and investigators, while traditionally the first point of contact for a patient, can’t answer every query themselves, and can’t be expected to be readily available. The helpdesks of clinical trial technology providers can provide expert assistance on the use of eCOA devices, but may not be able to address the whole picture of a patient issue, including clinical and medical aspects. But patients don’t need the complexity and potential confusion and delays of multiple points of contact for different enquiries (technical, clinical, etc.). Trials are increasingly global, bringing in countries and sites with limited clinical study expertise and local requirements including language, culture and regulations. The patient-centric contact centre needs to be available continuously (24/7/365), providing a single point

of contact with global coverage and local capabilities, ensuring that patients can easily access support and get effective, rapid response wherever they are located. Services should be tailored by an implementation team to meet the specific needs of the sponsor/CRO and protocol. The contact agents must be fully trained to provide accurate answers and fast routing of enquiries or issues to the right technical or clinical experts – all while maintaining patient confidentiality and adhering to regulations. Large, global CROs can provide the needed clinical and medical experts to support escalation of and knowledgeable response to patient queries or issues that require medical training and access to the study protocol and investigators brochure. As trials become more ‘patientcentric,’ the contact centre will be at the heart of keeping patients engaged, compliant, safe and retained, enabling sponsors/CROs to determine the efficacy and safety of new treatments more efficiently.

Julia Lakeland, BA (Hons.) is the Senior Director, Customer Care Services at PAREXEL. She leads the department responsible for the provision of externally facing, multilingual support services via global locations based in the UK, US, India, China and Japan. In her role, she has expanded the group from providing standalone technical support through to the global multi-functional clinical trial support centre that is today responsible for providing a range of both technical and vital clinical trial support services, including 24/7 medical escalation and patient support. Prior to joining PAREXEL, Julia was formerly with ClinPhone and has held positions within the company since 1999. Email: Autumn 2015 Volume 7 Issue 3

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Clinical Research Orphan Drug Trials: Putting the Patient First

Over recent years, there has been a notable increase in the number of orphan drugs being successfully brought to market. Here, Greenphire’s Jennifer Peters speaks to International Pharmaceutical Industry about the orphan drugs market, the unique logistical challenges faced by organisations when conducting clinical trials for this type of drug, and how addressing payment processes and financial management strategies can overcome them. Firstly, can you define what orphan diseases and orphan drugs are? Certainly. An orphan disease or disorder is a condition that affects a small percentage of the population. There are somewhere in the region of 5000-8000 rare diseases, affecting approximately 30 million people worldwide. So despite these orphan diseases being individually very rare, as a group, they are actually quite widespread. It’s worth noting that although the number of diseases may seem high, in fact, around 80% of sufferers are affected by just 350 of these conditions.1 While the nature of them varies greatly, we can pick out certain trends. For example, in certain cases, rare disorders and diseases are as a result of infections, allergies or the environment, but as high as 80% of sufferers have their condition due to genetics, which means they are likely to be present throughout that person’s entire life.1 Put simply, orphan drugs are pharmaceutical products aimed specifically at diagnosing, preventing or treating these diseases and conditions. So, what is your outlook on the orphan drugs market at the moment? Orphan drugs represent an increasing share of new drugs being studied and brought to market. In the US alone, over 450 new medicines are currently being developed, and between 2008 and 2013 an im-pressive one-third of FDA approvals were for orphan drugs.2 There is likely to be little slowdown in the growth of this market, with sales of orphan drugs in the US, Europe and Japan expected to total $176 billion by the end of 2020, which is an annual growth rate of nearly 11% per year. This can be put into context 48 INTERNATIONAL PHARMACEUTICAL INDUSTRY

when we consider that this figure is only around 4% for non-orphan drugs.3 With the overall cost of developing these drugs typically less than nonorphan drugs, partly due to smaller study populations, as well as the drugs commanding higher prices when they do launch, it is no wonder that the industry has backed the development of this type of medication over recent years. What factors do you think are impacting this rise? The potential for significant return on investment is an influencing factor, however, there is no doubt that the increase in orphan drugs being brought to market has been impacted by the introduction of the Orphan Drug Act of 1982. The act encourages organisations to develop drugs for diseases via a range of incentive programmes, including grants, research design support and market exclusivity for seven years (US), as well as tax credits of up to 50% of R&D costs and waived FDA fees.4 Such incentive programmes have significantly increased the number of orphan drugs in development and on the market. The US programme, for example, has successfully enabled the development and marketing of 400 drugs and biologics since 1983, compared to fewer than 10 in the 1970s.4 All this said, despite these advances, there is still only treatment for a relatively small percentage of rare diseases, confirming the need for further investment into this area. What are today's challenges when it comes to ensuring high-quality outcomes in orphan drug trials? Orphan drugs generally follow the same regulatory development path as non-orphan products, mean-ing organisations looking to develop this type of product are faced with many of the same challenges as the wider industry. For example, recent years have seen an increase in global trials as well as a rise in financial demands, meaning studies across all drug types have become more complex and consequently, more difficult to manage. In line with this, protocol complexity and related administrative burden has also grown significantly.

Are there any challenges specific to orphan drug trials? Yes. There are also some fundamental differences when conducting trials for orphan drugs compared with non-orphan products, which pose a number of unique challenges for sponsors and CROs, particu-larly in terms of logistics. Firstly, patient populations for orphan drug trials are naturally much smaller than non-orphan drug trials and often hard to come by. This means that designing and executing a trial which is effective the first time is paramount, as there is little opportunity to make and learn from mistakes. In addition to this, the study population is also likely to be geographically dispersed, so the distance between patients and trial sites can be a huge barrier to trial efficiency. The logistical challenges of physically getting patients to and from study sites can be difficult and is something that is often not given substantial thought in study design. Sponsors and CROs need to consider that the patients may have already made personal investment to obtain diagnosis or treatment for their condition. They may also have a caregiver that needs to travel with them, or they may require special accommodation due to their disease. All of this needs careful attention and planning by the study team because if the patient’s experience, including any cost implications, is not managed properly, then retention levels and quality of results are likely to be compromised. Is it difficult to find study sites and investigators suitably qualified and equipped to run a rare disease study? Absolutely. Finding and choosing a suitable clinical site for an orphan drug trial is one of the toughest challenges faced by sponsors and CROs. If a condition is particularly rare, there may only be two or three hospitals in the world that can conduct the study, and it is also feasible that these hospitals may not have the infrastructure in place typical of more experienced clinical sites. Sponsors and CROs must work closely with on-site study teams to elevate their processes and educate them on the level of rigour that needs to be applied, to ensure it is Autumn 2015 Volume 7 Issue 3

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Clinical Research prepared and has sufficient sup-port in place to be able to undertake the study, and importantly, get it right first time. In terms of the participants in orphan drug trials, are there any key considerations for sponsors and CROs looking to work with this population type? Because the stakes are so high with individual patients in an orphan drug trial, understanding them and managing their experience is paramount. Patients with a rare disease or disorder are likely to have been through a long and difficult process to get a diagnosis, with many patients in the US waiting around seven years for a diagnosis and slightly less in Europe. What’s more, before their condition is confirmed, most sufferers will have already been given on average two or three misdiagnoses. Even though they are potentially facing severely reduced quality of life and/or reduced life expectancy, because of the nature of rare diseases, there are often limited, or in some cases no treatment options available to patients. This, coupled with a lack of available information or resources on their condition, as well as limited access to qualified physicians, means that it is not uncommon for patients to have to serve as their own researcher and care coordinator. Even if there are treatment options available, they are often expensive, and patients can face potential difficulties in getting adequate coverage from payors. This challenging experience means that sufferers of rare diseases may face increased emotional and financial pressures, and may quite understandably be either very passionate about participating in a clinical study, or very resistant to do so. You say the patient experience is paramount, so what best practices can organisations employ to bet-ter manage this? ‘Patient-centricity’ is a buzz phrase in the clinical trials industry, and it’s no different with orphan drug trials. In fact, taking what I’ve just discussed about considering the patients’ circumstances, orphan drug trials should be even more centred on the individual. While a truly patient-centric approach is the only, and obvious, way to go, for some in big pharma, this is a difficult concept. Many organisations are still fighting the shift in approach and failing to recognise 50 INTERNATIONAL PHARMACEUTICAL INDUSTRY

that by improving patient management and the various administrative processes during the course of a trial, they can not only dramatically reduce the logistical challenges associated with undertaking this type of study, but also enhance patient engagement and boost compliance. As previously discussed, investigators conducting orphan drug trials may not have the infrastructure in place typical of more experienced sites. Their relevant experience is often clinical, and their staff may have limited ability to manage logistics and the complexities of paying travel vendors or reimbursing subjects. Our work with sponsors of orphan drug trials has revealed several necessary best practices which sup-port a patient-centric approach and help address the specific logistical challenges of orphan drug trials. Firstly, it’s vital to provide a single resource for patients and study co-ordinators to access help with logistical arrangements, providing instant and accurate information for patients. Arguably one of the most important elements of best practice within an orphan drug trial is the successful management of costs. No matter how temporary, sponsors should never place any financial burden on patients and should also limit cash outlay by clinical sites. For any costs that are absorbed by patients, sponsors need to be able to deliver immediate reimbursement remotely. Managing costs without sacrificing the patient experience is a key factor to success. Developments in clinical trial technology offer the opportunity to address this and streamline the whole study process. Can you provide further details on the clinical trial technology you mention and how it can help or-ganisations better manage the finance and logistics of their trials? Advancements in technology offer the potential to break down barriers in orphan drug trials, alleviating the challenges of having patients on different time zones and continents, and generally making the whole study process much more streamlined. By automating processes, web-based payment platforms provide sponsors with a single resource for patients and study coordinators to access help with logistical arrangements and remove the administrative burden from investigative sites. Sponsors and sites are able to deliver patient payments in real-time,

while tracking and monitoring all transactions, eliminating the potential for human error and overcoming many of the limitations associated with the calculation and execution of global payments in orphan drug trials. As mentioned previously, the wide geographic spread of the patient population in an orphan drug trial makes the requirement for patient travel highly likely. New technologies can now deliver travel services that are designed specifically for trials that require complex travel arrangements. This eliminates the administrative steps necessary to manage travel and patient reimbursements, making them an ideal solution for orphan drug studies. Finally, what does the future hold for the orphan drugs market? If current market trends and industry predictions are anything to go by, then there does not appear to be much to slow down the increase of orphan drugs trials, and it is likely that the number of orphan drugs that are successfully brought to market will rise. This, combined with the associated logistical challenges of this type of trial, will continue to drive demand for more effective patient centric solutions, which at the same time improve trial processes for study investigators. Ultimately, sponsors who recognise this and who implement solutions that provide more patient-focused management of study logistics, will reap the benefits of enhanced patient engagement and compliance, resulting in higher trial success rates in this unique area of clinical research. References 1. Diseases_2013.pdf 2. 3. 4.

Jennifer Peters is one of Greenphire’s founders and first investors. She currently serves as Greenphire’s Chief Experience Officer, ensuring that Greenphire’s clients have an outstanding user experience and continuing to assess and improve Greenphire’s processes on behalf of our clients. Prior to Greenphire, Jennifer spent over 10 years at a large global communications company, where she oversaw several regional offices including Boston, Minneapolis, and Philadelphia. Primarily focused on highly regulated industries such as life sciences and finance, Jennifer helped establish global relationships with pharmaceutical industry leaders including AstraZeneca and Wyeth, among others. She has published articles on translation in the life sciences industry, and can be read in DIA Forum and Future Pharmaceuticals. Email:

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Rapid and Traditional Methods in the Contract Microbiology Laboratory In the world of contract testing, we are bound by regulatory guidelines and high client expectations. We perform the necessary safety and performance testing of pharmaceutical and medical device products that will be used by the general public. It is therefore vital that we work to prescribed guidelines with our performance under constant review through audits by regulatory bodies and our clients. Most people associate science with cutting edge techniques and technologies in the laboratory setting. Unfortunately, though, most microbiology laboratories involved in contract testing perform very traditional and prescribed methods set out by regulators and requested by clients, leaving very little room for innovative technologies and techniques. Uptake of new techniques and technologies into standards such as ISO, Ph. Eur, USP, JP etc. is often slow, which can be frustrating for scientists and clients alike. Advisory boards and other interested parties can take many years to reach a consensus on how testing should be performed in these standards to meet the discerning eye of the regulatory inspector. However, there have been recent efforts to bring on new technologies into some of the standards, as well as efforts by advisory boards and companies to validate new rapid microbiology methods. RMMs are an expanding area, with limited uptake by scientists governed by GMP guidelines but far better adoption in other sectors, for example, “hygiene” type monitoring in the food industry, as well as in the clinical microbiology setting, where time is the most valuable commodity. As an expanding area of microbiology, RMMs are vast and diverse in nature and are now being looked at seriously by microbiologists as viable alternatives to the traditional methods we are accustomed to. There are pros and cons to any method used in testing, and RMMs are no exception to this. Some of these pros and cons have been set out for RMMs versus traditional microbiology methods in Table 1. 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY

RMMs can bring significant cost and time savings (Table 1), though the most common barriers to entry with RMMs are the initial cost of the investment and the costs and/or perceived difficulty in bringing these tests in-house in a compliant manner1. The costs of RMMs may be several thousand pounds to hundreds of thousands of pounds to purchase and implement, depending on the complexity of the equipment in question. As a result many companies will simply continue with existing traditional microbiology methods and/or contract the work out to a contract testing laboratory or specialist lab. Most companies investigating the use of RMMs in their processes are looking to significantly reduce their costs through increased throughput, time to result and reductions in labour. There is an increasing demand to get product to market more quickly, and more importantly to get them to market safely. In order to use RMMs to do so, microbiologists have to be convinced of their ability to detect and identify microorganisms, even more so than in traditional methods. This means potentially screening most, if not all, products in a batch prior to release, or even quicker turnarounds on products that rely on parametric release. In addition, many pharmaceutical and medical device manufacturers are also unsure how they cope with the VBNCs and stressed environmental organisms that can now be picked up by more sensitive methods, and are reluctant to address the changes that need to be made in-house to accommodate this shift1.

The Sterility Test The most obvious microbiological test that would benefit favourably by using a RMM is the sterility test. The traditional sterility test has a 14-day incubation period which prevents timely release of product to market, or subsequently means a product may have already been in use before a test result is confirmed, e.g. in short shelf-life products. Only a small number of samples within a batch of product are tested, meaning the number of samples tested is often not statistically significant (varies depending on product and batch size) and may mean a contaminant is present but simply not detected2. The product is, like in many microbiological tests, tested to destruction, meaning it cannot be investigated if a suspect result is found. In the sterility test, the end result is measured by turbidity determination with the naked eye, which is open to subjectivity and any turbidity caused by product presentation could present as a false positive result. The sterility test method also uses two liquidbased broths at set temperatures (2025°C and 30-35°C), which “theoretically” covers the growth requirements of a large number of organisms. Yet we know that VBNC organisms, slow-growing organisms and organisms with complex culturing conditions will simply not be detected using this method2. Current RMMs Traditional microbiology still rules in today’s laboratories. Microbiologists still conduct many standard assessments using Gram or other differential stains, colony morphology, cell morphology, selective media, manual counts and biochemical assays such as API and Vitek 2 to determine the presence (or absence), Autumn 2015 Volume 7 Issue 3

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Labs number and identity of microorganisms that they culture. There are many types of RMMs, each with different parameters and result formats. There are three main categories; qualitative, quantitative and identification. Qualitative RMMs detect the presence of microorganisms in products. There are a number of tests currently available that measure changes in impedance, CO2 (via colour change in media) or pressure (headspace pressure) that signal microorganism growth. There are also methods such as polymerase chain reaction (PCR), flow cytometry and endotoxin tests (Limulus ameobocyte assay test) that can be used to more rapidly detect presence of microorganisms (or related bacterial endotoxins in the case of LAL). ATP measurements are also becoming more commonplace and have been used very successfully in hygiene monitoring to detect contamination. There is some difficulty perceived when comparing RFUs (relative fluorescence units) yielded by the ATP assays with CFUs (colony forming units) detected by traditional means, and how exactly these relate to one another1.

as long as a couple of days depending on the microorganism’s growth requirements and “stress” status. An alternative to the more traditional microbiological tests is matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-ToF). This is a different phenotypic identification method used to determine the identity of a microorganism on the basis of a protein profile or ‘fingerprint’. It is relatively inexpensive to run samples in the MALDIToF equipment and results are available in minutes, but there is a large outlay cost that is seen to be prohibitive for small throughput in smaller laboratories. PCR or nucleic acid-based methods can be used to identify organisms based

on the 16s rRNA gene (or 16sDNA) in bacteria or the 26s rRNA gene, ITS or D2 region in fungi. They can provide a result in a matter of hours, most likely an overnight run, but can identify to a very distinct level (type or sub-type) so are used commonly in determining the exact source of sterility failures or serious contaminant route cause analysis3. Guidance on Validation of RMMs As discussed previously, a small number of companies have been successful in validating alternative methods to the acceptance of the regulatory authorities. The main goal in RMM validation is providing proof that the RMM exceeds or is at least equivalent in a number of areas as per 21 CFR <610.9> and other regulatory authority guidelines4.

Quantitative RMMs are capable of providing a numerical value on the microorganisms present in a known sample unit. This is useful across the spectrum of microbiological tests. PCR is again useful as it is capable of quantifying as well as detecting the presence of microorganisms (commonly RT-PCR) in a matter of hours. There are also other methods that utilise direct detection of microorganisms using digital imaging of microcolonies (far too small to be seen with the naked eye) growing on solid media or filters as in direct laser scanning, light scattering, ATP bioluminescence and auto fluorescence methods. Methods such as flow cytometry and raman spectroscopy are also coming to the fore in quantitative RMMs, providing a much quicker time to result than the standard incubation and detection procedures used in most microbiology laboratories1,3. Traditional biochemical tests can still be found in microbiological identification and have been refined over the years to be semi-automatic and less reliant on the user’s interpretation of results. As a result, these tests are able to produce results in as little as a few hours but can often take 54 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2015 Volume 7 Issue 3

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Labs of the guidelines are very similar to each other in their requirements for validation of RMMs. The regulatory guidelines may require a combination or all of the following to be completed, depending on the nature of the RMM in question and its purpose; testing for accuracy, precision, specificity, limit of detection, limit of quantification, linearity, range, ruggedness, robustness and equivalence testing6.

There are now even standard methods in the compendial procedures, for example in the microbiological control of cellular products Ph. Eur 2.6.275). which use RMMs. This would seem to derail the point that most companies make regarding regulatory bodies not being fond of RMMs. On the contrary, regulatory authorities want more robust, sensitive and timely tests to prevent the devastating and often high-profile cases of contamination of pharmaceuticals and biologicals that have been seen in recent years. Many will remember the multi-state incidents in the United States in 2012 of deadly meningitis caused by mould contamination in steroid injections.

Conclusion RMMs are definitely the future of microbiology and we are seeing rapid advancement in the technology capable of detecting, quantifying and identifying microorganisms. It is bringing with it some uncomfortable truths about how much we know about contaminants, VBNC and the downfalls of some of the traditional methods. Companies will have to look at this new data and interpret what it means to them and their product or process. Many laboratories will also have to branch out into techniques and new methods different to those they have become accustomed to over the years, and it is well known that old habits are notoriously hard to break. Many also believe there is value in keeping the traditional methods in microbiology alive, such as the Gram stain, identification by appearance, smell and biochemical reactions, and fear this will be forever lost when RMMs are used more widely. This is unlikely to be the case as many methods require some understanding of microorganisms, even at a basic level of bacteria, yeast, fungi, Gram positive, Gram negative, etc. to perform the tests and to understand what remedial steps have to be taken upon identification or detection of problematic microorganisms in a process or product. We will continue to rely on more traditional methods to determine such things as what decontamination processes should be used, whether processes should be changed, and whether personal protective equipment (PPE) should be worn to prevent cross-contamination during a process.

There are a number of documents that provide outline guidance on how to go about validating a RMM, such as the PDA Technical Report 336, Ph. Eur 5.1.6, USP Chapter <1223> and FDA CBER Draft guidance document, to name but a few. The validation methods are not wholly dissimilar to those for validating other methods in the GMP environment, and all

Acceptance of RMMs is slow in the pharmaceutical environment, but will be driven by the regulators championing these technologies and working with companies to help them overcome some of the hurdles along the way. Companies working on lean initiatives will also have to look hard at their processes and the bigger picture of the potential benefits in


cost savings, labour reduction and most importantly increased patient safety in order to bring RMMs to reality in a way that works for their process and product. Hopefully some of the early adopters of RMMs with encouragement of the regulatory bodies will facilitate uptake and confidence in RMMs. However, given the relatively slow change in many of the traditional microbiology methods over the past 70 or more years, it seems the likes of the traditional sterility test will be with us in current form for some time yet. References 1. PHSS. Bio-contamination Technical monograph No. 20 Biocontamination characterisation, control, monitoring and deviation management in controlled/GMP classified areas. (2014) 2. Jeanne Moldenhauer. Rapid Sterility Testing. (2011) 3. files/matrix.php, visited 6 August 2015. 4. 21 CFR <610.9> Equivalent methods and processes (2014) 5. European Pharmacopoeia Ph. Eur 2.6.27 Microbiological control of cellular products. 6. PDA. Technical Report No. 33. Evaluation, validation and implementation of new microbiological testing methods. (2013).

