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PHARMACY features 4

THE BREAST IMPLANT SCANDAL AND EUROPEAN MEDICAL DEVICE REGULATION The circumstances of the recent breast implant scandal are described in detail and the actions needed to prevent it in future are discussed. by Maria Donowa and Roger Gray


THE ROLE OF PHARMACISTS IN THE CLINICAL SUPPLY CHAIN FOR DRUG DEVELOPMENT There are major benefits of including a pharmacist in the clinical supply chain. by Wyndi Phillips


PHARMACEUTICAL QUALITY BY DESIGN Rationale and details of a new accredited distance learning postgraduate course. by Walkiria Schlindwein


EVOLUTION OF THE JAPANESE REGULATORY SYSTEM A new approach to healthcare product regulation, the Pharmaceuticals and Medical Devices Agency (PMDA), was established in Japan in 2004. This article outlines the current situation. by David Jeffreys


THE FALSIFIED MEDICINES DIRECTIVE – IMPACT ON WHOLESALERS The new Directive specifies that wholesalers need to check the safety features on the outer packaging. However, this could cause them major problems that would also affect manufacturers, pharmacies and patients. by Monika Derecque-Pois


THE FALSIFIED MEDICINES DIRECTIVE – THE SWEDISH WAY A system of coding and identifying products throughout the entire chain is being introduced in Europe following the publication of the Falsified Medicines Directive in 2011. A Swedish pilot study has shown the way. by Anita Finne-Grahnén

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• MARCH 2012

associate editors




Belgium: Philippe Bollen

Issue 12 March 2012

Bulgaria: Valentina Belcheva

ISSN 1759-202X Czech Republic: Ales Franc

EDITOR Joe Ridge, MRPharmS

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France: Jean-Pierre Paccioni

EDITORIAL BOARD Michael Anisfeld Alexander Florence Michael Gamlen Linda Hakes John Jolley

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European Industrial Pharmacy is published four times a year by: Euromed Communications Ltd Passfield Business Centre, Lynchborough Road, Passfield, Liphook, Hampshire GU30 7SB

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european INDUSTRIAL PHARMACY is the official publication of the European Industrial Pharmacists Group (Groupement des Pharmaciens de l’Industrie en Europe)


Cover picture: The Tower of Babel. Engraved by Isaac Basire and published in the works of Flavius Josephus, 1733. (See pages 7-8). Image: Fotolia

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editorial Dear Colleagues It is that time of year where as the EIPG President I have to write an editorial relating to Industrial Pharmacy and EIPG objectives. This year despite being early March I have to comment on 2 areas which impact the Pharmaceutical Industry as a whole. The first announcement is that of AstraZeneca which announced 7,000 job losses around the globe and which unfortunately means a number of site closures and job losses in Europe. When these events occur they are sad occasions and we within the Bureau of the EIPG provide our support and thoughts to those who have been affected. In particular, if there are pharmacists who need advice and support please feel free to contact the Bureau, your country representative or myself or Jane Nicholson via our website. We will do our utmost to help you and to link you to appropriate organisations who can also help. Not much I know, but as a very famous UK retailer often quotes, 'every little helps'. The EIPG is the Association for the Industrial Pharmacist whether you work in a large multi-national or in a Small Medium Enterprise and its times such as these when we can help. The second announcement and one which may impact the European Industry as a whole are the comments of Sir Andrew Witty the CEO of GlaxoSmithKline Pharmaceuticals. On the 7th February, Sir Andrew quoted the following: Europe has slipped in terms of its willingness to pay for innovation,” ........And so for GSK the answer to Europe’s unwillingness to pay for innovation is to “go and focus elsewhere,” Witty said. This will mean novel drugs are tailored to markets that are receptive to innovation, with clinical trials moved out of Europe. Payers in Japan and the US, “are not pushovers” but they are more pro-innovation. “We will still register drugs in Europe, but we won’t [shape] them for Europe,” Witty said. “At least for the next few years, Europe is stuck in a bad place." Strong words indeed, which we were reinforced on the 25th February when Sir Andrew with obvious frustration accused the British Government of delaying the use of new medicines. As an Industrial Pharmacist and now Academic,

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I can understand why Sir Andrew is frustrated and in fact is so alarmed with the current trend of approval delays and non reimbursement of new medicines particularly in the EU. As a Professor of Pharmaceutical Innovation at King's College London, I know only too well the dangers of not investing in Innovation or being encouraged to Innovate. Having worked in the Emerging Markets and just returned from an extensive visit in the Middle East, the environment in these countries positively encourages innovation and it is heartening to see how much a prominent role that Industrial Pharmacists play in these regions of the world. The industry has its detractors BUT a balance needs to be struck and even though I accept that the sector is profitable, it is saving lives and helping people to live longer – it is without a shadow of doubt that my father is only alive and well due to intervention by the Pharmaceutical Industry. The industry also invests in R&D within the EU and around the world and provides a research base which underpins our Universities and Research Institutes. Perhaps the Industry has been a victim of its own success, in that a recent UK Government survey has predicted that 1 in 3 UK women will live to beyond a 100 years, 1 in 4 UK men will live beyond 100 years and if MIT is to be believed that a baby has been born today, who will live to 150 years old! Nevertheless, one of the founding principles of the EIPG is to promote the Industrial Pharmacist and the Industry itself and as a consequence we shall take every opportunity to promote and to defend this Industry whenever the opportunity arises. The EIPG will also help colleagues and advise students who want to enter this sector of pharmacy and to provide a network of mentors.