Dr. Lynne Murdoch joined Wickham Laboratories Limited in 2014 as part of a strategic initiative to push forward research and development projects within the company. She received her degree in Microbiology and Immunology from the University of Strathclyde in 2007 and subsequently pursued a PhD in Microbiology/Electronic and Electrical Engineering. Building on her background in microbiology, Dr. Murdoch has spent her career gaining expertise in the identification and validation of new products, services and technologies for the life sciences field. Her most recent accomplishment is the launch of an R&D department at Wickham Laboratories Limited. Email: Autumn 2015 Volume 7 Issue 3



Contact Killing on Copper Surfaces: From Lab to Application As evidence grows for the key role of the environment in the spread of infection, the selection of materials for hygienesensitive environments is moving up the agenda, and copper is leading the way with unmatched efficacy against headline-making pathogens. This article provides an update on the expanding evidence base – from laboratory experiments to clinical trials – and illustrates the growing adoption in healthcare and other sectors. Proven Laboratory Efficacy Copper is well-established as a powerful antimicrobial with rapid, broad-spectrum efficacy against bacteria and viruses, including MRSA, E. coli and norovirus. ‘Antimicrobial copper’ is the umbrella term for pure copper and the family of copper alloys – including brass and bronze – that benefit from the metal’s inherent antimicrobial efficacy. Copper’s antimicrobial properties have been documented in scientific literature for more than a century, but it was not until 2000 that its efficacy against the pathogens responsible for healthcare-associated infections (HCAIs) began to be assessed. 15 years on, more than 60 papers report copper’s efficacy against bacteria, viruses and fungi – hence the term antimicrobial rather than antibacterial or antifungal. Antimicrobial copper touch surfaces work as an adjunct to existing infection control measures – such as handwashing and regular surface cleaning and disinfection – which should continue as normal once copper is installed. Claims of antimicrobial efficacy made for many antimicrobial products are based on JIS Z 2801 and ISO 22196 tests, conducted at >90% humidity, 35°C and over 24 hours under a plastic film. These basic tests are described as a proof of principle, and do not indicate how a material will perform in the field. To better represent actual inuse conditions when testing copper, 58 INTERNATIONAL PHARMACEUTICAL INDUSTRY

researchers developed new protocols to reflect typical room temperature and humidity, and used representative contaminants. Laboratory research on the antimicrobial efficacy of copper and copper alloys has been carried out and verified at institutions around the world, with results peer-reviewed and published in respected journals. They exhibit efficacy under typical indoor conditions, unlike silver-containing materials and triclosan, which showed no antimicrobial efficacy under these conditions, as shown in Figure 1.1

bacteria. A. Copper ions dissolved from the copper surface cause cell damage. B. The cell membrane ruptures, leading to loss of the cell content. C. Copper ions lead to the generation of toxic radicals which cause further damage. D. DNA becomes degraded and leaves the cell.

A Swiss research group investigated the role physical contact of bacteria with the copper surface has on contact killing.3 They engineered special copper surfaces covered with an inert polymer mesh with holes of less than 1 micron diameter. This size is smaller than the test organism, Enterococcus herae, which meant the grid prevented the bacteria from making contact with the copper surface. They found that while the release of ionic copper was no different, the Figure 1 MRSA viability on copper, silver- and triclosan- killing was reduced coated materials and stainless steel at room temperature and by seven orders of humidity over six hours.1 magnitude compared to untreated copper. They concluded that Kill Mechanism copper ion release and bacterial-metal The exact mechanism by which copper contact were important for efficient kills bacteria – so called ‘contact killing’ – contact killing. is still unclear, however several processes have been identified and research groups Resistance is Futile around the world are investigating, using As bacteria evolve resistance mechanisms different bacterial systems. One proposed sequence of events is given below,2 though it’s worth noting that the sequence and importance of different steps may be different for Gram positive and Gram negative Figure 2 Autumn 2015 Volume 7 Issue 3

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Labs to antibiotics, the possibility of resistance to copper developing needs to be considered. This is considered highly unlikely for three reasons: •

Copper kills microorganisms by multiple pathways rather than by acting in a specific way on one receptor as do most antibiotics. Microorganisms are killed rapidly, before they can replicate, thus they cannot pass on genetic material which could ultimately lead to the development of resistance. Copper is naturally present in the earth's crust and, to date, no resistant organisms have been demonstrated. Coppertolerant organisms do exist, but even these die on contact with copper surfaces. In comparison, resistance to penicillin by certain bacterial species began to appear within 30 years of its introduction.

Horizontal Gene Transfer At the University of Southampton in the UK, a research team led by Professor Bill Keevil – one of the foremost experts on copper’s antimicrobial properties – has demonstrated copper’s efficacy against bacteria and viruses, including norovirus and Influenza A. They have also investigated the kill mechanism – with a recent focus on the DNA destruction – and investigated horizontal gene transfer (HGT) on copper and stainless steel surfaces.4 HGT in bacteria is largely responsible for the development of antibioticresistance, which has led to an

increasing number of difficult-to-treat HCAIs. Professor Bill Keevil, Chair in Environmental Healthcare at the University of Southampton, explains: ‘Whilst studies have focused on HGT in vivo, this work investigates whether the ability of pathogens to persist in the environment, particularly on touch surfaces, may also play an important role. We show prolonged survival of multidrug-resistant Escherichia coli and Klebsiella pneumoniae on stainless steel surfaces for several weeks. However, rapid death of both antibiotic-resistant strains and destruction of plasmid and genomic DNA was observed on copper and copper alloy surfaces, which could be useful in the prevention of infection spread and gene transfer.’ Copper’s Role in Reducing HCAIs A recent translational science article discussed copper alloys as antimicrobial environmental surfaces, summarising the evolution of the evidence base for copper, from the laboratory to the clinical environment.5 The paper included the results of the largest clinical trial to date, which assessed copper’s efficacy in the most challenging of clinical environments: intensive care units . The multi-centre trial – funded by the US Department of Defense – took place in the ICUs of three hospitals and aimed to answer the question ‘Will the bioburden reduction associated with the installation of copper surfaces reduce the number of infections?’ The trial team found that replacing just six key, near-patient touch surfaces reduced the incidence of infections by 58%.6 Figure 1 shows the accompanying reduction in microbial burden on the six surfaces.7

Just 10% of touch surfaces were upgraded to antimicrobial copper, yet the impact was significant. This study is the first to report a correlation between environmental bioburden (whether in copper or control rooms) and the risk of acquiring an infection, and to show a Figure 3 Sustained reduction of microbial burden on reduction in that risk due to common hospital surfaces through introduction of a minimal intervention with copper. Proposed hygiene standard level is indicated an effective antimicrobial in orange.8 material. 60 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Figure 3 demonstrates this correlation, with quartile distribution of HCAIs stratified by microbial burden measured in the ICU room during the patient’s stay. There was a significant burden association between burden and HCAI risk, with 89% of HCAIs occurring among patients in rooms with a burden of more than 500 cfu per 100 cm2.6

Figure 4 Quartile distribution of HCAIs stratified by microbial burden measured in an occupied US ICU room. The trial found an 83% reduction in bacteria on copper alloy components in comparison with surfaces made of standard materials in the control rooms. This reduction corresponded to a 58% reduction in infection rates in patient rooms with components made of copper in comparison with patient rooms containing components made of standard materials. The authors concluded: Bacteria die on copper alloy surfaces in both the laboratory and the hospital rooms. Infection rates were lowered in those hospital rooms containing copper components. Thus, based on the presented information, the placement of copper alloy components in the built environment may have the potential to reduce not only hospital-acquired infections but also patient treatment costs. Does Copper Offer a Cost-effective Intervention? Copper and its alloys are sometimes perceived as expensive, however they continue to be widely used throughout industry because they offer good value. Most of a component cost comes not from the intrinsic material value, but a combination of fabrication and fitting costs. Copper alloys are widely used for complex components – such as taps and locks – because they are easy to fabricate. Fitting costs are broadly the same for any given component. Professor Tom Autumn 2015 Volume 7 Issue 3

Advertorial Temperature-safe Airfreight Packaging for Euro Pallets Minimising the Risk for a Full Euro Pallet of your Thermo Labile Products at a Reasonable Price Do you want to transport pallets with valuable pharmaceutical products at a stable temperature? Reliably and without power supply from outside? Many products that are shipped for pharma companies, importers and wholesalers can quickly be damaged if the correct temperature is not ensured during the entire transport. Substantial values are at stake. If the products are affected by warmth or freezing cold, the quality of the product decreases, gets ineffective or even becomes dangerous when used. In the last two years, there has been an increasing focus on temperature-safe transport, since the European Guidelines on Good Distribution Practice of Medicinal Products for Human Use (GDP) read: “The required storage conditions for medicinal products should be maintained during transportation within the defined limits as described by the manufacturers or on the outer packaging.” While cold chain 2°C to 8°C is well known in the logistics community, controlled room temperature (CRT) covers a large proportion of pharmaceutical products. The most common temperature ranges shown on pharmaceuticals are 2°C to 8°C, 15°C to 25°C and 2°C to 25°C. There is still a need for more safety, but there are cost restrictions. While thermo covers are not able to hold the temperature long enough in this range, active cooling systems are expensive; well-insulated packaging large enough for the pallet is the solution. How to Find a System that Works The logistics manager needs to find a suitable way to transport valuable goods from A to B. To find the right cost-effective and temperature-safe packaging, it is necessary to analyse the risks involved. There are a number of known problems in temperature-safe transport. If there are many companies involved and your product changes hands during transport, the task is complex and riskier. A huge problem is temperature

For a small number of elements this process takes 48 hours. Once the elements are solid you can start the packaging. First, the pallet of goods must be placed on the bottom part, and the delta T Fluid elements must be placed around the goods. Now close the pallet shipper with its four side panels. Finally put the Accu lid on top and, after wrapping with stretch foil, the system is ready to go. The whole procedure takes no more than 15 minutes. Now the freight can be transported from door to door, without the risk of leaving the pallet in an unprotected environment.

excursions, when the freight is outside protected environments. While the pallet is on a ramp waiting for loading or on the tarmac of an airport, temperatures can reach up to 60°C in Middle East countries, or fall far beyond freezing level in Scandinavian airports. Protecting your pallet of products from the beginning to the end will provide a significant improvement to avoid the described temperature excursions. delta T GmbH offers an insulated EPS Pallet Shipper with passive temperaturestabilising delta T fluid elements, that meets this criterion. The temperaturestabilising elements contain delta T fluid and absorb heat by their crystalline structure. The temperature inside the EPS Pallet Shipper stays in the selected range until the melting process is over.

How Long Will the Temperature Stay Constant? As long as desired. 120 hours is the standard run time, but the duration depends on the combination of the insulation and the number of delta T fluid elements, as well as the outer temperature. For one-stop airfreight routes, a 72-hour system without vacuum panel insulation is sufficient. By doubling the amount of fluid elements, the temperature will hold twice as long. Due to the construction of the lid-system, a patent of delta T GmbH, transport time could also be easily increased by changing cooling elements in the lid cavities during transport, or when encountering unexpected delays. Contact delta T GmbH Industriestrasse 13 35463 Fernwald Germany

Using the EPS Pallet Shipper 1200L for a 2°C to 8°C Airfreight Transport First the delta T fluid elements must be precooled for a certain period of time until the fluid is solid. This will occur when the temperature is at least 2 degrees below the fluid´s melting point. The pre-cooling time depends on the number of fluid elements. INTERNATIONAL PHARMACEUTICAL INDUSTRY 61

Labs Elliott, leader of the Selly Oak research, has stated that ‘the cost of fitting out the 20-bed trial ward was equivalent to the cost of just one-and-a-half infections.’ The US research group calculated the time to recoup the cost of installing the copper components.5 They first calculated the cost difference between all the copper and standard components used in the trial (52,000 USD). Then, they calculated the cost savings made during the 338 days of the trial by saving 14 infections at 28,400 USD each (397,600 USD). This gave a daily saving of 1,176 USD, so payback was calculated as 52,000/1,176 = 44 days.

Installations have taken place in hundreds of facilities around the world, with hospitals and clinics leading the way whilst care homes, schools, gyms, airports and train stations also incorporate antimicrobial copper touch surfaces to improve hygiene. The first pharmaceutical facility to install copper is PharmaQ – a manufacturer and distributor of pharmaceutical products for the healthcare industry, based in South Africa.

The calculation was based on the US cost of infections and the cost of copper components before they were commercially available.

PharmaQ’s then CEO, Dan Breet, hit upon the idea of using copper to tackle problems with the bacterial load on packing tables in the laboratory, which was frequently inspected by officials from South Africa’s Department of Health.

York Health Economics Consortium (YHEC) – leading global health economists based at the University of York in the UK – developed a model to enable estimates of payback to be made for new builds or refurbishments. The model uses costs of infection in UK ICUs and a cost differential between copper and standard components based on recent industry data.

One side of a stainless steel packing table was replaced with brass, and microbial levels on this were compared with those on the other, stainless steel side. The average count of colony forming units was consistently and significantly lower on the copper, and PharmaQ is planning a presentation at a future pharmaceutical conference and further deployment of copper surfaces.

The model allows different infection reduction rates to be inputted. Using the US data (58% reduction in infections), payback is achieved within one month and a sensitivity analysis shows that even at 20% efficiency, payback is within two months.

Laboratories are also harnessing the antimicrobial power of copper, with the latest example being an incubator at the University of Liverpool Biological Sciences Department in the UK. Preventing contamination within the incubator was a high priority, so they opted to install one with an antimicrobial copper lining, in addition to the standard HEPA filtration and a high-temperature decontamination cycle.

The model’s authors conclude: ‘This is an engineering solution needing capital budget (typically held by Facilities/ Estates) but with impact on infection prevention, cost of care and clinical outcomes. This therefore requires a high degree of understanding and collaboration at senior decision-making level.’ Awareness and Adoption Key healthcare watchdogs and horizonscanning bodies around the world – including ECRI Institute and The Canadian Network for Environmental Scanning in Health – have recognised the growing body of evidence for copper’s potential to boost infection control. It has also been acknowledged in the UK’s evidencebased EPIC 3 guidelines, which included copper as an emerging technology in 2014.9 62 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Availability Copper alloys offer a wide palette of colours – from the gold of brasses to the rich brown of bronzes right through to the silver/white shades of copper-nickels. Copper alloys will naturally darken over time, but this does not impact their antimicrobial efficacy. More colourstable alloys – traditionally used in naval applications – are also available. The evidence base for copper is growing, in both lab and field tests, and this is now leading to adoption of antimicrobial copper surfaces by hospitals, care homes and other hygiene-sensitive environments. The supply chain is responding by continuously growing the

range of antimicrobial copper products and alloy options available. References 1. Michels, H. et al. 2009. Effects of temperature and humidity on the efficacy of methicillin-resistant Staphylococcus aureus challenged antimicrobial materials containing silver and copper. Letters in Applied Microbiology. 2. Grass, G. et al. 2011. Metallic Copper as an Antimicrobial Surface. Applied and Environmental Microbiology. 3. Matthews, S. et al. 2013. Contact Killing of Bacteria on Copper is Suppressed if Bacterial-Metal Contact is Prevented and is Induced on Iron by Copper Ions. Applied and Environmental Microbiology. 4. Warnes, S.L. et al. 2012. Horizontal Transfer of Antibiotic Resistance Genes on Abiotic Touch Surfaces: Implications for Public Health. mBio. 5. Michels, H. 2015. From Laboratory Research to a Clinical Trial: Copper Alloy Surfaces Kill Bacteria and Reduce Hospital-Acquired Infections. Health Environments Research & Design Journal. 1–16. 6. Salgado, C.D. et al. 2013. Copper Surfaces Reduce the Rate of Healthcare-Acquired Infections in the Intensive Care Unit. Infection Control and Hospital Epidemiology. 7. Schmidt, M.G. et al. 2012. Sustained Reduction of Microbial Burden on Common Hospital Surfaces through Introduction of Copper. Journal of Clinical Microbiology. 8. Schmidt, M.G. et al. 2012. Sustained Reduction of Microbial Burden on Common Hospital Surfaces through Introduction of Copper. Journal of Clinical Microbiology. 9. Loveday, H.P. et al. 2014. Epic3: National Evidence-Based Guidelines for Preventing Healthcare-Associated Infections in NHS Hospitals in England. Journal of Hospital Infection. Angela Vessey, Director of Copper Development Association in the UK, studied Physiology (BSc) at Bedford College, University of London, and Applied Immunology (MSc) at Brunel University. Her early career was in medical research in the Immunology Division of the National Institute for Medical Research. She joined Copper Development Association – a non-profit trade association – in 1996 and became director in 2001. In 2005, she initiated the Antimicrobial Copper programme to disseminate information and to work with industry to make efficacious products available for healthcare facilities.

Autumn 2015 Volume 7 Issue 3

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Logistics and Supply Chain

Healthcare’s Fountain of Youth Undeniably, aging populations, chronic diseases and ongoing constraints on public finances are presenting significant challenges to healthcare systems in Europe. The European Steering Group (ESG) on sustainable healthcare recently noted that to achieve sustainability of healthcare systems, a fundamental transformation is needed “from acute care to chronic care, from hospital dependency to integrated care across all levels of health systems, as well as from cost and volume to value and outcome.” The ESG noted that patient-centricity in particular is key; citizens need to be encouraged to live active and healthy lifestyles to prevent diseases. And when prevention is not enough, patients need to be closely involved in the management of disease to ensure best possible outcomes. The effective use and application of information and communication technology will play a significant role in patient engagement. In his book, The Patient Will See You Now: The Future of Medicine is in Your Hands, Eric Topol refers to this as the “democratisation of medicine,” and describes how we are moving into an era of consumer empowerment, where individuals will embrace mobile technology for selfmonitoring and health management. A patient will be able to generate his or her own data on their own devices – such as blood pressure, blood glucose or even ECG (electrocardiogram) measurements – and immediately analyse that data via a smartphone application to act upon accordingly. With patients managing their own health information, there is a significant opportunity for more shifts from acute hospital care to outpatient, community and home settings. In fact, home care is already taking off, with growth surges expected over the next decade. But how will this impact the healthcare industry and the way we deliver health to patients? According to UPS’s 2014 Pain in the (Supply) Chain survey, which measures trends in healthcare supply chain management, 21 per cent of global survey respondents cited the shift to home care as a key trend driving business and 64 INTERNATIONAL PHARMACEUTICAL INDUSTRY

supply chain changes. Respondents reported that 30 per cent of products will support the home care channel in the next seven to 10 years, mainly due to increased personalisation, where therapies are matched to specific patient characteristics. What this means is that healthcare providers, pharmaceutical companies, and suppliers must all work together to serve the specific needs of patients at home. Linear and indirect supply chain structures – where products move from manufacturers through wholesalers to dispensers – are no longer sufficient. To support the increasing personalisation of healthcare and shift to a community and homecare setting, healthcare manufacturers and logistics providers need to manage alternative networks that are flexible and provide the most effective, efficient conduit to the market for each product in the manufacturer’s portfolio. But it is not only the reorganisation of care to a setting that meets the needs of patients, where the convergence of healthcare and consumer markets can be witnessed. There are other areas where the lines are starting to blur. High-tech companies and fast-moving consumer goods companies are now offering healthcare products, pharmaceutical companies are investing in diagnostics, medical devices are being created with pharmaceutical components, and many more previously unheard of collaborative activities are occurring between different sectors of the industry. This presents a huge opportunity for stakeholders in the healthcare sector to develop an integrated system where healthcare professional and patients, pharmaceutical manufacturers, worldclass technology companies and healthcare experts in the supply chain work hand-in-hand to foster greater efficiency and better health outcomes. To properly harvest the opportunities that technology presents, logistics and effective supply chains are a central element. Logistics will be key to delivery, returns management and servicing, which

might mean delivering new batteries, bringing replacement devices, or acting automatically on behalf of the care provider if error messages are received at the point of care. It enables the reduction of patient visits to care centres and solves the physical connectivity challenge bringing all the stakeholders together. In the UK, for example, logistics providers such as UPS already operate fully licensed pharmacies to fulfil patient prescriptions for home deliveries, and co-ordinate activities between hospitals, communitybased healthcare professionals and patients. Further value is brought to both the health service and pharma companies by collating and sharing data, giving better understanding of the performance of treatments over the long term across a wide range of patients. Efficient logistics networks will help bring the convergence of healthcare and consumer markets to life, and needs to be understood as a central element and value-adding component in the healthcare ecosystem.

Daniel Gagnon, Director, Healthcare Strategy and Marketing, UPS Europe. Daniel Gagnon is responsible for executing the UPS healthcare logistics strategy in Europe to offer healthcare companies access to a single standard for distribution and transportation of their products. Based in Brussels since 2010, Daniel has led many initiatives, including the development of temperature sensitive solutions, thermal packaging services, monitoring and intervention systems, compliance strategies, as well as communications and sales support programs. Email:

Autumn 2015 Volume 7 Issue 3

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Logistics and Supply Chain The Evolution of Temperature-controlled Transport How Innovation Overcomes the Biggest Challenges in Cold Chain Supply Not all of the products you need to ship are created equal — and neither is their packaging. Today’s customers require precise processes and innovative tools capable of moving their shipments around the world within an increasingly narrow temperature range. These temperaturecontrolled packages are part of what we call the “cold chain,” and may include such high-value products as vaccines, biological samples and biologics, drugs with active pharmaceutical ingredients and other products with a strict timeline, including drugs intended for emergency therapy or those with low stability and temperature excursion tolerance. Any number of factors can threaten the cold chain. Think about the last time your flight was delayed: did you imagine that the added time sitting at the gate could lead to packages stuck in storage, impacting everyone from researchers to providers? Or how about each time you look out your window to see a storm brewing — that storm could knock a shipment severely off-course, dumping serious consequences for clinical trials and patients along with the wind and rain.


These factors, and countless others (think stringent customs regulations, worker strikes, loss of power, varying climates, civil disruptions — just to start) can and do lead to shipment delays and dangerous and irregular temperature excursions. That spells serious trouble for a shipment’s integrity, and may often cause a breakdown in patient therapy and adherence, as well as trial delays and ultimately patient loss. Customers rely on the unsurpassed knowledge and flawless execution of their speciality logistics partners to find effective solutions that will maintain the integrity of their high-value product, carefully manage the temperature of the shipment to within a few degrees, and expedite the shipping process. In fact, it is often in a shipper’s best interest to invest in packaging that can function independently of the supply chain and keeps shipments on-temperature — even when conditions deviate. Temperature control has evolved significantly over the past 20 years, driven by more stringent global

regulations, customer demand for new temperature ranges, emerging markets with extreme temperatures and the growing value of drugs like biologics. Speciality logistics removes the hoping and praying out of cold chain supply by improving packaging and introducing exciting and innovative solutions to keep up with customers’ needs and provide options that fit their budget, from shortlasting polystyrene cases to liquid nitrogen dry shippers, all within the risk management approach required by the regulators. And innovation is a neverending project: look for new cold chain technology to be introduced this autumn at the 2015 World Courier Biomedical Seminar. Until then, take a journey to see how cold chain technology has evolved over the past two decades, and how it is adapting to address today’s challenges. Phase 1: Polystyrene and Polyurethane In the mid-1990s to early 2000s — what we call the “early days” of temperature-controlled transport for pharmaceutical products — semiactive packaging solutions made from

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expanded polystyrene and expanded polyurethane ruled the cold supply chain. These simple (but often mighty) insulation systems, often referred to as “styrofoam” or “polystyrene”, come in many sizes and consist of an outer shell of insulating material in a cardboard box and refrigerated or frozen coolants, such as water-based gel packs or dry ice. These packages are validated for a certain time period and shipping range — usually short-haul travel and shipments between +2˚C and +8˚C. Polystyrene and polyurethane are commonly used today as an inexpensive option for shipping products short distances, such as between a distribution centre and a treatment site. However, this low-tech solution is not right for every shipment. The packaging often experiences temperature excursions and requires different configurations for “summer” and “winter” climates, making it more susceptible to human error. And finally, polystyrene and polyurethane packaging cannot be reused and must be disposed of at the delivery site, making it a burden on the environment. Phase 2: Phase Change Materials (PCMs) As the shipping industry moved into the mid-2000s, customers called for more precise temperature ranges over longer distances. Technology began exploring passive packaging solutions capable of maintaining temperatures as low as -35˚C and as high as +25˚C, such as 68 INTERNATIONAL PHARMACEUTICAL INDUSTRY

rigid outer casings made from plastic or laminated plywood, often featuring aluminum edging or steel corners to prevent contact with the ground; vacuum insulated panels (VIPs) made from foam core and sealed with a tough metallic membrane; and most excitingly, phase change materials — or PCMs. PCMs quickly became the preferred method for many shippers. The advanced insulation technology proved to be five to seven times more effective than polystyrene and polyurethane, and created reliably stable shipping interiors over long journeys, giving shippers more control, better precision and a better chance of maintaining product integrity. What makes PCMs different and innovative? Their materials. PCMs are usually made from a salt solution or paraffin wax suspended in bricks, and store and release energy differently than water-filled blocks. PCM panels must be preconditioned in a refrigerator or freezer until they reach the correct temperature to allow the package to ship in range. Then, they are placed into a box typically fitted with vacuum insulated panels and sealed to prevent leakage. Although PCM technology may seem to be a pricey option, it is far more economical in the long run. PCMs often weigh less than polystyrene, polyurethane and water gel packs combined, meaning lower freight costs. They are more reliable and reduce the risk of shipping delay or

wasted product. And finally, PCMs can be disinfected and reused after reaching their destination (although customers may elect to use a single-use panel). Panels must be replaced every so often, however, as they lose effectivity. And here’s a fun fact: Before technology made improvements in temperature monitoring, PCMs were tested by World Courier teams putting various packaging configurations on the roof of their office in London, England to test the materials’ endurance at absolute external ambient temperatures. Phase 3: Evaporative Cooling and Liquid Nitrogen Shippers For a price, today’s shippers can use technology that is more like something from a sci-fi movie than cold supply chain. But make no mistake: These hightech solutions are revolutionising the way we control temperature in shipping. One of these options is evaporative cooling packaging, a smaller and lighter solution for temperature-controlled packages that need to be kept between +2˚C and +8˚C. While its smaller size limits the number of products that can use it, it also takes up less space and produces less waste. The intuitively named evaporative cooling packaging needs no preconditioning. Instead, it commonly features a container of water that, when pierced, evaporates to absorb heat and Autumn 2015 Volume 7 Issue 3

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Logistics and Supply Chain cool the shipment. The evaporation, when combined with other cooling agents, can help a shipment avoid temperature excursions for two to three days — but may not perform as well in colder climates. And as a particular bonus, this type of packaging can be stored on site with no preconditioning, but caution must be taken to use them within their shelflife. Liquid nitrogen is another exciting and viable shipping option, particularly for live samples and biologics. Biologics are drugs made from living tissue, either from animals, plants or microorganisms. Liquid nitrogen makes it possible to ship these samples and others at -196˚C, low enough to avoid cell death and extend the sample’s life. This method comes with a warning label: Liquid nitrogen can be dangerous, and packages traveling at such low temperatures must meet specific IATA guidelines. If a shipper plans to ship their product by air using the liquid nitrogen method, it must be contained in a “dry shipper” — a specially designed vessel with a space specifically for liquid nitrogen, and a dry, porous insert to absorb accidental spills or leaks. The package is protected by an additional casing and monitored using a data logger. Dry shippers are reusable, but must be maintained and replaced regularly. Shippers may also select a “wet shipper” to ship their product using liquid nitrogen. Wet shippers allow for liquid nitrogen to flow between panels, with no absorbent pad. This method obviously presents a higher risk than dry shippers, and are not allowed on passenger flights — making them the less popular choice for pharmaceutical shippers. Phase 4: Monitoring Of course, evolution in cold chain packaging is almost meaningless without tools to ensure a shipment’s integrity. Research shows that most temperature excursions occur within a mile of a shipment’s destination — meaning we need technology capable of monitoring a temperature-controlled shipment from packing through transport, storage and delivery. Monitoring became more prevalent in the mid-2000s, when high-tech loggers, or monitors, were added to 70 INTERNATIONAL PHARMACEUTICAL INDUSTRY

packages to mitigate risk and show realtime temperature excursions throughout a shipment’s journey. New monitors with GPS capabilities can detect when they are in-flight on a plane and turn themselves off automatically, but these types of monitors do not have global approval. These monitors add a greater level of visibility. This is vital to ensure that shipments move through the supply chain without interruptions. In fact, customs officials in Saudi Arabia check temp monitors within a shipment and will refuse customs clearance admission into the country to a shipment showing temperature excursion. Monitoring technology is improving all the time. For example, developers are currently creating a plastic film that can be added to a box in order to measure its temperature and alert concerned parties if and when temperature excursions occur. Phase 5: The New Norm Even as cold chain technology continues to evolve and present us with new and exciting ways to transport temperaturecontrolled products, PCMs and vacuum insulated panels (VIPs) remain the gold standard of cold chain transport. Although these methods can be more expensive — and require time-consuming preconditioning as well as meticulous planning to mitigate risk of temperature excursion, it’s hard to beat the control, precision and stability they offer. There is a perception that vacuum insulated panel boxes are used to transport critical and temperature-sensitive materials. Therefore, they are sometimes prioritised by customs when it comes to clearance, once they see the clean-sided, sturdy boxes. meaning these shipments may clear through investigative sites much more quickly — resulting in fewer delays, mistakes and waste. Phase 6: The Future of Temperature Control Packaging will continue to evolve as drug values soar, customer needs change and regulations become more rigorous. Experts have already predicted a myriad of ongoing innovations, including advancements driven by realtime temperature data as well as more efficient reusable packaging. While patience is a virtue, evolutions in temperature-controlled packaging and monitoring technology can’t come soon

enough for many of us. The current cold chain is far from perfect, and still suffers major deficiencies related to improper temperature control during transport and storage. For example, research shows that in the developing world, up to 25 per cent of vaccines still reach their destination in a degraded state. Additionally, challenges continue to arise as shipments are sent to new and different locations around the globe. Packaging now needs to be able to withstand significant (and often rapid) changes in climate (think shipping from a hot climate in India to freezing temperatures in China) while maintaining a stable interior temperature. Phase 7: Finding the Right Partner Are you feeling a little intimidated? Don’t be. There is no question that selecting the correct packaging for your shipment — while also staying on budget and accounting for as many unforeseen obstacles as possible in order to maintain the integrity of your high-value product — is a tall order. Luckily, you don’t have to do it alone. Selecting the right speciality logistics provider can mean the difference between a precise delivery and a missed connection, expired product, delayed trial or worse. These trusted partners will help you manage your resources, as well as leverage their experience and unsurpassed knowledge to anticipate issues and select packaging suited to your needs.

Sue Lee 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, multi national, 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: Autumn 2015 Volume 7 Issue 3

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Manufacturing Pharmacopoeial Comparison of In-process and Finished Product Quality Control Tests for Parenterals: IP, BP & USP Abstract The present study deals with a brief overview of the comparative study of quality requirements for in-process and finished products quality control tests of the Indian Pharmacopeia (IP), British Pharmacopeia (BP) and United States Pharmacopeia (USP) for some conventional dosage forms. The concept of the total quality control test refers to the process of striving to produce a quality product by a series of measures, requiring an organised effort in order to eliminate errors at every stage in the production. In-process product testing is done in order to check the conformance of the final product with the compendial standards as specified in the pharmacopoeias. As the final sample taken for the finished product testing is only a representative of a large batch, a significant difference still remains. The pharmacopoeias have laid down the specified limits within which the value should fall in order to be compliant as per the standards. The official pharmacopoeias in different parts of the world specify the quality requirements for pharmaceutical products. However, the parameters and standards differ to some extent from each other. Hence an attempt is being made to compare and bring out the harmonised limits within which a product should fall in order to meet the pharmacopoeial specifications that satisfy quality requirements for many regions. The main aim is to study the quality control tests for parenterals and to list down the similarities and differences as per various pharmacopoeias. The parameters examined for parenteral dosage forms as per the pharmacopoeias were compared and certain similarities and differences were observed. It was noted that, except for a few parameters, the quality control tests were broadly similar. Keywords: Indian Pharmacopeia, British Pharmacopeia, United States Pharmacopeia, Parenterals quality control, In-process quality control. Introduction In the pharmaceutical industry, total quality of the product must be ensured in order to prevent the kind of product which does not comply with the specifications laid down by the pharmacopoeias, and at the same time it is also necessary for controlling the errors during the production process. Quality can be defined as the suitability of the goods or service to the determined qualifications. Quality control emphasises testing of products for defects and reporting to management, who make the decision to investigate or deny the release. Both the inprocess and finished product quality control tests help to ensure the total quality of the product. The entire dealing process (in-process and finished product quality control tests) involves stringent quality control tests to make products totally flawless before they are released into the market. In-process tests may be performed during the manufacture of either the drug substance or drug product, rather than as part of the formal battery of tests which are conducted prior to release. In-process controls (IPC) are checks that are carried out 72 INTERNATIONAL PHARMACEUTICAL INDUSTRY

before the manufacturing process is completed. The function of in-process controls involves monitoring and, if necessary, adaptation of the manufacturing process in order to comply with the specifications. This may include control of equipment and environment too. In-process materials should be tested for their physical parameters and quality attributes which are later approved or rejected by the quality control department, based on the results obtained during the manufacturing process. Rejected in-process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing. Standard operating procedures should be established and followed that describe the in-process controls and tests. Certain tests conducted during the manufacturing process, where the acceptance criterion is identical to or narrower than the release requirement, (e.g., pH of a solution) may satisfy requirements when the test is included in the specification. References to certain procedures are quite similar in pharmacopoeias in each region, even though there are minor changes within each of them. Wherever and whichever procedures are appropriate, pharmacopoeial procedures should be utilised. Whereas differences in pharmacopoeial procedures and/or acceptance criteria have existed among the regions, a harmonised specification is possible only if the procedures and acceptance criteria defined are acceptable to regulatory authorities in all regions. In-process controls may be performed at regular intervals during a process or at the end of the process. The objectives of in-process control are both quality control and process control. The classic interpretation of the term in-process control includes the recording of measured values by members of the in-process control group. Finished product controls (FPC) are checks that are carried out after the manufacturing process is complete with respect to qualitative and quantitative characteristics along with test procedures and their acceptance limits, with which the finished product must comply throughout its valid shelf-life. In order to determine the specifications of the finished product, the quality characteristics related to the manufacturing process should be taken into account. An appropriate specification for each aspect of quality studied during the phase of development and during the validation of the manufacturing process should be determined. At least those aspects considered to be critical should be the object of specifications routinely verified. The specification limits of the finished product at the time of batch release are set by the marketing authorisation applicant, such that the specifications proposed at the end of shelf-life are guaranteed and are established on the basis of a critical detailed review of the data gathered from the batches analysed.

Autumn 2015 Volume 7 Issue 3


Manufacturing The concept of total quality control test refers to the process of striving to produce a perfect product by a series of measures requiring an organised effort in order to eliminate errors at every stage in the production. In-process product testing is required in order to check the conformance of the product with the compendial standards as specified in the pharmacopoeias. The pharmacopoeias have laid down the specified limits within which the value should fall in order to be compliant as per the standards. As the final samples taken for the finished product testing is only a representative of a large batch, a significant difference still remains because of minor variation in the specified limits in different pharmacopoeias. Since the markets have opened up due to globalisation, it is necessary for a product to comply with the standards of the place where it is to be marketed. As the official pharmacopoeias are different in different parts of the globe, there is a need for the harmonised limit within which a product should fall to meet the pharmacopoeial specifications of that region. The aim of the study is quality control tests for some conventional dosage forms and listing down the similarities and differences as per various pharmacopoeias. In-process and Finished Products Quality Control Tests for Parenterals Parenteral products are unique dosage forms of drugs because they are injected through the skin or mucous membranes into the internal body compartments. Thus, because they have circumvented the highly efficient first line of body defence, the skin mucous membranes, they must be free from microbial contamination and from toxic compartments, as well as possessing an exceptionally high level of purity. All components and processes involved in the preparation of these products must be selected and designed to eliminate, as much as possible, contamination of all types, whether of physical, chemical or microbiologic origin. Parenteral preparations can be given by various routes such as intravenous, intraspinal, intramuscular, subcutaneous and intradermal. Table 1: Test procedure for parental preperations The parenterals quality control (PQC) tests are • Uniformity of content. • Uniformity of weight. • Particulate matter. • Extractable volume. • Sterility test. • Pyrogen test. • Clarity of solution. • Bacterial endotoxin test. PQC 1 - Uniformity of content Test Procedure As per IP: Determine the content of active ingredient(s) of each of 10 containers taken at random, using the method given in the monograph or by any other suitable analytical method of equivalent accuracy and precision. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 per cent of the average value. The preparation under examination fails to comply with the test if more than one individual value is outside the limits 85 to 115 per cent of the average value, or if any one individual value is outside the limits 75 to 125 per cent of the average value. 74 INTERNATIONAL PHARMACEUTICAL INDUSTRY

If one individual value is outside the limits 85 to 115 per cent, but within the limits 75 to 125 per cent of the average value, repeat the determination using another 20 containers taken at random. The preparation under examination complies with the test if, in the total sample of 30 containers, not more than one individual value is outside the limits 85 to 115 per cent, and none is outside the limits 75 to 125 per cent of the average value. Note — The test for uniformity of content is not applicable to suspensions for injection containing multivitamins and trace elements. As per BP:Test A Tablets, powders for parenteral use, ophthalmic inserts, suspensions for injection. The preparation complies with the test if each individual content is between 85 per cent and 115 per cent of the average content. The preparation fails to comply with the test if more than one individual content is outside these limits, or if one individual content is outside the limits of 75 per cent to 125 per cent of the average content. If one individual content is outside the limits of 85 per cent to 115 per cent but within the limits of 75 per cent to 125 per cent, determine the individual contents of another 20 dosage units taken at random. The preparation complies with the test if not more than one of the individual contents of the 30 units is outside 85 per cent to 115 per cent of the average content, and none is outside the limits of 75 per cent to 125 per cent of the average content. Test B Capsules, powders other than for parenteral use, granules, suppositories, pessaries. The preparation complies with the test if not more than one individual content is outside the limits of 85 per cent to 115 per cent of the average content, and none is outside the limits of 75 per cent to 125 per cent of the average content. The preparation fails to comply with the test if more than three individual contents are outside the limits of 85 per cent to 115 per cent of the average content, or if one or more individual contents are outside the limits of 75 per cent to 125 per cent of the average content. If two or three individual contents are outside the limits of 85 per cent to 115 per cent but within the limits of 75 per cent to 125 per cent, determine the individual contents of another 20 dosage units taken at random. The preparation complies with the test if not more than three individual contents of the 30 units are outside the limits of 85 per cent to 115 per cent of the average content, and none is outside the limits of 75 per cent to 125 per cent of the average content. As per USP:Stage 1: Take 10 units randomly and perform the assay. It passes the test if the relative standard deviation (RSD) is less than 6% and no value is outside 85-115%. It fails the test if one or more values are outside 75-125%. Stage 2: Take 20 more units and perform the assay procedure. Passes the test if RSD of all the 30 tablets is less than 7.8%, not more than one value is outside 85-115%, and no value is outside 75-125%, or else the batch fails the test. General Procedure: Determine the content of the active ingredient of each of 10 containers taken at random. The preparation under examination complies with the test if the individual values thus obtained are all between 85 and 115 per cent of the average value. The preparation under the examination fails to comply with the test if more than one individual value is outside the limits 85 to 115 per cent of the average value, or if any one individual value is outside the limits 75 to 125 per cent of the average value. If one individual value is outside the limits 85 to 115 per cent but within the limits 75 to 125 per cent of the average value, repeat the Autumn 2015 Volume 7 Issue 3

Chapter Title determination using another 20 containers taken at random.

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The preparation under examination complies with the test if in the total sample of 30 containers, not more than one individual value is outside the limits 85 to 115 per cent and none is outside the limits 75 to 125 per cent of the average value. PQC 2 - Uniformity of weight Remove labels and wash the container and dry. Weigh the container along with its contents. Empty the containers as completely as possible. Rinse with water and with ethanol and dry at 1000C to a constant weight. Allow to cool in desiccators and weigh. The difference between the weights represents the weight of the contents. Repeat the procedure with a further 19 containers and determine the average weight. Not more than two of the individual weights deviate from the average weight by more than 10% and none deviates by more than 20%. As per IP:This test is applicable to capsules that contain less than 10 mg or less than 10 per cent w/w of active ingredient. For capsules containing more than one active ingredient, carry out the test for each active ingredient that corresponds to the aforementioned conditions. The test should be carried out only after the content of active ingredient(s) in a pooled sample of the capsules has been shown to be within accepted limits of the stated content. Note â&#x20AC;&#x201D; The test is not applicable for capsules containing multivitamins and trace elements. Determine the content of active ingredient in each of 10 capsules taken at random using the method given in the monograph or by any other suitable analytical method of equivalent accuracy and precision. The capsules comply with the test if not more than one of the individual values thus obtained is outside the limits 85 to 115 per cent of the average value, and none is outside the limits 75 to 125 per cent. If two or three individual values are outside the limits 85 to 115 per cent of the average value, repeat the determination using another 20 capsules. The capsules comply with the test if in the total sample of 30 capsules, not more than three individual values are outside the limits 85 to 115 per cent, and none is outside the limits 75 to 125 per cent of the average value. Test Procedure Weigh individually 20 units selected at random and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage given in the pharmacopeia and none deviates by more than twice that percentage. IP/BP and USP limits for tablet weight variation are given below.

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PQC 3 - Particulate matter For sub-visible particles: Two methods are specified; one involving the counting of particles viewed under the microscope, and the other based on the count of particles causing light obscuration. Both methods are applied on small samples. Method 1: Microscopic particle count test: This method is suitable for revealing the presence of particles, the longest axis or effective linear dimension of which is 10m or more.