Best wishes Gino

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he recent silicone breast implant scandal in Europe has led to questions about whether or not European medical device regulations are sufficient to protect patients not only from unsafe breast implants, but unsafe medical devices in general. Maria Donawa, MD is President and Roger Gray is VP Quality and Regulatory of Donawa Lifescience Consulting, Rome, Italy. Website:

What were the events that led to the discovery of substandard materials being used to manufacture the breast implants?

During the last quarter of 2009, the French Competent Authority for medical devices, the Agence française de sécurité sanitaire des produits de santé (Afssaps) noted an increasing number of adverse event reports of shell ruptures of silicone-filled breast implants manufactured by the French company, Poly Implant Prothese (PIP). Following several unsuccessful exchanges with PIP, in March 2010, Afssaps conducted an inspection of the company, which revealed that from 2001 to the time of the inspection, most of the 400,000 implants manufactured by PIP contained a silicone gel different from the one it declared in the implant’s design dossier and manufacturing files1. Afssaps immediately suspended the marketing and use of PIP implants, informed the European Commission of the events, and strongly advised other EU Competent Authorities to take all measures to verify that the implants were no longer distributed, used or exported 2. The agency then began assessing whether or not there were increased risks of adverse events related to these implants. In March 2010, PIP filed for bankruptcy.


In September 2010, Afssaps reported that the analysis confirmed that the gel filling the tested implants was not as described in the PIP design file. The tests revealed that the gel was not of the level of quality required for breast implants. The implants showed a higher than average fragility in an elongation test, and a significant heterogeneity of mechanical properties among the implants was revealed. A June 2011 report provides an overview of Afssaps activities and details of the tests conducted, a summary of the vigilance data analysed, and follow-up recommendations for women with PIP implants 3. Despite the release of an expert report by French National Cancer Institute concluding there were no grounds for emergency removal unless there was the presence of clinical and/or radiological signs suggesting a change in the implant, the French Minister for Labor, Employment and Health, recommended explantation of the PIP silicone breast implants, even without any clinical signs of deterioration. How are medical devices, specifically, breast implants regulated in Europe?

Breast implants are regulated by the Medical Devices Directive

(93/42/EEC; MDD), covering the vast majority of medical devices, which became mandatory in June 1998 4. Directives must be transposed into European national laws in order for their requirements to be mandatory. Medical devices that comply with any national transposition of the Directive can be affixed with the CE mark and sold throughout Europe. The European regulatory system for medical devices is risk-based. As the risks related to the use of a device increase, so does the level of regulatory control. The MDD requires that manufacturers determine the classification of their devices based on a set of rules found in Annex IX of the Directive. The four classes of devices under the MDD correspond to increasing levels of risk and therefore control: class I (lowest risk), class IIa (lower intermediate risk), class IIb (higher intermediate risk), and class III (highest risk). The conformity assessment procedures, which are necessary for demonstrating compliance with the MDD, are carried out under the sole responsibility of the manufacturer for devices in class I. For devices in the higher risk classifications, the intervention of a third party conformity assessment body, called a “Notified Body” is required. These bodies are designated by Member State Competent Authorities to carry out conformity assessment procedures. It is important to note that the medical device Competent Authorities have very limited pre-market responsibilities, and are not responsible for conducting CE marking conformity assessment procedures. The Notified Body responsible for conformity assessment activities for PIP was TÜV Rheinland ®. From 1998 to 2003, most breast implants were in class IIb; however, in September 2003, they were reclassified into class III. All existing designs of breast implant, including the PIP implants, had to be reassessed against the more extensive requirements for class III devices before they could continue to be marketed.

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The MDD offers several means of demonstrating that class III devices comply with the Directive, which range from establishing quality systems to test programs. However, the vast majority of manufacturers select the conformity assessment procedure requiring the implementation of a full quality assurance system for the design, manufacture and final inspection of the device. This route was also chosen by PIP. The full quality assurance system route to the CE mark for class III devices also requires the development of a design dossier containing detailed information on the device design, and this must be submitted to the Notified Body for approval and issuance of a design examination certificate. The Notified Body must also conduct periodic surveillance quality audits to ensure continuing compliance. An important feature of the European device regulatory system is that the directives contain only general requirements, whereas detailed technical specifications are contained in European harmonised standards. For example, EN 13485 is the harmonised standard for medical device quality management systems. In addition to general standards, those covering specific types of product have also been mandated. For example, EN 14607 specifies requirements for mammary implants. In addition to harmonised standards, a series of European guidance documents have been developed to promote a common approach to compliance with the Directive. In the case of breast implants, the European guidance document, Guidelines for Conformity Assessment of Breast Implants According to Directive 93/42/EEC Relating to Medical Devices 5, was issued in 1998. The document provides important guidance on pre-market activities such as: the evaluation of hazards applicable to breast implants; review of clinical data by the Notified Body; requirements for post-market surveillance; and the