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Manufacturing Method: Invert the container of the preparation 20 times. For large-volume parenterals, single units should be tested. For small-volume parenterals less than 25 ml in volume, the contents of 10 or more units should be combined in a clean container. Where the volume of liquid in a container is very small, the test solution may be prepared by mixing the contents of a suitable number of containers and diluting to 25 ml with particle-free water. Small-volume parenterals having a volume of 25 ml or more may be tested individually. Powders for parenteral use should be constituted with particle-free water. Fit the membrane filter on to the membrane filter holder. Filter under reduced pressure 200 ml of the purified water for a particulate matter test at the rate of 20 to 30 ml per minute. Apply the vacuum until the surface of the membrane is free from water and remove the membrane and dry it carefully below 50º C. After the filter is dried, place it under the microscope. Adjust the microscope to get the best view of the particles that are equal to or greater than 150µm. Ascertain that the number is not more than 1. Fit another membrane filter and wet it with purified water for particulate matter test. Pour the sample solution into the filter. For viscous solutions, dilute suitably with purified water for particulate matter test and filter. When the amount of solution on the filter becomes small, add 30 ml of water. Repeat the process three times with 30 ml of the water. Apply the vacuum gently until the surface of membrane filter is free from water. Dry it and observe under a microscope. Count the number of particles that are equal to or greater than 10 µm, the number of particles equal to or greater than 25µm and the particles equal to or greater than 50 µm. Method 2: Light obscuration particle count test. Use a suitable apparatus based on the principle of light blockage, which allows an automatic determination of particle size and the number of particles according to size. Method: Invert the container of the preparation 20 times. For large-volume parenterals, a single unit should be tested. For small-volume parenterals less than 25 ml in volume, the contents of 10 or more units should be combined in a clean container. Where the volume of liquid in a container is very small, the test solution may be prepared by mixing the contents of a suitable number of containers and diluting to 25 ml with

particle-free water. Small-volume parenterals having a volume of 25 ml or more may be tested individually. Powders for parenteral use should be constituted with particle-free water. Remove four portions, each of not less than 5 ml; count the number of particles greater than 10 µm and 25 µm. PQC 4 - Extractable volume Suspensions should be shaken before the contents are withdrawn. Oily injections may be warmed but should be cooled to 25ºC before carrying out the test.

Single-dose containers for IP :Method I: Where the nominal volume does not exceed 5ml. Use six containers; five for the tests and one for rinsing the syringe used. Using a syringe with appropriate capacity, rinse the syringe and withdraw as much as possible the contents of one of the containers reserved for the test and transfer, without emptying the needle, to a dry graduated cylinder of such capacity that the total combined volume to be measured occupies not less than 40% of the nominal volume of the cylinder. Repeat the procedure until the contents of the five containers have been transferred and measure the volume. The average content of the five containers is not less than the nominal volume and not more than 115% of the nominal volume. Alternatively the volume of contents in millilitres can be calculated as mass in grams divided by the density. Method II: Nominal not less than three containers separately to dry graduated cylinders such that the volume to be measured occupies not less than 40% of the nominal volume of the cylinder and measure the volume transferred.

The contents of each container are not less than the nominal volume and not more than 110% of the nominal volume. Multi-dose containers: Same as single-dose containers PQC 5 - Sterility Test Culture media: 1. Fluid thioglycollate medium: For anaerobic bacteria. Use fluid thioglycollate medium by incubating it at 30 to 35°C. 2. Soybean-casein digest medium: Fungi and aerobic bacteria. Use soybean-casein digest medium by incubating it at 20 to 25°C under aerobic conditions. 3. Alternative thioglycollate medium: For use with turbid and viscid products and for devices having tubes with small lumina.

Test procedure: Method A (membrane filtration) is preferred where the substance under examination is 1. An oil, 2. An ointment that can be put into solution, 3. A non-bacteriostatic solid not readily soluble in the culture medium, and 4. A soluble powder or a liquid that possesses bacteriostatic and / or fungistatic properties. For liquid products where the volume in a container is 100 ml or more, method A should be used.


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Manufacturing Method A – Membrane Filtration The method calls for the routine use of positive and negative controls. Apparatus: Cellulose nitrate filters are used for aqueous, oily and weakly alcoholic solutions, and cellulose acetate filters are recommended for strongly alcoholic solutions. Diluting Fluids: (IP, BP): Fluid A: Dissolve 1 g of peptic digest of animal tissue (such as bacteriological peptone) or its equivalent in water to make 1 litre, filter or centrifuge to clarify, adjust to pH 7.1 ± 0.2, dispense into flasks in 100ml quantities and sterilize at 121° C for 20 minutes. Fluid B: If the test sample contains lecithin or oil, use fluid A to each litre of which has been added 1 ml of polysorbate 80, adjust to pH 7.1± 0.2, dispense into flasks and sterilise at 121° C for 20 minutes. Quantities of sample to be used: For parenteral preparations: Whenever possible, use the whole contents of the container, but in any case not less than the quantities prescribed in Table 3(E), diluting where necessary to about 100 ml with a suitable diluent such as fluid A. For ophthalmic and other non-parenteral preparations: Take an amount within the range prescribed in column (A) of Table 3(E), if necessary, using the contents of more than one container, and mix thoroughly. For each medium use the amount specified in column (B) of Table 3(E), taken from the mixed sample.

Test method: For aqueous solutions: Aseptically transfer a small quantity of fluid A on to the membrane and filter it. Transfer aseptically the combined quantities of the preparation under examination prescribed in the two media onto one membrane. If the solution under examination has antimicrobial properties, wash the membrane(s) by filtering through it (them) not less than three successive quantities, each of 100 ml, of sterile fluid A. Do not exceed a washing cycle of five times or 200 ml, even if it has been demonstrated during validation that such a cycle does not fully eliminate the antimicrobial activity. The quantities of fluid used should be sufficient to allow growth of a small inoculum of organisms (approximately 50 CFU) sensitive to the antimicrobial substance in the presence of the residual inhibitory material on the membrane. After filtration, aseptically remove the membrane(s) from the holder, transfer the whole membrane or cut it aseptically into two equal parts. Transfer one half to each of two suitable media. Incubate the media for not less than 14 days. Observe the containers of media periodically during the 14 days of incubation. If the test specimen is positive before 14 days of incubation, further incubation is not necessary. For products terminally sterilised by a validated moist heat process, incubate the test specimen for not less than seven days. For liquids immiscible with aqueous vehicles, and suspensions: Carry out the test described under for aqueous solutions but add a sufficient quantity of fluid A to the pooled sample to achieve rapid filtration. Sterile enzyme preparations such as penicillinase or cellulose


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Manufacturing may be added to fluid A to aid in dissolving insoluble substances. If the substance being examined contains lecithin, use fluid B for diluting.

be used for inoculation in the culture media varies according to the quantity in each container. Follow the directions given in the Table 3(E).

For oils and oily solutions: Filter oils or oily solutions of sufficiently low viscosity without dilution through a dry membrane. Dilute viscous oils as necessary with a suitable sterile diluent such as isopropyl myristate that has been shown not to have antimicrobial properties under the conditions of the test.

Test method: For aqueous solutions and suspensions: Remove the liquid from the test containers with a sterile pipette or with a sterile syringe or a needle. Transfer the quantity of the preparation under examination prescribed in Table 3(E) directly into the culture medium, so that the volume of the preparation under examination is not more than 10 per cent of the volume of the medium, unless otherwise prescribed. When the quantity in a single container is insufficient to carry out the tests, the combined contents of two or more containers are to be used to inoculate the media.

Allow the oil to penetrate the membrane and filter by applying pressure or by suction, gradually. Wash the membrane by filtering through it at least three successive quantities, each of approximately 100ml, of sterile fluid B or any other suitable sterile diluent. After filtration, aseptically remove the membrane(s) from the holder, transfer the whole membrane or cut it aseptically into two equal parts. Transfer one half to each of two suitable media. Incubate the media for not less than 14 days. Observe the containers of media periodically during the 14 days of incubation. If the test specimen is positive before 14 days of incubation, further incubation is not necessary. For products terminally sterilised by a validated moist heat process, incubate the test specimen for not less than seven days. For ointments and creams Dilute ointments in a fatty base and emulsions of the water-in-oil type to give a fluid concentration of 1 per cent w/v, by heating, if necessary, to not more than 40ยบ C with a suitable sterile diluent such as isopropyl myristate previously rendered sterile by filtration through a 0.221 m membrane filter that has been shown not to have antimicrobial properties under the conditions of the test. Filter as rapidly as possible and complete the test as described under for oils and oily solutions. In exceptional cases, it may be necessary to heat the substance to not more than 44ยบ C and to use warm solutions for washing the membrane. For soluble solids: For each medium, dissolve not less than the quantity of the substance under examination, as prescribed in Table 3(E), in a suitable sterile solvent such as fluid A and carry out the test described under for aqueous solutions using a membrane appropriate to the chosen solvents.

If the preparation under examination has antimicrobial activity, carry out the test after neutralising this with a suitable neutralising substance or by dilution in a sufficient quantity of culture medium. When it is necessary to use a large volume of the product it may be preferable to use a concentrated culture medium prepared in such a way that it takes account of the subsequent dilution. Where appropriate, the concentrated medium may be added directly to the product in its container. Incubate the inoculated media for not less than 14 days. Observe the cultures several times during the incubation period. Observe the containers of media periodically during the 14 days of incubation. If the test specimen is positive before 14 days of incubation, further incubation is not necessary. For products terminally sterilised by a validated moist heat process, incubate the test specimen for not less than seven days. For oils and oily solutions: Use media to which has been added a suitable emulsifying agent at a concentration shown to be appropriate in the validation of the test, for example, polysorbate 80 at a concentration of 10g/litre and which has been shown not to have any antimicrobial properties under the conditions of the test. Carry out the test as described under for aqueous solutions and suspensions. During the incubation period shake the cultures gently each day. However, when thioglycollate medium or other similar medium is used for the detection of anaerobic micro-organisms, keep shaking or mixing to a minimum in order to maintain anaerobic conditions. For ointments and creams: Prepare by diluting to about 1 in 10 by emulsifying with the chosen emulsifying agent in a suitable sterile diluent such as fluid A. Transfer the diluted product to a medium not containing an emulsifying agent. (Before use, test the emulsifying agent to ascertain that in the concentration used it has no significant antimicrobial effects during the time interval for all transfers.) Mix 10 ml of the fluid mixture so obtained with 80 ml of the medium and proceeds as directed under for aqueous solutions and suspensions. For solids: Transfer the quantity of the preparation under examination to the quantity of medium specified in Table 3(E) and mix. Proceed as directed under for aqueous solutions and suspensions.

For solids for injection other than antibiotics: Constitute the test articles as directed on the label, and carry out the test as described under for aqueous solutions or for oils and oily solutions, as applicable. Method B: Direct inoculation method The quantity of the substance or preparation under examination to 78 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Observation and Interpretation of Results: At intervals during the incubation period and at its conclusion, examine the media for macroscopic evidence of microbial growth. If the material being tested renders the medium turbid so that the presence or absence of microbial growth cannot be easily determined by visual examination, 14 days after the beginning of incubation, transfer portions (each not less than 1 ml) of the medium to fresh vessels of the same medium and then incubate the original and transfer vessels for not less than four days. If no evidence of microbial growth is found, the preparation under Autumn 2015 Volume 7 Issue 3

Manufacturing examination complies with the test for sterility. If evidence of microbial growth is found, the preparation under examination does not comply with the test for sterility. Do not repeat the test unless it can be clearly shown that the test was invalid for causes unrelated to the preparation under examination. The test may be considered invalid only when one or more of the following conditions are fulfilled:

If the test is declared to be invalid, repeat with the same number of units as in the original test. If no evidence of microbial growth is found in the repeat test, the preparation under examination complies with the test for sterility. If microbial growth is found in the repeat test and confirmed microscopically, the preparation under examination does not comply with the test for sterility.

a. Microbial growth is found in negative controls. b. Data on microbial monitoring of the sterility testing facility show a fault. c. A review of the testing procedure used for the test in question reveals a fault. d. After identifying the micro-organisms isolated from the containers showing microbial growth may be ascribed without any doubt to faults with respect to the materials and/or technique used in conducting the test procedure.

PQC 6 - Pyrogen test The test involves measurement of the rise in body temperature of rabbits following the intravenous injection of a sterile solution of the substance under examination. Do not use animals for pyrogen tests more frequently than once every 48 hours. After a pyrogen test in the course of which a rabbit's temperature has risen by 0.6º C or more, or after a rabbit has been given a test substance that was adjudged pyrogenic, at least two weeks must be allowed to elapse before the animals is used again. Test animals: Healthy adult rabbit of either sex (1.5 Kg) Recording of temperature: Use a temperature-sensing device such as a clinical thermometer or thermistor or other suitable probes (accuracy of 0.10). Insert the thermometer or temperature-sensing probe into the rectum of the test rabbit to a depth of about 5 cm {7.5 cm –USP}. Preliminary test (sham test) Injecting intravenously 10 ml per kg body weight of a pyrogen-free saline solution warmed to about 38.50 C. Record the temperatures of the animals, beginning at least 90 minutes before injection and continuing for three hours after injection of the test solution. Any animal showing a temperature variation of 0.6° C or more must not be used in the main test.

Product News

Improved Membrane Chromatography Performance Redesigned Sartobind® membrane adsorber capsules offer higher binding capacities, reduced void volumes, less buffer consumption and lower operational costs To more effectively recover large molecular weight proteins, such as blood factors and conjugated proteins or viruses and viruslike particles, Sartorius Stedim Biotech (SSB) has reconfigured its Sartobind® membrane chromatography capsules. A range of capsule sizes with a 4 mm bed height is now available from the 1 mL nano unit up to the new 2.5 L jumbo version. The capsules’ upstream flow channels have been optimized, and an internal core forms a miniaturized downstream channel, resembling that in existing 8 mm bed height capsules. The new Q, S and salt-tolerant STIC PA ion exchanger capsules, all with a 4 mm bed height, increase dynamic binding capacity by approximately 15% and reduce void volumes by approximately 40% compared with their predecessors, while maintaining high flow rates of 10 to 30 membrane volumes per minute. By improving breakthrough behavior, subsequent polishing steps to remove DNA, HCP, aggregates and viruses from recombinant proteins are significantly more reliable and, as less buffer is used, Sartobind® also reduces operational costs.

Sartobind® membrane adsorbers: the new design of capsules enables higher binding capacities and reduced void volumes

“Traditionally, membrane adsorbers have been using available filter housings, often ignoring chromatographic process parameters, such as back-mixing effects and elution volumes. This new generation of membrane adsorber capsules takes these specific requirements into account and reflects substantial progress for bind and elute applications,” commented Dr. Fischer-Frühholz, membrane chromatography expert at SSB. Furthermore, Sartorius Stedim Biotech has added new 400 mL and 800 mL Sartobind® Q, S and Phenyl capsules with an 8 mm bed height to its portfolio. These optimized capsules increase dynamic binding capacity up to 48% when compared to adsorbers installed in filter housings. Contact: Sartorius Stedim Biotech, Goettingen, Germany Phone: +49.(0)551.308.0, Email: INTERNATIONAL PHARMACEUTICAL INDUSTRY 79

Manufacturing Main test: Carry out the test using a group of three rabbits. Preparation of the sample: Dissolve the substance with pyrogen-free saline solution. Warm the liquid under examination to approximately 38.5° C before injection. Procedure: Record the temperature of each animal 90 minutes before the injection and continue for three hours after the injection for every 30 minutes. Record the "initial temperature" of each rabbit and temperature after 30 minutes. Rabbits showing a temperature variation greater than 0.2° C between two succes¬sive readings in the determination of "initial temperature" should not be used for the test. Do not use any rabbit having a temperature higher than 39.8° C and lower than 38° C. Inject the solution slowly into the marginal vein of the ear of each rabbit over a period not exceeding four minutes. The volume of injection is not less than 0.5 ml per kg and not more than 10 ml per kg of body weight. The difference between the "initial temperature" and the "maximum temperature" which is the highest temperature recorded for a rabbit is taken as its response. When this difference is negative, the result is counted as a zero response. Interpretation of results: Having carried out the test first on a group of three rabbits, repeat if necessary on further groups of rabbits given in the Table 3(G), depending on the results obtained.

If the summed response of the first group does not exceed the figure given in the third column of the Table 3(G), the substance passes the test. If the response exceeds the figure given in the third column of the table 3(G) but does not exceed the figure given in the fourth column of the Table 3(G), repeat the test as indicated above. If the summed response exceeds the figure given in the fourth column of the Table 3(G), the product fails the test. PQC 7 - Clarity of solution General procedure :Constitute the injection as directed on the label. 1) The solid dissolves completely, leaving no visible residue as undissolved matter. 2) The constituted injection is not significantly less clear than an equal volume of diluents for water for injections contained in a similar container and examined in the same manner. PQC 8 - Bacterial endotoxin test The test for bacterial endotoxins (BET) measures the concentration of bacterial endotoxins that may be present in the sample or in the articles to which the test is applied using alysate derived from hemolymph cells or amoebocytes of horseshoe crab, Limulus polyphemus. The endotoxin limit for a given test preparation is calculated from the expression K/M, where M is the maximum dose administered to an adult (taken as 70 kg for this purpose) per kg hour. The following methods can be used to monitor the endotoxin concentration: Method A: Gel-clot limit test method Method B: Semi-quantitative gel clot method Method C: Kinetic turbidimetric method 80 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Method D: Kinetic chromogenic method Method E: End point chromogenic method Gel-clot limit test method: Prepare the solutions and dilutions with water BET. If necessary, adjust the pH of the solution to 6.0 to 8.0 using sterile 0.1M hydrochloric acid BET, 0.1M sodium hydroxide BET of suitable buffer prepared with water BET. Prepare the sample solution at any dilution at or below MVD. Use two positive controls, one having the concentration of 2λ and the other spiked to get the concentration of 2λ. Add an appropriate volume of negative control (NC), standard CSE solutions in water BET, test solution and positive control (PPC). At regular intervals add an equal volume of the appropriately constituted lysate unless a single vial is used. Mix it and place it in an incubator. Incubation should be done at 37º±1º C undisturbed for 60±2 minutes. Remove and examine the receptacles carefully. A positive reaction is recorded when firm gel is formed that retains the integrity when inverted through 180º in one smooth motion. If no firm gel is formed then it is a negative reaction. Calculation: Calculate the average of the logarithms of the lowest concentrations of endotoxin in each series of the lowest concentration of endotoxin in each series of dilutions. Geometric mean end point concentration = antilog (Ʃe/f) Where Ʃe = sum of the log end point concentration of the series of dilutions used; f = number of replicate test-tubes. The value must be in between 0.5λ and 2.0λ Interpretation of results: The product under examination complies with the test if the negative control and test solutions are negative, and if the positive control is positive. Retests: If a positive control is found for one of the test solution duplicates and a negative result for the other, the test may be repeated as described above. Results of the retest should be interpreted as for initial test. Semi-quantitative gel clot method Preparation of the test solutions: Prepare the test solutions at concentrations of MVD, 0.5MVD, 0.25MVD. Procedure: Same as Method A Calculation and interpretation of results To calculate the endotoxin concentration in the product, determine for the series of test solutions the lowest concentration or the highest dilution giving a positive (+) reaction. Multiply this dilution with λ to obtain the endotoxin concentration of the product. For instance, if MVD is equal to 8 and the positive reaction was obtained at 0.25 MVD and 1 was equal to 0.125EU/ml. Calculate the endotoxin content of the product under examination from endotoxin concentration. The product under examination meets the requirements of test if the endotoxin content of less than endotoxin limit stated in the individual monograph. Kinetic turbidimetric method and kinetic chromogenic method Using CSE, prepare solutions of not less than three endotoxin concentrations to get a standard curve. Carry out the procedure in duplicates, of each standard endotoxin solution in accordance with the instructions of the lysate manufacture.

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Manufacturing Preparation of test solutions: Solution A: Solution of the product under examination at the initial dilution (test solution) Solution B: Test solution spiked with CSE at a concentration at or near the middle of the standard curve (PPC) Solution C: Standard solutions of CSE in water BET covering the linear part of the standard curve Solution D: Water BET (NC) Method: Add solution D, followed by solutions C, A, B. Add lysate and carry out the assay solution in accordance with the instructions of the lysate manufacture. Calculation: Calculate the endotoxin concentration of solutions A and B from the regression equation obtained with solutions of series C. Calculate the mean percentage recovery of the added endotoxin by subtracting the mean endotoxin concentration in solution A from the mean endotoxin concentration in solution B. Interpretation of results: The assay is valid only if 1. The standard curve is linear for the range of CSE concentrations used; 2. The coefficient of correlation r is not greater than 0.980; 3. The mean % recovery of the added endotoxin in the positive product control is between 50% and 150%. End point chromogenic method Add solution D, followed by solutions C, A, B. The chromogenic substrate and lysate are added to the solution and incubated for the recommended time. Stop the reaction and measure the absorbance

at the specified wavelength in accordance with the instructions of the lysate manufacture. Interpretation of results: The assay is valid only if 1. The standard curve is linear for the range of CSE concentrations used; 2. The coefficient of correlation r is not less than 0.980; 3. The mean % recovery of the added endotoxin in the positive product control is between 50% and 150%.

The concept of total quality control test refers to the process of striving to produce a perfect product by a series of measures requiring an organised effort in order to eliminate errors at every stage in the production. In-process product testing is required in order to check the conformance of the product with the compendial standards as specified in the pharmacopoeias. The pharmacopoeias have laid down the specified limits within which the value should fall in order to be compliant as per the standards. As the final samples taken for the finished product testing is only a representative of a large batch, a significant difference still remains because of minor variation in the specified limits in different pharmacopoeias. Since the markets have opened up due to globalisation, it is necessary for a product to comply with the standards of the place where it is to be marketed. As the official pharmacopoeias are different in different parts of the globe, there is a need for the harmonised limit within which a product should fall to meet the pharmacopoeial

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Manufacturing specifications of that region. The aim of the study is quality control tests for some conventional dosage forms and listing down the similarities and differences as per various pharmacopoeias. In-process and Finished Products Quality Control Tests for Parenterals Parenteral products are unique dosage forms of drugs because they are injected through the skin or mucous membranes into the internal body compartments. Thus, because they have circumvented the highly efficient first line of body defence, the skin mucous membranes, they must be free from microbial contamination and from toxic compartments, as well as possessing an exceptionally high level of purity. All components and processes involved in the preparation of these products must be selected and designed to eliminate, as much as possible, contamination of all types, whether of physical, chemical or microbiologic origin. Parenteral preparations can be given by various routes such as intravenous, intraspinal, intramuscular, subcutaneous and intradermal. The parenterals quality control (PQC) tests are • Uniformity of content. • Uniformity of weight. • Particulate matter. • Extractable volume. • Sterility test. • Pyrogen test. • Clarity of solution. • Bacterial endotoxin test.

Conclusion From the above review it can be concluded that though IP, BP and USP included most of the in-process and finished products QC tests for some conventional dosage forms. However, some difference was observed. Some of the tests are available only in some pharmacopoeia. The differences in the tests and their limits as specified in the different pharmacopoeias needs to be harmonised and streamlined in such a way that if the test meets the specified limit as per a harmonised one, it meets all the requirements of all the pharmacopoeias and later the regulatory requirements of that particular country. This is important for the products which are marketed globally. Because of this, a huge amount of time, money and manpower can be minimised. References 1. Indian Pharmacopoeia. The controller of publication, New Delhi; Ministry of Health and Family Welfare. India. 5th ed. 2007. Volume I. 2. Indian Pharmacopoeia. The controller of publication, New Delhi; Ministry of Health and Family Welfare. India. 5th ed. 2007. Volume II. 3. Indian Pharmacopoeia. The controller of publication, New Delhi; Ministry of Health and Family Welfare. India. 5th ed. 2007. Volume III. 4. British Pharmacopoeia. Published on behalf of Medicines and Health Care Products Regulatory Agency; The Department of Health, Social Services and Public Safety. Great Britain, sixth ed. 2010, Volume II. 5. British Pharmacopoeia. Published on behalf of Medicines and Health Care Products Regulatory Agency; The Department of Health, Social Services and Public Safety. Great Britain, sixth ed. 2010, Volume III. 6. British Pharmacopoeia. Published on behalf of Medicines and Health Care Products Regulatory Agency; The Department of Health, Social Services and Public Safety. Great Britain, sixth ed. 2010, Volume IV. 7. United States Pharmacopoeia 29 National Formulary 24 (USP29– NF24) Supplement 1, current from April 1, 2006 through July 31, 2006.

Shilpi Khattri , Ph.D. Research Scholar, Regulatory Affairs, JSS College of Pharmacy, JSS University, Mysore. Email:

Comparison of Specifications and Parameters:

Summary The available QC tests from various pharmacopoeias supplement each other, and each pharmacopoeia gives more details on a special issue than the others. Each pharmacopeia has its own specifications for each test.

Balamuralidhara V. Assistant Professor Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email:

T.M. Pramod Kumar, Professor Regulatory Affairs Group, Department of Pharmaceutics, JSS College of Pharmacy, JSS University, Sri Shivarathreeshwara Nagara, Mysore – 570 015, Karnataka, India Email:


Autumn 2015 Volume 7 Issue 3


Better Ways to Handle Tablets Using IBCs In this article, Director of Pharmaceutical Sales at Matcon Limited, considers the benefits and challenges of handling tablets in larger volumes and using IBCs. Still Handling Tablets in Drums? It is common to find Intermediate Bulk Containers (IBCs) being used for handling powders and granules in solid dosage manufacturing processes, from initial dispensing through to tablet compression or capsule filling. The benefits of using IBCs for efficient and flexible materials handling at this stage of the process are widely appreciated and applied in modern facilities.

from the tablet presses, transport them from compression to coating and again from coating to primary packing (blister packing or bottle filling), sometimes via tablet inspection or tablet printing. In some facilities, tablets have been stored and transported in drums for so long that the reason for using this method has been lost (“we have always done it this way”). In other instances, I have been told that small containers – and particularly plastic drums – were selected due to the low initial investment cost and the concern that larger containers would damage the tablets. There are however a number of limitations associated with handling tablets in drums or small containers: 1. Efficiency and traceability: a. Many drums are required to hold a full batch of tablets – this is not LEAN, as large numbers of drums mean more movements and more manual operations.

However, when it comes to tablets, these are still traditionally handled in small containers such as drums, small kegs or boxes. What’s Wrong with Handling Tablets in Drums? Having had the opportunity to visit many different solid dosage manufacturing facilities around the world, I regularly see tablets being handled in drums or small containers. Most often these are plastic drums with liners, used to collect tablets

b. Slow and inefficient transfers – when processes are running slow or are stopped because of the way that the tablets are transferred, this directly impacts on the Overall Equipment Effectiveness (OEE) and the productivity of the facility as a whole. c. Challenges to inventory control and traceability – as the batch is split in to many small sub-lots. 2. Health & safety: a. Manual movement and lifting of the drums – handling all of these small containers means repetitive manual work and the risk of injuries to operators. b. Requirement for PPE to protect operator – manual handling and open drum connections expose operators to the tablets and make it necessary for operators to use PPE as a primary containment method. 3. Quality/GMP risks: a. Open connections during drum filling/emptying – with a high


risk of contamination and crosscontamination of the tablets. b. Manual scooping or tipping of drums – risk of tablet damage as tablet quality is dependent upon the operator handling them with care. The Advantages of Thinking Bigger… If larger batches of tablets can be handled in a single container, then this would replace many drums and have significant LEAN benefits: •

Fewer containers required per batch

Reduced movements containers

Reduced number of connections/ disconnections

Less space required for storage of containers (when empty and also inter-process)

Reduced cleaning requirement



This is possible using Tablet IBCs, which enable tablet batches of up to 750Kg to be handled in a single container. These benefits are at their greatest when the tablet handling batch size has been optimised to fit the process. Requirements and variables differ from facility to facility; however, the diagram below shows this optimisation concept applied to a 600Kg batch coating process. In this example, a double-sided tablet press feeds to 2 x 1000L IBCs. Each IBC will receive 600Kg of tablets, which represents a coating batch. After compression, one of the IBCs will feed these tablets by gravity into a 600Kg batch coater and then, following the coating process, the full batch of tablets will be emptied from the coater by gravity into another IBC and taken to packing. As drums require multiple connections and disconnections and significant manual operations at each stage of the process, IBCs need only one connection/ disconnection at each point. There is no splitting or combining of the tablet batches, which makes for easy inventory control and product traceability.

Autumn 2015 Volume 7 Issue 3

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Manufacturing •

Close the liner

Place a lid

Print off a label and attach it to the drum

Place the drum on a pallet

Carrying out so many operations for 20 or more drums is a very timeconsuming and wasteful activity. By collecting tablets in a Tablet IBC of a size that matches the next process step (e.g. coating), then the operating time is reduced considerably.

Tablet IBC Filling 1 displaying tablet spiral

Of course, for this approach to be successful, the uncoated tablets must be loaded into the IBC without damage. This requires a particular type of Tablet IBC such as the one illustrated. This Tablet IBC has a polyethylene construction and a special tablet spiral to protect the fragile tablets during loading. Connection with the IBC inlet can be open or closed depending upon the containment requirement. In either case there is only the requirement for one IBC connection/disconnection per batch, as compared with drums where there may be many changeovers per

batch. The result is better protection to the operator (enhanced safety) and better protection to the product (quality/GMP). Feeding To – and Receiving From – Batch Tablet Coaters Using IBCs The process of opening and tipping drums into a batch tablet coater is completely manual, time-consuming and often hard work for operators! There are health and safety risks associated with lifting and tilting heavy drums. In addition, the way in which tablets are loaded into the coater is fully operator-dependent and, as such, there is a risk of tablet damage at this stage. On the other hand, using a Tablet IBC, the full coating batch is contained within a single container from which the tablets are automatically fed into the coater in a gentle and controlled way. As well as removing manual operations, this approach also enables the tablet coater to be loaded quickly and efficiently. After coating, the full batch of tablets can be swiftly loaded into a single IBC, ready for movement to primary packing.

Tablet IBC Filling 2 In the next three sections we look at the specific use of IBCs for tablet handling at compression, batch coating and primary packing, focussing on the ways in which IBC systems can improve production efficiency, tablet quality and operator safety. Collecting Tablets from Compression in IBCs Collecting tablets in drums or small containers means that a complete, compressed batch needs up to 20 - 50 of these units. Each drum filling operation can involve the following activities: •

Collect empty drums

Add liner

Connect the liner to the outlet of the tablet press

Monitor fill level of tablets and change drums when full


IBCs feeding to and receiving from Tablet Coater Autumn 2015 Volume 7 Issue 3

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Manufacturing A significant increase in production throughput can be obtained when utilising full batch IBCs rather than individual drums at this stage, especially when filling and emptying the new, faster film-coating equipment. Because the waiting time of the coater is drastically reduced, the overall coating output can increase by 20-30%.

In contrast, loading the packing line with a single Tablet IBC eliminates the manual handling of drums and tablets and removes open transfers. The IBC acts as a hopper, automatically feeding the tablets to the inlet of the packing line by gravity. As this requires no operator input, operators in this area can then focus their attention fully on the packing process – not on ‘materials handling’.

Using IBCs to Feed to Primary Packing If the batch of tablets is split across 20 – 50 drums then, once again, there is a requirement for a high level of manual operation to open the drums, open the liner and transfer the tablets to the inlet of the blister packing or bottle filling lines. It is common that this transfer involves manual scooping of the tablets or tipping the drums.

What are the Challenges with Handling Tablets in Larger Containers? The two main challenges with handling tablets in larger containers, such as IBCs, are the risk of tablet damage and also the design of the facility to accommodate the use and movement of larger containers.

Additionally, the drums are often located and opened up within the packing room itself, which takes up valuable space around the machine and results in a cluttered working environment. The open drums and manual handling methods bring risks to operators and the quality of the tablets.

The Risk of Tablet Damage: Tablet damage can be in the form of broken or marked tablets. To handle tablets without damage, it is important to design the complete tablet handling system to minimise tablet drop heights, acceleration, impact and tablet crushing. This requires careful consideration of all aspects of the system, including hopper and chute angles, materials of construction and the design of the IBC valve.

In addition, it is important to conduct tests, wherever practical, in order to confirm that the IBC system can handle the range of tablets. Design of Facility: Compared to a single drum, the IBC has a larger footprint and inlet height, which can mean that there can be the requirement for additional floor space within the process rooms. In addition, the width of doorways and corridors must be able to accommodate the movement of IBCs. It is important that materials handling is therefore considered early in the design stage to avoid compromises. Summary Handling tablets in larger, single containers offers significant benefits as compared to using traditional drums or small containers, including: •

Increased production throughput

Reduced operator handling time

Improved traceability

Reduced risk of human error

Improved operator health and safety

The combination of these benefits can significantly reduce manufacturing costs whilst improving production efficiency, quality and safety.

Shaun Baker is Director of Pharmaceutical Sales at Matcon Limited and an active member of ISPE Central Region Committee in the UK. With over 15 years’ experience in materials handling and processing, specifically in pharmaceutical applications, Shaun has developed a practical understanding of the challenges faced in the industry – and solutions that are available. Email: IBC Feed to Packing


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Manufacturing Tooling Design – How Tooling Options can Benefit Different Types of Pharmaceutical Formulations During Tablet Compression It can be a labour of love to get a tablet to market. With time and monetary investments made throughout the process from research to development and scaleup, one of the most challenging steps in the process can be the actual manufacture of the product. Issues range from tablet quality to equipment malfunction – all of which can result in downtime and delayed market deployment. However, there are steps that can be taken to eliminate or minimise these issues before manufacturing even begins. Proper tooling and tablet design can greatly improve the tablet manufacturing process. But how do you know what’s suitable? How is it possible to eliminate issues before they occur? Through good cross-team communication and a thorough knowledge of your product’s performance characteristics. At the point when your R&D team hands off a product to be manufactured, they are intimately aware of the formulation’s physical and chemical makeup. As the formulation is granulated and prepared for compression into the final tablet, how well have the formulation’s characteristics been discussed with the tablet compression team? Were they involved in the tablet and tooling design process? It’s important that these experts be involved well before it’s time to produce tablets, because these staff members often hold the key to your tablet’s successful compression and product launch.

symbiotic relationship as they work together to generate your tablets. If one is not suited to the other, you may end up with unfortunate results. It’s necessary for the characteristics of your tooling (material, design, etc.) to complement that of the powder (particle size, powder abrasiveness, compression ratio, tablet breaking force specification, etc.) The three most common processing routes to prepare different powdered components for compression are direct compression blending, dry granulation, and wet granulation. Determining which route to employ is based on the tablet properties needed to meet the clinical requirements of the medicine. Direct compression is used if the ingredients (API, excipient, etc.) are able to be blended and a tablet compressed that meets tablet dissolution and content uniformity requirements. Direct compression is a convenient (and the least costly) method to blend together the

active pharmaceutical ingredient (API) and the excipients, fillers and lubricants required to make the desired tablet. Care must be taken to ensure blend uniformity is achieved before proceeding to compression. Granulation is the process of collecting particles together and forming granules, either through compaction or by adding a binding agent. Dry granulation is employed when ingredients in a formulation are sensitive to moisture or heat and are not amenable to direct compression blending. This is a mechanical bonding of particles without using a liquid to bind them. In this method, the particles are compacted commonly by using a roller compactor, or chilsonator. This increases their density and results in granules being formed from smaller particles. The resulting ribbon or pellets are then milled into a powder with the desired particle size distribution, which will be put through the

Powder characteristics, ambient relative humidity, tablet design – these factors may all play a part in successful (or unsuccessful) tablet manufacturing. An experienced tablet compression team can provide guidance on how to avoid issues such as sticking, picking, and potential tablet defects before any tablets are produced. The first line of defence for avoiding tablet compression problems is tablet design, which should be done with input from all team members, including an experienced tooling vendor. The prepared powder formulation and compression tooling share a 90 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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Manufacturing compression process on a tablet press. When the physical properties of the API preclude the use of direct compression or dry granulation, then wet granulation is utilised. The API and excipients are mixed under high shear conditions and liquids are sprayed into the mixture to induce particles to stick together. Binders are added as part of the liquid or as part of the powder charge to enhance granule growth. Once the granules are formed, they are dried and subsequently milled and blended to yield the desired formulation. Although wet granulation can be an expensive and time-consuming process, it is sometimes necessary to meet drug performance specifications. Wet granulation can cause problems during tablet compression if there is latent moisture retained in the finished powder. Capping, laminating, sticking and picking are common tableting issues that may need to be addressed and resolved before manufacturing. Often the tablet compression tooling is considered responsible for these issues, when the root cause should have been identified and eliminated during the development process. There are an infinite number of tablet design and tooling options, including materials of construction of the compression tooling available to tablet manufacturers today. With all of the options available, it would be beneficial for tablet manufacturers to consider how


their granulation method and powder preparation could influence the tablet and tool design to improve the end result. The tablet compression tooling should be engineered and manufactured with consideration for the product being compressed. Often there is too much emphasis put on utilising a company standard tablet configuration, even though each formulation is unique. Ideally, tablet designs and compression tools should be configured for each individual product and formulation. Today, with many manufacturers utilising direct compression blends to reduce costs, the company standard tablet configuration should be modified or success is challenged. A formulation that compresses easily with tools that have a deep or compound cup also will compress readily in a shallow or standard cup tool. The opposite is not always the case. Formulations that are difficult to compress receive better results using shallow or standard cups, not deep or compound cups. Consider a powder made using dry granulation. These powders can experience particle segregation leading to excessive fines (dust.) Fines that recirculate around the die table are reintroduced into the feeder, causing changes in blend uniformity. This can result in tablet property variability as fines have different compaction properties. In addition to compaction issues, there

are other problems that can arise from excessive fines. First, because of their very small size, fines are more likely to result in migration of small particles into areas of the press which can be detrimental to the tableting process. As the fine particles migrate between the lower punch tip and die (see Diagram A), it may cause tip binding, lower punch tip wear, die bore wear, cam wear, excessive ejection force and heat generation, which can be a cause of sticking and tablet discolouration. Other possible tableting deficiencies that result from sifted particles are capping and lamination. Sifted product can contaminate machine components and the lower punch guides, compromising the lubricity value for the lower punch barrel and head. This can result in the accelerated wear of various press components, leading to issues such as tool binding and resulting in manufacturing losses. Even if the press continues to run properly, the fine particles will make the press much more difficult to clean â&#x20AC;&#x201C; adding time when preparing and implementing a product changeover. While excessive fines can be addressed before tablet compression begins, if it becomes necessary to use a formulation that is prone to fine particles, there are tooling design options that can alleviate or reduce the effect of fines on the tablet compression process â&#x20AC;&#x201C; thus allowing the tableting process to

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Manufacturing be executed successfully. It’s because of these issues that your tablet compression team should be involved throughout the product development process. If the final formulation’s inherent characteristics may cause tablet compression issues, it may be possible to modify the tablet and corresponding tooling design to avoid them. For instance, the tablet compression team may suggest that the lower punches be manufactured with a narrow tip width and deeper than normal relief (see Diagram B). Although it is a small adjustment to the design, narrow tip width is a good choice for dry blends because it can help to reduce and, in some cases, eliminate many of the issues relative to the fines that result from the dry granulation process. As fines have a greater propensity to adhere to the die wall, a narrow tip combined with a deeper relief provide an improved scraping action to help clear the die bore of any built-up excess granulation. The build-up of fines in the die bore combined with the repeated linear motion of an unmodified lower punch results in increased friction between the lower punch tip and die bore. This friction causes heat which can lead to other issues, especially for heat-sensitive products or those with low melting-points. Not only will the deeper tip relief scrape excess product from the die bore more effectively, it will also cause less friction and result in less friction-generated heat. This is because the narrow tip width reduces the tip to die bore contact area. There are many tooling options and materials available to produce robust, long-lasting punches and dies. Often, the tooling used to compress the tablets becomes an afterthought. Keeping your tablet compression team engaged can bring significant cost savings as well as increased efficiency when tablet manufacturing commences. Armed with knowledge about the powder’s characteristics, tablet manufacturers are encouraged to consult with the tooling supplier to design and select the most appropriate material and tooling design. Standard tool steels are routinely chosen for their overall balanced characteristics and for their ability to handle shock loading conditions. Some steels are only suitable for punches while others are only suitable for dies. For 94 INTERNATIONAL PHARMACEUTICAL INDUSTRY

example, due to its high chrome and high carbon content, D3 steel exhibits high wear resistance but is very poor at accepting impact loads and compression stress. Therefore it is a preferred material for dies but a poor choice for punches. Steels with higher chromium content are good in situations where the product being compressed is corrosive or sticky, while tool steels with higher Rockwell hardness are ideal in situations where abrasive wear is a primary concern. There are tooling options such as shortened, strengthened lower tips and undercut dies that can be utilised to prevent the bending of lower tips when making very small tablets. Additionally, the punches can be designed with an extended head flat to increase dwell time for difficult to compress products. These are just a few of the solutions available to tablet manufacturers. Tooling can be specifically designed to complement the formulation properties from which the tablet will be compressed. Even at the critical tablet design stage, pre-pick or taper of the engraving (see Diagram C), along with unique cup configurations and modifications, can be implemented to prevent issues such as sticking, picking, capping, lamination, and accommodating the desired compression force. Some products requiring a higher compression force may benefit from a shallower cup depth and/or the addition of land. Even something as simple as changing the finish on the punch face can make a big difference on how a specific formulation runs in the press. Punch tips can be coated in chrome to improve wear resistance and other coatings can be utilised to combat other problems. Adding a coating is not the preferred method for alleviating tableting issues. Choosing the proper steel type and tooling configuration to compress marginal powders is preferred and can provide a long-term solution where coatings generally cannot. Some coatings can be cost-prohibitive and offer negligible results. It is still best practice to ensure the delivery of a proper formulation. Often powders simply cannot be compressed effectively. Thorough, clear communication between internal departments and involving the tooling supplier throughout the tablet development process is truly the best way

to ensure successful tablet production. This ensures that once the granulation reaches the tablet compression unit, the most suitable tooling has been prepared to complete the process. Such preparation can bring measurable savings to your organisation. Not only will tablets be produced efficiently and on schedule, meeting critical launch dates, but also the equipment used for production will be subjected to less wear and likely require less unscheduled maintenance. Some reputable tooling suppliers provide in-house scientific services and are partnered with university-based research organisations to provide unique insights into powder properties and compression profiles that offer solutions supported by data and current best practices. It is recommended that tablet manufacturers communicate with and take advantage of available resources and the experience of their tooling supplier.

As an engineer with Natoli Engineering Company, Kevin Queensen’s experience has been focused primarily on specialty tablet/tooling designs along with determining new max compression force calculation methods and performing Finite Element Analysis (FEA). He holds a B.S. in Mechanical Engineering and was recently asked to join our Technical Support/Engineering Team to assist customers with tablet and tooling designs and solving technical issues. Bill Turner is the Technical Service Manager of Tooling and Tablets at Natoli Engineering Company, Inc. He has also served as Engineering Manager and Tablet and Tool Designer for 25 years. He educates and trains Natoli sales and service staff and conducts training seminars to the industry in tablet design, tool design, and troubleshooting, both in-house, and on site. Autumn 2015 Volume 7 Issue 3




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Automated Efficiency Making Pharmaceuticals More Energy-efficient with Industrial Automation Iconic imagery of smoke-bellowing chimneys, silhouetted against illuminated skies, is a traditional way of illustrating the Industrial Revolution as an idyllic era of industrial pride. Back then, health and safety were non-existent and ‘climate change’ meant nothing more than the changing of the seasons. This industrial era brought a lot of change – not only did it mark a turning point for global industry, but also meant the beginning of a dramatic change in the way humans impact the environment. With Britain at the forefront of global industry in the 18th century, environmental ignorance was bliss. Fast forward to today; environmental sustainability is a hot topic for the media, the general public and manufacturers alike. In fact, energy-efficiency is now a primary objective, alongside profit and productivity, for manufacturers to work towards. Regardless of the sector or size of an organisation, the dedication to carbon footprint reduction is evident across the entire manufacturing industry. Here, Jonathan Wilkins, marketing director of industrial automation components supplier European Automation, analyses the impact of industry regulations, such as the Energy Savings Opportunity Scheme (ESOS) and initiatives like ISO50001, on the pharmaceutical manufacturing sector. He also discusses how eco obsolete technology (EOT) can help manufacturers meet their efficiency goals. EOT describes technology which, despite being no longer produced by the original equipment manufacturer (OEM), still complies with current energyefficiency standards and can therefore continue to be used in manufacturing environments. Although EOT will no longer be available for purchase from the OEM, it will most likely still exist in the stock of industrial automation parts suppliers. Regulatory Compliance The delicate nature of the pharmaceutical sector means that in order to upgrade or replace industrial parts, manufacturers must comply with a number of strict 96 INTERNATIONAL PHARMACEUTICAL INDUSTRY

industry regulations. As a result, obsolete technology is often relied upon to keep production up and running. The main regulatory procedure that pharmaceutical manufacturers must comply with is good manufacturing practice (GMP). GMP sets the guidelines for manufacturing, testing and quality assurance in the pharmaceutical sector to ensure that all products are safe for human consumption. GMP covers a number of basic legal responsibilities for drug manufacturing. The regulation states that manufacturing processes must be clear and controlled, and that any changes to the production process, including changes or alterations to equipment, must be recorded and evaluated by the relevant enforcement agency. Unsurprisingly, this rule can make upgrading, replacing or changing manufacturing equipment an incredibly lengthy procedure. In spite of this difficultly, upgrading and changing equipment is sometimes essential in order to meet the requirements of other industry regulations. For example, any organisation designing, manufacturing or testing pharmaceuticals to be exported to the United States of America must also comply with the guidelines set by the United States Food and Drug Administration (FDA). Title 21 CFR Part 111 is the name given to the most recent addition to the FDA Code of Federal Regulations (CFR). Major enforcements of CFR21/11 focus on the necessity of electronic data recording for both the food and beverage, and the pharmaceutical sectors. Enforcement of this regulation could help to irradiate poor data-handling in the pharmaceutical sector. To minimise human error, manufacturers are encouraged to invest in automated hardware and software to manage and record data from the factory floor. For example, by feeding information through a programmable logic controller (PLC), human machine interface (HMI) or a supervisory control and data acquisition (SCADA) system, important data can be

properly recorded and analysed quicker and more accurately. By implementing industrial automation, manufacturers can keep in line with GMP and in the event of a product recall, this vital data can be easily accessed. Pharmaceutical products concern the entire population and improper practice during the manufacturing stage can have disastrous consequences. With this in mind, it is unsurprising that such strict regulations are enforced and abided by. In contrast, environmental regulations for manufacturers are a continuing source of controversy. While some organisations embrace efforts to ‘go green’, others continue to debate the necessity, fairness and cost implications of these regulations. Unfortunately for the critics, some mandatory schemes have now been put into place, at least in the United Kingdom. Energy Savings Opportunity Scheme The Energy Savings Opportunity Scheme (ESOS)2 is a mandatory programme for large companies, across all sectors, including pharmaceutical. Organisations that qualify for ESOS have more than 250 employees and have annual turnovers in excess of 50 million Euros. Large enterprises are required to perform regular energy audits, identify energy reduction opportunities, notify the Environmental Agency and keep updated records. Fines of up to £50,000 can be issued to companies that fail to comply with ESOS regulations, so for manufacturers, being energy-efficient has never been more important. The deadline for submitting the first audit is drawing near – December 5, 2015. ISO 50001 While ESOS is a mandatory scheme within the European Union, pharmaceutical companies now have the opportunity to go beyond this compliance and gain ISO 50001 certification. ISO 50001 is an internationally recognised, optional initiative that encourages organisations to establish systems and processes to improve performance and efficiency and in turn, lower the energy consumption of their facilities. Autumn 2015 Volume 7 Issue 3


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Manufacturing An earlier version of this quality management system (QMS), ISO 9001, has been a part of pharmaceutical quality management for years and still remains a well-enforced standard across the industry. To some extent, ISO 50001 can be seen as an extension to the already established ISO 9001 scheme. As a result, the pharmaceutical industry is a step ahead of other sectors for achieving ISO 50001 certification. While ISO 50001 is not compulsory, the scheme works as a great energyefficiency benchmark for manufacturers to aim towards. The ultimate goals of the scheme are to reduce greenhouse gas emissions, minimise environmental impact and save on energy costs for organisations across the globe. In fact, the International Standard Organisation (ISO) estimates that ISO 50001 has the power to influence up to 60 per cent of the world’s energy use. Further Efforts to Increase Energyefficiency In the United Kingdom, industry is responsible for 25 per cent of total CO2 emissions. The latest report by the Sustainable Development Unit (SDU) showed that the NHS alone produced a huge 25 million tonnes of carbon dioxide equivalents (MtCO2e) in 20123.


It comes as no surprise that pharmaceutical manufacturing contributes a large proportion of those healthcare-associated greenhouse gas emissions. As stated in the SDU report, 21 per cent of the NHS emissions were attributable to pharmaceuticals. Medical devices were responsible for a further 11 per cent. In 2012, a voluntary target was set by the NHS Carbon Reduction Strategy to cut carbon emissions for NHS units by 10 per cent by the end of 2015, and by 34 per cent by 2020. Unfortunately, the NHS is struggling to meet these targets. The latest estimates from 2014 suggest that the NHS will barely achieve half of its 10 per cent reduction target for 2015. In another industry effort, the Association of the British Pharmaceutical Industry (ABPI) states that many of its member companies strive to contain their environmental impact and many have pledged to reduce their carbon footprint. By working alongside the Carbon Trust, the ABPI has developed and made freely available a tool for calculating the carbon footprint of tablet medicines in blister packs. “As a generality, the major elements of the pharmaceutical manufacturing

carbon footprint are in chemical manufacturing and air handling for controlled manufacturing environments,” explained Mike Murray, technical affairs manager at the Association of the British Pharmaceutical Industry. “Many of our members have seen great reductions in the carbon intensity of their chemical manufacturing operations through application of green chemistry and engineering principles. Looking forward, innovative technologies for these activities will help further reduce carbon footprint.” It’s clear that the pharmaceutical manufacturing sector must evaluate the changes that need to be made in order to improve its energy-efficiency. The Industrial Automation Solution When done correctly, implementing industrial automation in a manufacturing environment can dramatically reduce carbon emissions and save energy. Simultaneously, this technology increases productivity, reduces downtime and ultimately, saves money. In fact, up to 80 per cent of potential savings in a manufacturing environment can be achieved by improving automation4. Overspecification is a notorious issue for manufacturers, especially when it comes to motors. Historically, motors

Autumn 2015 Volume 7 Issue 3

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Manufacturing will run continuously at maximum speed throughout the entire production process, but when maximum speed is not required, energy is needlessly wasted. Let’s put it this way: you wouldn’t leave your TV on while you were out of the house, would you? So why would manufacturers allow industrial equipment to run when it is not required? By fitting a variable speed drive (VSD) onto a motor, you’re introducing the option to control and adjust the speed of the motor during the production process. Pretty much any industrial process uses electric motors and VSDs are the best way to adjust speed to the requirements of each different application. Typically, manufacturers use VSDs as a form of process control, but their ability to conserve energy has become an equally significant benefit. VSDs are just one example of increased productivity and significant energy savings that industrial automation can achieve for manufacturers. But energy-efficiency isn’t just about easy wins like VSDs. By putting data collection and analysis systems in place, a company can engage on a continuous improvement road when it comes to energy consumption. HMIs, PLCs and SCADA systems can be used to monitor and record data in manufacturing processes, which not only helps with CFR21/11 compliance, but can also identify areas of significant energy consumption. Considering the benefits of automation for industry, most would assume that automation is becoming standard industry practice, but according to an estimate by the UK’s trade body for automation, GAMBICA, industrial automation is still only used in ten per cent of manufacturing applications5. So why aren’t manufacturers reaping the benefits of industrial automation? Many assume that implementing automation would require an entire system overhaul. As a general rule, industry is not keen on drastic change, especially costly system upgrades. In addition to the high costs involved, the rigorous testing requirements of industries like pharmaceuticals and medical can dramatically limit options for upgrading. For pharmaceutical, there is no such thing as a quick fix.

This is where eco obsolete technology (EOT) comes in. Eco Obsolete Technology The term ‘obsolete’ simply means that the original equipment manufacturer (OEM) has stopped producing the part. While these parts may be difficult to source, obsolescence doesn’t make a part impossible to find. In fact, many industries rely heavily on obsolete components to keep production up and running. EOT is the name given the industrial components that successfully comply with energy-efficiency regulations even after they have been rendered obsolete by their manufacturers. Just because the OEM has stopped manufacturing the product, it certainly doesn't make the part useless overnight.

References 1. visited on August 4, 2015. Guidance for Industry. Part 11, Electronic Records; Electronic Signatures – Scope and Application 2. w w w. g o v. u k / e n e r g y - s a v i n g s opportunity-scheme visited on August 4, 2015. 3. visited on August 4, 2015. 4. uk/en/aboutus/Documents/ To p 1 0 _ e n e r g y _ s a v i n g % 2 0 options_0911UK.pdf visited on August 4, 2015 5. basic Energy Efficiency’s Automation Lens. Page 6.

Similar to the way the vinyl music format is still appreciated for its sound quality, older energy-efficient automation components are still widely used in industry because they remain relevant and effective – even by today’s standards. By embracing EOT, manufacturers are given the opportunity to become more energy-efficient, without spending millions on system upgrades. Industries from aerospace to oil and gas are already reaping the efficiency benefits of EOT. In fact, obsolescence management is becoming extremely important across industry, especially with the increasingly rapid developments of industrial automation. The manufacturing industry has come a long way since the carefree days of the Industrial Revolution. We are now in the complex and interconnected world of Industry 4.0. Industry today needs to make sure that the lives of existing ecofriendly technologies are prolonged for as long as possible, before discarding them. After all, getting rid of perfectly functional industrial automation components is anything but environmentally friendly. While today’s countless regulations and energy-saving initiatives may seem like just another hoop to jump through, it is vital that pharmaceutical manufacturers take every opportunity available in order to reduce their carbon footprint. After all, we need to ensure that our effort to improve public health does not come at the expense of the environment.


Jonathan Wilkins is the marketing director of European Automation, a supplier of obsolete industrial automation components. A professional brand advocate and commercial marketing strategist, Jonathan focuses on delivering growth via a multi-channel approach that has a significant positive impact on business. He has been part of the European Automation team since its humble beginnings four years ago and has nearly a decade of experience in marketing. Email: jonathan.wilkins@euautomation. com Autumn 2015 Volume 7 Issue 3

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Packaging Packaging: Protecting Your Contents Biologic products such as vaccines and active pharmaceutical ingredients (APIs) are sensitive to potential contamination at multiple stages of the manufacturing process. Therefore, ensuring that the packaging or container conforms to the highest industry standards is of the utmost importance. To preserve product integrity, safety and efficacy from manufacture to market, you need to be aware of the risks of critical product contamination and to know how best to mitigate those risks. These can include restricted container availability, the possibility of a container leaking or shattering, or product interactions with extractables and leachables (E&Ls) – all of which can lead to delays in regulatory approval, with associated costs to both time and resources. However, the first and most fundamental risk to evaluate is the levels of container cleanliness. The Importance of Validation Before exploring the details around the various cleanliness parameters, you should know the differences between

product and process validation, along with the varying degrees of effort required to achieve these. The first form of validation is process validation. Data from the process provide assurances that the equipment used in the process (e.g., irradiating or autoclaving) pass installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). This validation provides documented evidence in the form of a certificate of process and a high degree of confidence that the manufacturing process will consistently yield a product of predetermined quality. Relying on this form of validation ─ which certifies the equipment used in the process only ─ is the fastest method and associated with the lowest cost, although it also carries the highest level of relative risk. The second principal form of validation is product validation. Unlike process validation, product validation puts the finished product (i.e., the container) through quantitative (and, in some cases,


qualitative) biological, chemical and physical validation protocols to ensure that it consistently meets a certain parameter (e.g., sterility assurance level of 10-6). This type of validation can require multiple production lots, statistical sampling, and real-time shelf-life analysis, depending upon the user’s particular requirements. Following a full validation, the product is typically exempt from subsequent release testing for that particular parameter unless changes are made. However, release testing can be done, if requested, to provide additional confidence in product claims, such as in the case of endotoxins where it is difficult to challenge the system as indicated above. Product validation results in a certificate of analysis, certifying the final product itself. While this validation offers the lowest relative risk, it also carries both the longest time to execute and the steepest financial costs. Ultimately, the validation options are up to the user and the intended application should be considered. For example, a

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container used for waste storage would have less risk than one used for the final bulk drug product. A middle ground where a partial product validation is executed could make use of smaller sampling sets or only look at the accelerated shelf-life analysis; it could also include release testing for extra security. There are numerous options available within the existing validation system to accommodate individual needs. What Do We Mean By “Clean”? It can be easy to presume that because a container is designated as cleanroom-produced or gamma irradiated, that it likely meets the required levels of cleanliness. However, there is an inherent degree of ambiguity in these terms that needs to be dispelled at the earliest possible stages of manufacturing. While the main drivers behind selecting a particular container are often simply low levels of particulates or pyrogens, there are additional aspects that require clarification. For example, does irradiating or autoclaving mean that a product is sterile? What does steam or gamma sterilisation achieve? Are the terms referring to the validation of a process, such as with certain equipment, or to the product itself, where quantifiable claims are proven to be repeatable and reliable? Often there can be more than one answer to these queries, and thus defining these terms is important for maintaining critical environment conditions. Cleanroom-produced Cleanroom-produced is a frequently requested parameter of many containers and is included in the regulatory requirements for a variety of vaccines and biologics. While this process provides a great deal of security and familiarity with the controls and techniques likely employed, it does not provide any quantitative indication of the levels of sterility, particulates, or endotoxins in the container that is being produced. Simply claiming that a bottle is cleanroom-produced does not guarantee that these parameters have been achieved.

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Irradiated or Autoclaved Irradiation typically takes the form of gamma or E-beam, while steam is used for autoclaving. Performing these processes is often misinterpreted as meaning a container is sterile. However, these terms only confirm that the process of irradiation or autoclaving has occurred and are not an indication of the sterility assurance levels (SAL) of the container. For this reason, it is important to investigate these terms when selecting containers specifically requiring sterility claims. Sterility Unlike the previous examples, a claim of sterility is a product claim rather than a process claim, meaning that it is directly related to the container itself. Sterility is one of the most common claims seen on product containers, and understanding the different levels is important for minimising the risk of product contamination. The SALs are used to define the probability of microorganisms remaining after the sterilisation process, and the SAL level required needs to match the demands of the application: • •

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Packaging Sterility is typically achieved through irradiation or autoclaving. Claiming a product to be sterile requires that the container in its final packaging must be assessed for the claim of sterility using statistically sound and proven methods. Low Particulate “Particulate-free” is a commonly misused term. Particulates can never be eliminated, and there are no “particulatefree” containers. As such, reduction of particulates is necessary at every stage of the manufacturing process, and particulate limits are a requirement of the United States Pharmacopeia (USP) and European Pharmacopoeia (EP) guidelines for injectables. All containers involved during the various stages of manufacturing can contribute to the overall particle load in the final container. This product claim becomes increasingly important downstream in the manufacturing process. Suppliers left with no other alternative will typically conform to USP<788> guidelines for low-particulate claims, even though this guideline applies to the final injectable product. It is important to remember that a

claim of low particulate only refers to loose particulates and does not consider embedded particulates that can be in the form of foreign contamination or the form of charred resin inherent to the moulding process. Embedded particulates simply cannot be removed, and are instead controlled or mitigated through manufacturing experience and preventative maintenance. The best way to ensure that plastic containers are of the highest quality is to ensure that the resins used in their production are USP Class VI and <661> tested and compliant, and that the supplier has inspection procedures in place to help limit impacted products leaving the factory. Low Pyrogen Pyrogens, or endotoxins, come from bacteria. A low pyrogen claim is another example of a product claim rather than a process claim. As with particulates, it is not possible to make claims that containers are pyrogen-free. Low pyrogen claims are assessed by USP<85> bacterial endotoxin tests. Pyrogens tend to be very difficult to remove from containers and as such, a “system challenge” –intentionally contaminating a container with an


endotoxin in order to show that it can be removed – is not typically performed. Processes such as washing and cleanroom production can help to create a container that can be validated for low pyrogen levels. Statistically testing the “starting levels,” or baseline of pyrogens, and demonstrating that the progression through validated processes (handling, washing, irradiation, etc.) do not contribute additional levels of pyrogens are currently the best ways to validate that a product can reliably meet an endotoxin claim. This is a good example of product and process claims overlapping. Extractables and Leachables (E&Ls) Extractables are chemical species that migrate from packaging or container materials into the contents when exposed to different solvents under exaggerated temperature and time conditions. Leachables, on the other hand, are chemical species that make their way into the product from the container under normal application conditions. E&Ls are an important factor to consider as they have the potential to interact with a product at multiple stages of development and production, which could affect efficacy, safety, and

Autumn 2015 Volume 7 Issue 3


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Non-volatile organic compounds Volatile organic compounds Metals

Tests for extractables are performed at high temperatures with a range of chemicals to ensure that as many extracts as possible are documented under a simulated “worst-case scenario.” These tests are not meant to help choose which container is the most suitable for the application at hand, but rather to ensure that an unsuitable container is not selected. They function as screening tests, guiding users to the next step. Once a container has been found not to be a potential immediate threat to the efficacy or safety of the product following initial extractables testing, leachables testing will be required. This testing is performed under real-use conditions of temperature and time, with the actual product that will be stored in the container. As a result, an accurate representation of the leachables that could migrate from the container into the product is provided.

quality. There is an overlap between the two, such that the leachables seen are a subset of the extractables, but some of the extractables may not have been seen in the leachables studies. While some user groups have developed guidelines and recommendations, there are no required testing protocols for E&Ls. However, groups such as the BioPhorum Operations Group (BPOG) have worked hard to develop a standardised extractables testing protocol for single-use systems (SUS) in biomanufacturing. This protocol will help users to make informed choices when comparing SUS components from different suppliers. Based on the problems E&Ls can cause, their presence must be evaluated in those components that come into contact with the product during formulation, intermediate storage, and final packaging. This analysis enables a greater understanding of how to manage E&Ls during development for container closure systems (CCS) and packaging materials. E&L studies set out to identify several key aspects: • Semi-volatile organic compounds 106 INTERNATIONAL PHARMACEUTICAL INDUSTRY

It is worth noting that while most leachables form part of the extractables profile, this is not always the case. Since the chemical composition of the product stored in the container may not be covered by the water, acid, base and alcohol extractions that were performed as part of the extractables study, new chemicals may be found within the leachables profile. The Ins and Outs of Container Shelf-life Once the packaging or container is ready to bring to market, it is essential that all claims remain uncompromised for a defined period: shelf-life specifies the time the claims will remain in effect. Shelf-life studies for containers can include both accelerated aging, which is required to enable products to be placed into the market in a timely manner, and real-time aging, which can be ongoing after the product is already being sold. Shelf-life testing should confirm that the product claims are still capable of being met at the end of a stated shelf-life. Sterility is most often the focus of shelf-life testing. Manufacturers need to be sure that once a container has been sterilised, this “sterile barrier” remains in place throughout the length of the shelf-life. In the majority of cases, not all packaging layers are tested for the

integrity of this sterile barrier as this would involve testing each layer, including the inside and outside of the container, the innermost package, a carton liner (if used), and any layers of packaging in between. The likelihood of introducing contamination with this extensive testing is high risk. Therefore, the sterile barrier is usually limited to just the fluid path and the closure which are simple to test and have the least potential for false positives from contamination introduced through the testing process itself. As a result, it is usually prudent to assume that additional layers of packing are in fact not a validated sterile barrier, and should be sprayed down prior to entry into critical environments such as cleanrooms. Focusing on the Process, Not the Container Clearly, there are many critical factors to consider when selecting a container or packaging that will preserve the integrity, safety and efficacy of a valuable product. First, manufacturers should have an understanding of the terminology and processes involved in achieving various parameters of cleanliness, and whether these are process or product validated. Next, they must ensure that E&L studies are available where needed and that custom studies can be performed if required. Lastly, they have to be aware of the range of plastic alternatives that offer numerous benefits over glass counterparts. In summary, many manufacturers opt to use an experienced external supplier capable of providing the relevant knowledge in package and container selection, allowing them to focus on the important process at hand, rather than the specifics of the container.

Kacey Wiley Pouliot is a senior product manager of intermediate storage and critical environment, vaccines and biologics at Thermo Fisher Scientific, where she handles bioproduction and critical environment services. She received a Bachelor of Science degree in Chemistry from the University of Massachusetts and a Master of Business Administration degree from Daniel Webster College. She can be reached at Autumn 2015 Volume 7 Issue 3

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Packaging Where are Pharmaceutical Anti-counterfeiting Technologies Headed? Introduction Interpol estimates the annual turnover from pharmaceutical crime as USD 75 billion worldwide.1 In the US alone, the number of IPR-related seizures in the pharmaceutical and personal care industries amounted to USD 72,939,399, or 6% of the market share for FY2014.2 Improvements in technology, however, have allowed government officials, brand owners and experts in the field to curb this alarming trend. Particular focus has been placed on pharmaceutical packaging as a means to solve drugproduct counterfeiting. An attempt is made to explain the constraints under which the pharmaceutical industry is working to implement anti-counterfeiting solutions (regulatory, design, and financial constraints), to describe some of the major pharmaceutical anticounterfeiting technologies applied to packaging in use today (barcodes, RFID, invisible printing, etc.) and to offer some recommendations for the future. Background The Falsified Medicines Directive (2011/62/EU) adopted in June 2011 and put into force in January 2013, calls for the obligatory application and harmonisation of safety features on the outer packaging and labelling of individual packs of medicinal products. These measures seek to reduce the sale of falsified medicines in the legal supply chain, particularly via the internet. The scope of the safety features is threefold: one, “verify the authenticity of the medicinal product”; two, “identify individual packs”; and three, verify “whether the outer packaging has been tampered with.” EU-FMD Delegated Act The Directive calls on the European Commission to prepare and adopt delegated acts that will lay down the technical specifications of the safety features,4 determine the methods for the verification of the security elements,5 and institute a repository system to store and manage them.6 The notes published from the 74th meeting of the Pharmaceutical Committee, held on March 17, 2015, indicate that the European Commission is set to publish these acts in Q4 2015.7 108 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Once published, pharmaceutical companies will have exactly three years to comply with the EU-FMD, roughly by the end of Q4 2018. The minutes also give some insights into which features were identified as the most cost-effective. The measures begin with the introduction of a 2D barcode8 containing data such as product, serial and batch numbers. Authentication is then described as an “end-to-end verification system”9 enabling the control of the authenticity of medicinal products at the point of dispense. Finally, the repository system should be established and managed by relevant stakeholders,10 in other words manufacturers, distributors, and providers. As for tamper-evidence, “the choice […] is left to the manufacturer.” Unique Identifier 2D Barcode A matrix code or 2D barcode as a traceability solution is a valid one, as it can encode large amounts of data, such as batch number, expiry date, and national reimbursement number (as opposed to a traditional linear or one-dimensional barcode). It can also provide, with a single scan, detailed information on the current and past locations of a medicinal product. Finally, this system is noticeably cheaper than other technologies, such as radio-frequency identification or RFID systems, as the only cost involved is the ink. This said, barcodes are visible to the naked eye and are thus more vulnerable to counterfeiting. They are also subject to damage (e.g. excessive handling, exposure to chemicals, water and dirt) and therefore less reliable over time. Finally, barcodes must be scanned one by one, within line of sight, feasibly impacting the workflow process. RFID There has been growing interest in RFID technology as a means to reduce medical errors, curb drug counterfeiting, and promote patient safety. Applied as a tag or label on pharmaceutical packaging, the unique identifier is embedded in a microchip and uses radio waves to store and transfer data from product to

reader. Unlike barcode scanners, the RFID reader can detect hundreds of tags or labels at once and can be held at a distance. Because the unique identifier is embedded in a microchip, RFID tags cannot be altered and are therefore more reliable and more secure over time. Unlike barcodes, RFID tags can ultimately be applied to any type of material, withstand damage, and thus ensure a longer product lifespan. Despite the many advantages of barcoding and RFID as traceability measures, what these two technologies fail to do is verify the authenticity of medicines. Indeed, authentication, as defined by the International Standard 12931, is the “act of establishing whether a material good is genuine or not.”12 So whereas identification is the process of making claims about the characteristics of a product, authentication is the process of actually confirming the validity of those claims. The concept of a unique identifier as means to identify an individual pack can only work if there is also a reliable authentication system in place. Safety Features Overt (Visible) Features Some pharmaceutical companies have added visible security features to their packaging to prevent counterfeiting. These include holograms, kinegrams, optically variable devices or OVDs, security inks, embossing, micro printing, and moiré, to name a few. These features are prominently visible and are therefore conducive to a visual inspection of the medical pack. However, because they are visible to the naked eye, counterfeiters can also in theory create a replica virtually indistinguishable from its original counterpart, and dupe the average end user into thinking the pack is authentic. For this reason, a visible safety feature should at least be incorporated with an invisible one, if not be eliminated altogether. Covert (Invisible) Features A covert feature is by nature more difficult or even impossible to detect and therefore copy. Indeed, the knowledge of its very existence remains within Autumn 2015 Volume 7 Issue 3

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Packaging a very small and restricted group of trusted industry specialists, an approach that restricts consumer access. Because invisible safety features typically do not require any additional consumables, they can be simple and low-cost to implement, easily added or modified, and applied in-house, without regulatory approval. Examples include invisible printing, latent images, digital watermarks, taggants, and substrates (e.g. UV fluorescent fibres, chemical reagents and even odours), among others. There are several constraints to keep in mind when selecting a covert safety feature for pharmaceutical packaging. Cost-effectiveness Per the Falsified Medicines Directive (2011/62/EU), “When establishing the safety features due consideration shall be given to their cost-effectiveness.”12 Covert safety features can be simple and low cost to implement, if they require no additional consumables, no special reading devices, and no production changes. For example, invisible printing, while generally achieved through the use of special inks, can be realised using regular visible inks or varnish and standard printing processes (e.g. Cryptoglyph). Integrated with prepress, this technology embeds a pseudo-random pattern of microdots (10 to 20 microns) in the imperfections of the printed material. When applying overprint varnish, this process adds a pseudo-random pattern of micro-holes (40 to 80 microns) to the coating. Non-intrusive and totally invisible, these microdots or holes cover the entire surface of the packaging


or label without changing its design. Digitally encoded within the artwork, this form of invisible printing can be easily integrated into any existing packaging or label assembly process at zero production cost. Highly secure, this technology can only be deciphered with a 128-bit encryption key. Another cost-effective authentication solution uses the concept of fingerprinting to authenticate moulded products, such as vials, containers and lids, test tubes and caps (e.g. Fingerprint). This technology leverages the surface irregularities naturally occurring in a mould and uses these unique features as the means of authentication. The process simply requires capturing a digital image of the moulded product and storing it in a database. This image is then used as a reference to perform product authentication. As with invisible printing, fingerprinting does not require any additional consumables, markings or production changes. Instead, this solution uses the object ‘as is’, making it economical and easy to deploy. Harmonisation In addition to cost, the Falsified Medicines Directive (2011/62/EU) requires that “Safety features for medicinal products should be harmonised within the Union in order to take account of new risk profiles, while ensuring the functioning of the internal market for medicinal products.”14 Taking steps towards harmonisation means establishing common standards to identify, authenticate and trace medicinal products between the Union and the member states. Good automated manufacturing practice (GAMP) is a set of

guidelines for manufacturers and users of automated systems in the pharmaceutical industry that is already influential throughout Europe and recognised internationally. This set of industry best practices helps ensure that a medicinal product meets the expected qualities in all aspects of its production. Applied to pharmaceutical packaging printing, this system guarantees that the computer system will “…consistently produce results that meet its predetermined specification and quality attributes.”15 As a digitally printed covert safety feature, Cryptoglyph has performed as expected, continuously and with minimal attention for fifteen years and is developed in accordance with GAMP 5 CSV guidelines, making it an ideal candidate for pharmaceutical packaging authentication. Another example of safety feature harmonisation is the World Customs Organization’s Interface Public-Members (IPM), an online tool that provides frontline customs officers with real-time product data. Today, 85 countries have joined IPM. In 2013, AlpVision was one of the first providers of authentication solutions to become IPM Connected16 in an effort to tackle pharmaceutical counterfeiting, among other forms of illicit trade. Harmonisation also entails developing a system that can be easily used by all stakeholders—manufacturers, suppliers, distributors, pharmacists and possibly patients. Unlike most covert anticounterfeiting features available on the market today, AlpVision’s product authentication solutions do not require any highly specialised equipment to be detected. A regular smartphone

Autumn 2015 Volume 7 Issue 3

Safely Packaged The EU Falsified Medicines Directive will help prevent contaminated medicine and counterfeit drugs from reaching vulnerable patients by implementing stringent safety features.

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Variable data and coding systems for cartons and labels Random and sequential numbering Data management including code creation, verification, reporting and parent/child code aggregation No code duplication for a minimum of 10-years Tamper-evident features that fit existing pack styles and do not disrupt packing line performance


application can be used to verify the authenticity of a package. When it’s time to authenticate a product, the relevant stakeholder launches a custom application, positions the smartphone over the item and if the pattern is present, receives a positive authentication message within seconds. Automated, this system eliminates interpretation and training, significantly reducing human error. It is also developed using an everyday consumer electronic, making authentication easier and more universal. Repositories System Per the Falsified Medicines Directive (2011/62/EU), “The costs of the repositories system shall be borne by the manufacturing authorisation holders of medicinal products bearing the safety features.”17 The advantages of digital covert security features are threefold: one, they can often be applied inhouse or through certified printers. Two, they are web-based and hence do not require expensive hardware. And three, the server can be housed by a brand owner, a national government, or a designated body anywhere in the world, all together limiting involvement of thirdparty suppliers and minimising and even eliminating unnecessary costs. What’s Next? Although predicting what the EU-FMD Delegated Act will bring is difficult, we can safely say that the provisions include the obligatory application of a unique identifier in the form of a 2D barcode, in combination with a safety feature for product authentication, and a device 112 INTERNATIONAL PHARMACEUTICAL INDUSTRY

for tamper-evidence. Not only do these measures need to be interoperable EUwide, they also need to be cost-effective. To say that this is a challenge would be an understatement. While the manufacturer has very little leeway in terms of the unique identifier, the choice of a safety feature for product authentication is broader. The manufacturer would therefore be well advised to select a digital covert security feature that would not only comply with the Directive, but also be simple to implement and deploy, highly secure against counterfeiting, instantly detectable using an everyday consumer electronic like the smartphone, and overall cost-effective. References 1. Europol, 2015 Situation Report on Counterfeiting in the European Union, April 2015, p. 11 2. U.S. Department of Homeland Security, U.S Customs and Border Protection, Intellectual Property Rights Seizure Statistics, Fiscal Year 2014, p. 6 3. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products, p. 7 4. See Reference 3, p. 7 5. See Reference 3, p. 8 6. See Reference 3, p. 8 7. 74th meeting of the Pharmaceutical Committee, 17 March 2015, p. 3

8. See Reference 7, p. 3 9. See Reference 7, p. 3 10. See Reference 7, p. 3 11. European Commission, Health and Consumers Directorate-General, Delegated act of the detailed rules for a unique identifier for medicinal products for human use, and its verification, Concept paper submitted for public consultation, 18 November 2011, p. 4 12. International Standard ISO 12931, International Organization for Standardization, 2012, p. 2 13. Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products, p. 7 14. See Reference 14, p. 2 15. Computer System Validation – It’s More Than Just Testing, STS Consulting, Retrieved 17 August 2015, p. 1 16. World Customs Organization, IPM – Interface PUBLIC-MEMBERS, IPM Connected, http://ipmpromo. wcoomd p u b l ica t ions.o rg/i pmconnected, visited 21 August 2015 17. See Reference 14, p. 8

Dr. Fred Jordan, CEO, AlpVision. Dr. Jordan is cofounder of AlpVision and has served as CEO since June 2001. He is the author of numerous publications and patents and coinventor of Cryptoglyph and Fingerprint, AlpVision’s core technologies. In 1999, he obtained his PhD from the Swiss Technology Institute (EPFL) – Signal Processing Institute (ITS) in Lausanne. Email: Autumn 2015 Volume 7 Issue 3


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Packaging Get it Right the First Time Tips on Maximising Efficiency in Blister Packaging Development For technical products across many industries, small details are often modified without customers perceiving significant visual or functional changes. Manufacturers of such products or devices implement these changes to save costs, simplify the manufacturing processes, or make a product more reliable. Typically, these alterations are relatively simple to introduce as there are no regulatory restrictions on them; so long as customers are still happy, no feathers are ruffled. The pharmaceutical industry, of course, is an entirely different ballgame – one in which changes, not only to products are closely scrutinised, but seemingly non-momentous tweaks to product packaging require a great deal of both fiscal and human resources. As a rule, it must be sufficiently proven that a modification has no negative impact on the product and/or the end consumer. This show-your-work verification as to a change’s efficacy can add significant time and expense to the overall modification process. The best way to avoid making changes to pharmaceutical packaging is simple: get it right the first time. This is, of course, easier said than done. But a variety of best practices can be put into place to help shorten development times prior to product introduction and avoid expensive modifications afterward. For example, it can be advantageous to create virtual models of an in-development package – a preliminary step that can help engineers determine factors such as ideal packaging material, which is important to avoid both inadequate underpackaging and unnecessarily expensive over-packaging. There also are tools available that help make appropriate decisions regarding processability, as well as those that consider “if/then” product efficacy factors that may have been overlooked otherwise. Following are tips on how to utilise some of these tools to make packaging development a more efficient, exacting process. 114 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Barrier Properties: Selecting the Ideal Packaging Material For many years, there has been a trend of pharmaceuticals becoming more sensitive to moisture. In order to sufficiently protect pharmaceuticals from moisture and achieve the required shelf life, a packaging material must be selected that provides an appropriate moisture barrier. Often, a specific packaging specification is selected in the development phase in order to conduct stability tests; if this test is successful, this packaging specification can, of course, be used. What this test won’t reveal, however, is whether you’re actually overdoing it. Indeed, the results of the stability test do not convey whether a specification with a lower water vapour barrier would have been sufficient. For example, a thermoform laminate with a relatively thicker barrier foil may be specified even though a thinner barrier foil would have sufficed. The same often is also true for polyvinylidene chroride (PVDC) coatings and their coating weights. If a material with an insufficient water vapour barrier was selected for the stability test, the test will not be passed. When this occurs, an additional test must be conducted to identify a suitable packaging material, which results in additional costs and delay. For that reason, the rational tendency is for packaging developers to overcompensate by using a barrier of protection above and beyond what they deem necessary to pass the examination. Here, fear of failure supersedes exacting optimisation – with costly overpackaging as an unfortunate side-effect. Luckily, this guessing game can be largely marginalised by simulating the barrier properties of various packaging types, toward the goal of realising the ideal material selection for the stability test. This is a particularly attractive option when a fairly wide range of film specifications for thermoform blisters are available from which to choose; for example PVC/PVDC laminates with various coating weights or ACLAR/PVC

laminates. A simulation is especially useful for thermoform laminates, because the barriers of their formed blister cavities can only be estimated to a limited extent using the barrier properties indicated in the technical datasheets provided by suppliers. This is because these datasheets refer to the barrier values of the unformed, flat laminate, which can be misleading: during cavity formation, the laminate is made thinner and the barrier reduces correspondingly. The situation is further complicated by the fact that the laminate is not made evenly thinner; some areas of the cavity are thinner than others. The degree of thinning and the resulting barrier must be simulated to distinguish truly reliable values.

Example: Simulation of the thickness distribution of a thermoform blister cavity. Aluminium laminates are often superior in this regard, providing a “trump card” of sorts. This is because the aluminum in the laminate provides a 100% barrier against water vapour (and oxygen). In addition, the barrier properties of aluminium are independent of its thickness; a coldform foil offers the same barrier against water vapour and oxygen after deep drawing as it does before deep drawing. Even if a coldform foil is chosen, such an examination can still make sense. As stated, coldform foil offers the highest barrier against water vapour. However, there are fine differences in coldform barrier properties pertaining Autumn 2015 Volume 7 Issue 3

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Packaging to the cross-permeation effect. Namely, a very small amount of water vapour may enter the cavity from the punched edge of the blister. A suitable simulation can demonstrate whether it may be advisable to use coldform foil with polyethylene (PE) instead of polyvinyl chloride (PVC) to diminish this possibility, or to use a coldform foil with a desiccant to absorb the moisture coming from crossmigration.

Example: Simulation permeation effect.



for the inconsistent degree of material stretching that takes place during cavity formation. Here, areas with the highest degrees of elongation cannot be predicted based on experience, but must instead be calculated (simulated) as a large number of parameters are at play. There are also cases in which an existing (forming) tool design must be used and no detailed technical drawing is available. In such cases, the maximum elongation can be examined by taking a measurement. This is done by deep drawing a laminate on which a “highdefinition grid” has been printed. By evaluating the grid after deep drawing, it can be determined whether high rejection rates must be assumed for later production. If this is the case, the design of the forming tool should be revised.

limitations have made it near-impossible to gauge the overall negative influences of pinholes in laminates and lacquered foils. Here again, a simulation can estimate the barrier reduction caused by pinholes, and the results used to estimate the influence that moisture permeation caused by pinholes is likely to have on a given product. For example, this can be helpful if the aluminium thickness for a packaging laminate, or the lid foil in the case of a blister pack, needs to be determined. After all, the lower the aluminium thickness, the higher the probability it will have a pinhole. The simulation can be used to estimate whether a thinner aluminium foil presents a risk for the product.


Shaping Bottom Laminates The forming performance of base laminates is limited, and this must be considered in the cavity design of blister packs. If a laminate is overstretched during deep drawing – regardless of whether it is a thermoform or coldform laminate – tears or pinholes could occur that critically diminish or even entirely eliminate protection. Even if these errors are detected in-line, a poor cavity design can result in escalated costs due to increased waste and decreased productivity. And then there’s the worst-case scenario; that these defects are not caught – a daunting prospect considering that not all pinholes are created equal. If pinholes form due to a defective cavity design, coldform foil offers the advantage that these defective blister packs can be identified with a so-called “pinholes detector”. This type of inspection does not exist for transparent thermoform blisters. It is, then, critical to have a comprehensive understanding of material limitations during the development phase, especially as they pertain to cavity forming. In most cases, FE-based (finite element) simulations can assist experts in making appropriate suggestions. This kind of simulation helps compensate 116 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Example: Evaluation of the elongation distribution of a coldform cavity The Influence of Temperature Typically, products being packaged are subjected to a certain temperature influence because the lid foil and base laminate are heated up during blister sealing. The degree of heating is dependent upon many parameters, such as the heat conductivity of the laminate being used, its melting and sealing temperatures, and its sealing time. FE-based simulation tools can be used to estimate temperature influence – an important step especially when packaging potentially temperaturesensitive products. The results can affect not only the laminate choice, but the specific foil/laminate combination. For example, it could be beneficial to use coldform with PE over coldform with PVC, as the sealing temperature for PE laminates is lower. The Influence of Pinholes in Aluminium As pinholes in aluminium are very rare, it is correspondingly difficult to find test samples that can be used to measure the influence of aluminium pinholes. Even when they do occur, detection device

Example: Simulation of a pinhole Summary Simulation can be a worthwhile tool in finding ideal materials during the packaging development process. The inappropriate use or overuse of a material is unnecessarily costly in terms of material investments; the risk of insufficient materials is, of course, an even greater threat. Defining early on both suitable materials and the production process by which they are utilised can avoid unwanted surprises through optimal packaging solutions.

Thomas Schwarz is Development Engineer, Pharma Division for Constantia Flexibles, which offers packaging solutions to the pharmaceutical and healthcare industries.. The company recently introduced Constantia DryFoil, a blister solution offering highest-possible protection against moisture cross-diffusion (ingress) by substituting traditional PVC with a special polyethylene desiccant layer. Autumn 2015 Volume 7 Issue 3

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Packaging Sterile, High-Quality Components for Increased Patient Safety Quality-wise, the main focus in pharmaceutical manufacturing has been primarily on the drug product and its primary container. Many pharmaceutical and packaging manufacturers have placed emphasis on those materials in direct contact with the drug product itself, such as the glass vial, plastic syringe and elastomeric stopper or plunger. Additional packaging elements, such as caps and seals, haven´t been the primary focus. However, in recent years, regulatory guidelines have influenced the requirements for crimping processes significantly. Annex 1 – Manufacture of Sterile Medicinal Products – of the EMA’s good manufacturing practice guidelines specifies that the production of sterile products is subject to “special requirements in order to minimise risks of microbiological contamination”. The EMA has stressed that quality assurance is “particularly important” and that manufacturers must “strictly follow carefully established and validated methods of preparation and procedure”

to help ensure that drug products are clean and packaging sterile when used by patients. When it comes to processing, precautions must be taken to minimise contamination and the EMA refers in particular to two processes in the fillfinish area of those manufacturing plants that also perform aseptic filling: aseptic crimping and clean crimping. Aseptic Crimping A drug product’s biological and particulate cleanliness is best assured using aseptic crimping techniques and pre-sterilised components. Aseptic crimping requires the use of sterile seals, and for this process – as well as for reflecting the trend towards controlling particulate cleanliness – knowledge about particle specification limits may be requested. In order to meet aseptic crimping requirements, there are sterile, highquality seals available. Such seals have a bioburden level prior to sterilisation (as referred to in EMA Annex 1 Clause 80) as well as a specified particulate level.


Use of such a product helps to maintain cleanroom cleanliness levels and ensures quality for the end-user. Clean Crimping For clean crimping procedures, capping and crimping are performed in a nonaseptic environment under Grade A (Class 100/ISO 5) air supply. EMA Annex 1, Clause 120 notes that when vial capping is undertaken outside of the aseptic core, “vials should be protected by Grade A conditions up to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a Grade A air supply until the cap has been crimped”. Although the use of non-sterile seals is not excluded by the EMA Annex 1 for clean crimping processes, there is a growing uncertainty regarding the introduction of non-sterile, potentially contaminated components into the clean crimping area and the effects on operational efficiency that this might cause. Today’s high quality standards demand that contamination should be

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avoided by all means. Performing a clean crimping process with non-sterile seals means that comprehensive investigations need to be performed and maintained in order to ensure that stopper-vial integrity is not an issue. This type of testing may not be the core competency of the pharma company and, as such, may become a source of variability that can impact drug quality and regulatory compliance. Biological contamination when using non-sterile components, as well as failures or interruptions in the clean crimping processes, can not only potentially maximise the risk to patients, but also increase total costs for the business. Combatting Inefficiency and Contamination In order to ensure the various requirements and guidelines for aseptic and clean crimping processes, different seal qualities with the appropriate features and benefits required by the product itself and, ultimately, the enduser are needed. Just as different drugs may require different primary containers, secondary packaging also maintains a range of levels to ensure that the right quality is provided for the product and the manufacturing process. To guarantee clean crimping procedures, pharma and biopharma companies are increasingly turning towards ready-to-sterilise and ready-to use sterile packaging components. The use of high-quality, sterile products and components is necessary to avoid reject rates and higher production costs.


For many, a high-quality sealing component that is vision controlled, consistent and reliable during the capping process is an excellent choice. In particular, this type of seal can be a cost-effective method for clean crimping processes. Since filling machines are becoming faster and more efficient, appropriate crimping procedures might also impact reject rates related to failures within the crimping and capping process. Even though rejects of finished drug product at the end of the line â&#x20AC;&#x201C; due to inappropriate crimping â&#x20AC;&#x201C; reduce operational efficiency and increase total costs of ownership, many crimping processes are carried out with basic products a traditional way. Using highquality sterile packaging components ensures a stable crimping performance, which minimises the risk of external contamination, line stoppages and equipment down-time. Increasing quality levels for seals would include sterile, ready-to-use components that have specified and controlled bioburden levels before sterilisation. This type of seal can be used for clean crimping under Grade A air supply. Regarding aseptic crimping processes, pharmaceutical and packaging manufacturers should seek out a clean, certified and sterilised seal that is developed for immediate use in cleanrooms and isolators. It should have a specified, low level of bioburden prior to sterilisation, as well as a certified particle level. Such a seal will be specifically manufactured for use inside

a Grade A environment and designed for aseptic crimping processes. It will ensure biological cleanliness to meet regulatory guidelines and is the ideal solution for aseptic crimping procedures, in addition to helping ensure that patients are receiving a safe, effective and clean drug product. Whether a manufacturer decides to use aseptic crimping or clean crimping, the choice of seal can aid in the process by creating operational efficiency and eliminating potential sources of bioburden and particulates. High-quality seals are intended to meet operational and regulatory challenges, and consistently achieve reproducible and safe container integrity for the drug product. Use of such a seal will increase filling line efficiency and drug product safety, helping to meet the regulations and expectations of an industry for which quality is an evergrowing concern.

Sylvia Marzotko is Manager, Marketing Projects Europe at West Pharmaceutical Services and is responsible for project management, as well as product-related activities such as launch preparation and execution. She holds a degree in Business Administration with a focus on Marketing from the University of Duisburg-Essen, Germany. Email: Autumn 2015 Volume 7 Issue 3

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Packaging How to Tackle Counterfeiting; A Global Public Health Issue Today, counterfeit products can be found in every country and every sector of the global economy. According to international organisations like the World Health Organisation, counterfeiting concerns between 5 and 9% of global trade and approximately 10% of the global pharmaceutical market. It is estimated that 50% of drugs available on the internet are counterfeit, while this figure can reach up to 70% in some African or Eastern European countries. The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) also recently announced that UK customs officials have seized counterfeit drugs estimated to be worth nearly £16m. Patients and Pharmaceutical Brands are in Danger Criminals who trade in fake medicines are finding sophisticated ways to infiltrate legitimate supply chains. The high demand for specific drugs works as an incentive for them to take advantage of consumers who cannot afford the cost of authentic products. Price differences fixed by national governments or multinational companies drive parallel trade, which then grows in high correlation with counterfeiting. According to Interpol, patients across the world put their health, even life, at risk by unknowingly consuming fake drugs, or genuine products that have been doctored, badly stored or that have expired. In addition, counterfeit products can also affect a brand’s reputation. Taking Action to Tackle the Issue What are the drivers of counterfeit growth and how can private actors like Essentra help international and national regulators tackle this global issue? Four drivers appear to be driving counterfeit growth: supply chain complexity, the development of e-commerce, the increasing sophistication of counterfeiters and the lack of coordinated enforcement capacity. Supply Chain Complexity The supply chain for pharmaceuticals is now global. This means increasingly complex supply chains, supported by multiple opportunities for significant cost

savings, but also unfortunately increased opportunity for illegal activity. The focus should therefore be on monitoring and maintaining the integrity of the supply chain by paying more attention to details and having proper protocols in place. Tamper-evidence technologies introduced in the shipping process can also give a clear indication to the consumer if tampering has occurred. Development of E-commerce Many legitimate platforms exist, but the internet has given counterfeiters direct and easy access to the consumers. As a result, rogue internet pharmacy sites are proliferating, and it becomes harder to track the criminals and their products down. Counterfeit Sophistication The discrepancy between the potential profit from counterfeiting and the relatively low risk of punishment encourages criminals to invest their resources into making their products look as similar as possible to authentic goods. Working with companies to help them develop cutting-edge covert technologies such as infra-red (IR) and ultra-violet (UV) inks, microtext, and microscopic tagging, both invisible and difficult to detect and replicate without specialist detection equipment, is part of the solution. Lack of Coordinated Enforcement Capacity There is currently no effective regulation or sufficiently strong enforcement capacity across the industry to tackle counterfeiting. Putting the topic on governments’ agendas and setting it as a top priority for businesses will be essential to help enforcement agencies develop a coordinated initiative that will make the fight simpler and less time-consuming. It is today impossible for governments to monitor all exports and imports of goods; only a joint effort between industry and governments will enable a realistic solution. Serialisation Alone is Not a Panacea Serialisation, as promoted in the EU Falsified Medicines Directive, is not a panacea, as coding alone


is not authentication. Training and enforcement methods have not yet been addressed. Coding initiatives have focused exclusively on digital methods, with under-exploitation of physical protection opportunities. However, in the pharmaceutical industry, the consumer, whose life could be endangered, should be able to check on their own if a product is counterfeited or authentic. By giving more responsibility to the patient, the industry could help raise awareness on the issue. Only allowing companies to choose a “layered” combination of physical and digital attributes will deliver enhanced protection. That is why packaging specialists have developed technologies to integrate security within the product packaging. These solutions often include technologies that can allow instant authentication, but also solutions that are more complicated to detect or replicate without specialist detection equipment, as well as tamper-evidence, tear tape and integrated design.

Ian Lemon is Essentra’s Global Product Director, Health and Personal Care, Ian Lemon is responsible for leading the company’s product offering in this category, as well as its new product development in line with customer and category needs and demands. He has over fifteen years of experience delivering value-added packaging solutions and has worked with several of the world’s leading FMCG businesses. Email: Autumn 2015 Volume 7 Issue 3

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Packaging Nested Vials for Improved Lyophilisation Efficiency Lyophilisation vials are normally washed and sterilised prior to processing and filling, which requires the use of cleanrooms, washing machines and sterilisation tunnels — depending on the level of containment needed — to perform these tasks. However, to improve efficiency and to reduce both time and costs, prewashed and sterilised readyto-use packaging materials may offer a solution and improve the overall process.

Container production, depyrogenation and washing are done prior to nesting, after which the package is sterilised by gaseous ethylene oxide (ETO). Vial/ tub transport, filling, stopper setting, lyophilisation and closure with pressfit caps can all be done with the vials in the nest. For in-process-control and crimping, the vials have to be removed from the nest and reinserted for further processing.

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

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

The advantage of such nested vial systems is that they can be used with existing nest-filling systems and allow pharmaceutical companies to freezedry and handle filled vials inside the nest. In collaboration with GEA, one of these systems - SCHOTT adaptiQ - has been tested to ascertain its suitability for the freeze-drying process in both a standard pilot plant and a productionscale lyophiliser, specifically to assess its handling capabilities with a standard loading and unloading system.

Other key points are Flexibility: existing nested filling equipment can be used; machinery for the optimised filling of small batches is available. Product quality: the vials are supplied clean, sterile and ready-to-fill in a nest/ tub; there’s no glass-to-glass contact during transport, fill and finish; and the system offers increased safety benefits for highly potent products. Cost of ownership: Lower capital employed and reduced running costs, minimised defects during filling and reduction of cleanroom space required.

Johannes Selch, Product Manager, ALUSTM, at GEA, was available to discuss the results. “Our focus,” he says, “together with SCHOTT, was to find out how the nested vial product influences the freeze-drying process, particularly in terms of handling (loading and unloading), in a production environment. The obvious advantage is that there’s no need to use a washing machine or a sterile tunnel in front of the filling line. The vials are supplied clean, sterile and ready-to-use in a sealed, nest/ tub configuration. The user can then bring the nest/tub into their containment area — be it an open/closed RABS system or an isolator — where it can be manually or automatically opened.” In essence, all process steps are possible within the nest, handling is smooth and reliable, and there’s no glass-to-glass contact. 124 INTERNATIONAL PHARMACEUTICAL INDUSTRY

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

unable to come into contact with other vials, to prevent scratches and breakage and consequently lower the reject rate. The nests also have walls for freeze-dryer handling, finger cut-outs for manual removal and an alignment guide for precise positioning. Individual nests can be linked together and a wide variety of sizes are available, from 2/4R (100 vials) and 6/8/10/15R (48 vials) to 20/25/30R (25 vials) in an industrystandard tub format (Figure 1). And, as it has been designed for existing nest-fillers and novel flexible filling equipment, the system is scalable from research and development (R&D) to commercial production. Under Test Conditions “Having tested the nested vials using a standard tray-loading system, they performed perfectly well,” notes Johannes, “irrespective of whether the nests were fixed together or left unattached (Figure 2). Unloading using a standard system was also problem-free.” He commented that the interconnectivity most likely plays a greater role in manual handling; but, for automated systems, the nests can be used as individual units. “In development and when processing very expensive product in small batches, the connectivity would also be an advantage, as it facilitates manual loading and unloading,” he noted, adding: “Key advantages here are simplified and stable loading/unloading, and less downtime as a result of higher loading/ unloading speeds.” Autumn 2015 Volume 7 Issue 3

Chapter Title

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Packaging Nesting/de-nesting can also automated quite easily, providing • •


reliable removal of vials (individually or in batches) stable reinsertion of vials after checkweighing/closure.

Further research is ongoing with machine vendors to further advance nested processing. Containment issues can also be avoided with the use of nested vials, which are suitable for both open and closed RABS, isolators and GEA’s Automatic Loading and Unloading System (ALUSTM). Capacity Restriction Regarding capacity, Johannes said: “We have calculated how many vials can be processed, with and without nesting, using a standard loading/unloading procedure without frames or trays. Using a freeze-dryer with standard shelf dimensions, a process capacity reduction of up to 40% was recorded using nested vials compared with non-nested ones (hexagonal format).” Commenting on the results, Johannes said: “We can process 200–300 nested vials a minute to improve the overall efficiency (100 vials/nest means 2–3 nests/min), but the 40% capacity loss is significant. To fully utilise nested vials and to compensate for this loss in the future, it will be necessary to address the issue at the design stage and produce tailormade freeze-dryers.” It is presumed that nested vials will, initially, be used to process very expensive products. It’s apparent that the increased stability inherent in the system is a clear benefit for high-value or highly potent compounds. And, being able to guarantee that no vials fall or become damaged is a key consideration. Even an average non-nested fall rate of 0.02% when working in a high containment facility or with a limited supply of a toxic product would be problematical and time-consuming to remediate. Johannes adds: “The current trend would suggest that nested vials will not be used for high-volume, low-value product processing, only for small batches of high-value products. This does not preclude the use of an automatic loading and unloading system, though; more and more often, automatic loading/unloading systems are used to prevent operator

intervention, reduce contamination risks and protect both the product and the user, particularly when potent products are involved (Figure 3).” Processing Tests In a comparative drying test at pilotplant scale, a 3% mannitol solution was processed in a standard freeze-dryer. Nested and non-nested (hexagonal format) vials were used. The test showed that placing the vials in nests resulted in a 10% faster drying cycle. It could be concluded that the surrounding plastic had no detrimental insulating effect, and that the less dense arrangement of the vials in the nest led to a positive influence on the total drying time. Scaling up to a production-level freeze-dryer, a comparable test was done with 3% mannitol. Once again, a similar result was obtained. In addition, stoppering was also examined and the result was nearly identical for both sets of vials. It was remarkable, though, that fixing the vials in the nest prevented the stoppers from sticking to the freeze-dryer shelves, and that no nested vials fell over during the procedure. When looking at residual moisture values, it was noted that the nested vial results were slightly better than the non-nested vials at the edges of the containers. The additional space between the vials enhances the sublimation flow and reduces the total level of residual moisture. “Overall,” notes Johannes, “apart from the tiny variation in residual moisture levels, there is absolutely no difference between the results obtained from the nested and non-nested vials in a production-scale freeze-drying process. The data are extremely comparable.” “For the pharmaceutical m a r k e t , however, it is important to demonstrate that nested vials can effectively be used in both a pilot and full-scale freeze-dryer, and with a standard loading/unloading system, without risk, and that the same results can be achieved compared with using a regular hexagonal vial format (Figure 4). And, as far as we know, there is also no disadvantage associated with


nested vials when it comes to resolving lyophilised end-products,” he added. To summarise, SCHOTT adaptiQ® vials allows nested freeze-drying and it is demonstrably possible to use the nests in existing automatic loading and unloading systems. They meet the pharmaceutical industry’s requirements that the nest is made from a proven material and that the bottoms of the vials are freely accessible to enable the freeze-drying of sensitive formulations without having to remove the vials from the nest. The nest-and-tub configuration, as used for pre-fillable syringes, offers a lower packaging density that allows for equivalent or faster drying cycles. The higher price for ready-to-fill sterile vials compared with conventional vials will be more than compensated at a total cost of ownership (TCO) level. Investment, energy use and utility consumption can all be reduced by eliminating washing machines, water for injection (WFI) systems and sterilisation tunnels. And, despite big pharma being a very conservative industry, there are clear applications for this technology in both R&D and full-scale production. A system is already in operation, at start-up phase, in Asia. Comprising a GEA freeze-dryer with a back-pusher unloading system, full-scale production is expected to commence in 2015. Conclusion It is unlikely that nested vials will replace non-nested ones in standard freezedrying and vial-handling production cycles. However, this innovative development does open up new possibilities for future production. Nested vial-handling can easily be implemented into existing and proven lyophilisation equipment and, as such, both the nests and the technology are “ready to use.” Gregor Deutschle, Global Product Manager SCHOTT Pharmaceutical. He focuses on aseptic filling and works closely with filling line manufacturers and lead customers to develop new packaging solutions.

Johannes Selch, Product Manager ALUS, APC GEA Germany. Responsible for GEA ALUSTM Systems. (Automatic Loading and Unloading system for Pharma production Freeze Dyer lines). He focuses on aseptic loading and unloading production Freeze Dryer lines. Autumn 2015 Volume 7 Issue 3


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Chapter Title Reviews Anglonordic Life Science Conference - A Review

Spanish government also offers strong support through low-interest credits and incentives during the start-up and growth phases of life science companies. There is an excellent infrastructure for innovation, showing an exponential growth of science and technology parks, research centres and institutes of technology. All of this makes Spain very attractive to international companies looking to expand their businesses and to set up scientific and technological alliances with Spanish companies and institutions.

In total 300 decision-makers representing 200 companies attended this popular event and set a record for the number of delegates attending and the number of pre-booked one-to-one meetings. 55 companies were investment firms, making every fourth company attending an investor. The conference, entering its 12th year, was held on 23 April at the 1VS Westminster Conference Centre in London. It started in the evening of 22 April, with an exclusive drinks reception at the Spanish Ambassador’s Residence, located in Belgravia, London. In order to increase the networking possibilities and to make the conference more productive, the conference executive committee decided to merge the Anglonordic Biotech Conference with the Anglonordic Medtech Conference and the new name, starting this year, is the Anglonordic Life Science Conference.

Because of increasing interest and this year’s conference being sold out, the plan is to move to a new facility in London in 2016 and to increase the number of delegates to 450. Every year the conference has a guest country that brings a delegation of R&D companies and investment firm (this year Spain), and next year the committee is planning to expand this concept to include three guest countries. The new venue and the guest countries for 2016 will be announced on the conference website in July.

“Every year we receive the same positive feedback from the delegates and this year was no exception. I very much look forward to next year when we move into a new bigger facility and also increase our numbers of delegates, one-to-one meetings, guest countries and presentations,” says Mattias Johansson. For more information the conference, visit

about www.

Contact: Mattias Johansson, Director and Founder of the Anglonordic Life Science Conference: mattias.

This year’s guest country was Spain. The country was ranked 10th in the world in terms of scientific power, and 5th by scientific production in EU15 in 2013. The

“The outcome of this year’s event was very successful and it was sold out a couple of weeks ahead of the conference. We have kept our successful concept and our "by-invitation-only" policy. The select audience is restricted to decisionmakers representing drug discovery and medtech companies from the Anglo-Nordic regions and international pharmaceutical and investment firms. Service suppliers can only attend as sponsors or exhibitors,” says Mattias Johansson, Director, Anglonordic Life Science Conferences. 128 INTERNATIONAL PHARMACEUTICAL INDUSTRY

Autumn 2015 Volume 7 Issue 3

Chapter Reviews Title

Quality By Design A review of Gerresheimer press day at Vaerloese Gerresheimer has been the global specialist in all types of plastic bottles for decades. Their work incorporates quality by design during the production of pharmaceutical primary packaging. On 3rd September, Gerresheimer organised a press day for international clients to demonstrate their newly innovated products, through a guided tour at their plant in Vaerlose/Denmark. Medicaments need plastic packaging. Pharmaceutical primary packaging requires high quality, safety and reliability, as a small failure can put patients at risk. That is the main reason why quality standards are quite strict and have special requirements. Gerresheimer’s main responsibility is to innovate plastic bottles which satisfy the patient’s needs. These products have a tamper-evident ring to indicate whether they have been manipulated or inadvertently opened. Some medications are required by law to have a child-safe closure, which means that they can be opened by adults only. Some of the products are senior-friendly and designed to be opened easily by people with limited motor skills.

“Our Strength is Our People” Gerresheimer has a strong reputation in the market as a pharmaceutical supplier. Their favourite principle is; they never expect more from others than they expect from themselves. They treat each other as they want to be treated. The company has established worldwide locations for the production of plastic packaging. The organisation has developed manufacturing facilities in Europe, South America and India. Their goal within major projects is to create annual meetings between the different regions. This management process is a great opportunity to inspire other colleagues from those regions. The company is made up of many acquired companies which

were leaders in their specialist fields. By the combination of their expertise and the promotion of continuous learning and knowledge-sharing, Gerresheimer is striving towards an even higher level. Due to their product (Duma, innovated in 1967), the company has built a strong reputation, and brought solid packaging to the global pharma market.

“Quality is Crucial” Gerresheimer’s quality objectives are efficient production combined with an internationally standardised, monitored zero-defect strategy. All of its plants manufacture millions of different FDAregistered containers and closures for a wide range of pharmaceutical drugs. There are 1500 employees worldwide in the plastic packaging segment, and the facilities have a production area of more than 118,000 square metres with both class 7 and 8 cleanrooms.

Vaerloese/Denmark – The Specialist for Ideas Founded by Peter Dudek in 1964, the Danish company was originally called Dudek Plast. Since then, the company has innovated its successful Duma and Dudek branded plastic containers for solid medications with different closure and safety systems. Its quality line has been continuously improved over the years in collaboration with regular customers, and their latest product is Duma Twist Off Advanced. There are

two Danish production facilities, in Vaerloese and Haarby, and the products are manufactured by 100 employees in a total area of 23,000 square metres nowadays. Precise Administration of Eye-drops The global specialist of all types of dropper bottles for decades has been

Gerresheimer. Its newly innovated solution for eye-drop administration is called DropAid. It makes the dropper bottle easy to open, and it also allows the user to reliably position the bottle. The eye-drops actually end up in the eye rather than anywhere else. It is incredibly easy to use, and is ideal for elderly people and children. The product showcased at Pharmapack in Paris as an example of how creative pharma packaging can be.

The Gerresheimer Group Gerresheimer is a leading global partner to the pharma and healthcare industries. The company’s special glass and plastic products contribute to health and well-being. Gerresheimer is a global organization with 11,000 employees and manufacturing operations in the local markets, close to customers. It has over 40 production facilities in Europe, North and South America and Asia generating revenue in excess of EUR 1.3 billion. The comprehensive product portfolio includes pharmaceutical packaging products as well as convenient and safe drug delivery systems such as insulin pens, inhalers, prefillable syringes, vials, ampoules, bottles and containers for liquid and solid pharmaceuticals with closure and safety systems, plus cosmetic packaging products. INTERNATIONAL PHARMACEUTICAL INDUSTRY 129

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Autumn 2015 Volume 7 Issue 3

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Orphan Drug Designations Are the EMA and FDA Looking for the Same Information? Raising Clinical Trial Standards Through Competency-Based Training

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