need to provide information on the risks of surgery. Informative annexes include detailed guidance on preclinical tests that should be conducted, an example of a clinical evaluation plan and criteria of acceptability. Once all applicable requirements of the MDD have been met and the Notified Body has approved the design dossier and certified the company’s quality management system, the manufacturer issues a Declaration of Conformity, stating the device regulatory requirements have been met, and places the devices affixed with the CE mark on the European market. The MDD requires that the manufacturer implements a system of active postmarket surveillance, which includes the obligation to report serious device adverse events to the Competent Authority. Vigilance procedures and records are routinely checked during Notified Body audits. Did the European regulatory system function adequately?

Afssaps recognised an increase in PIP silicone breast implant rupture rates in the last quarter of 2009, conducted an inspection of PIP facilities in March 2010, discovered the use of substandard device materials, removed the devices from the market and conducted analytical testing to evaluate the health risks. In addition, from April 2010 to January 2012, fourteen publications were posted on the Afssaps website providing information on the events and advice to women who had been implanted with PIP silicone breast implants. On this evidence, it would appear that Afssaps met its responsibilities for post-market surveillance. Although serious problems were not found until 2010, the fraudulent activity reportedly began in 2001, allowing hundreds of thousands of silicone breast implants of varying quality to be implanted in unsuspecting patients. Why were these problems not discovered by the Notified Body? A TÜV

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Rheinland ® press release6 states that its auditors were shown conforming silicone samples and corresponding documents during PIP quality system audits. The Notified Body stated that these materials must have been replaced with the substandard materials once the auditors left the premises. In any case, to better assess why the use of unapproved materials during production of the PIP silicone breast implants was not identified during Notified Body audits, it would be necessary to examine the Notified Body audit reports and relevant PIP design and manufacturing documentation, discuss how the Notified Body audits were performed, be informed of whether or not Afssaps preannounced its inspection, and consider any differences between how the Notified Body audits and Afssaps inspection were conducted. It was widely reported in the media that PIP personnel hid documentation on the actual materials used. Would unannounced audits have uncovered the deception? Perhaps – however, it is interesting to note that the US FDA conducted unannounced domestic device inspections for many years before changing to the current policy of pre-announced device inspections. Unannounced Notified Body audits may be introduced as a result of the PIP event, but the benefits of doing so must be seen to outweigh the disadvantages. It may prove much more useful to examine audit time constraints and the manner and depth to which audits are conducted. What enforcement powers do regulators have regarding medical device compliance with the MDD?

The MDD contains four articles that Member States must transpose into national law that concern Member State enforcement powers. Readers should refer to the MDD for the complete provisions of these articles and to the national laws and regulations of each Member State



to understand how they have transposed them. What changes are being discussed regarding the European regulation of medical devices?

In 2008, the European Commission began considering a revision of the legal framework for the regulation of medical devices. Background information and the results of a public consultation can be found on the European Commission website, as well as a ‘Roadmap’ 7on the changes being contemplated. According to the Roadmap, proposals will be made for a medical device regulation instead of a directive. The change from directive to regulation is important because a regulation does not need to be transposed into national laws; regulations become law Europewide upon implementation. The use of directives has previously led to certain variations in implementation of some provisions among Member States, which the Commission is keen to limit in the future. The Roadmap provides general information regarding the possible changes; however, draft proposed texts of the regulatory revision have been leaked, revealing the current thinking on features that the European regulatory system for medical devices should possess. For example, it is possible that Notified Bodies will be required to pay unannounced visits to manufacturers and that more stringent conformity assessment procedures for high risk medical devices will be required. The currently expected date of publication of the proposed regulation is June 2012, but it would not be surprising if this date slipped because of the PIP furor. Need for careful analysis and effective decisions

The medical devices Directives were adopted to ensure that medical devices provide patients, users and third parties with a high level of protection and attain the performance levels attributed to


them by the manufacturer. Such a regulatory system needs to be efficient as well as effective. It also needs to ensure that medical devices are available so we can benefit from the technological innovation that is the hallmark of the medical device industry. A regulatory system to cover all medical devices, which range from the simple to the most complex technologies imaginable, is not easy to create or maintain and for this reason, it should be periodically analysed and modified to make needed improvements. This is what is occurring in the midst of the events surrounding the PIP scandal. Of course all reasonable measures should be taken to prevent such events from occurring in future, but at the same time, any changes should not jeopardise the availability of the medical devices that we need. What immediate actions are being taken? A European Commission press release8 lists the immediate actions being requested of Member States: • Verify the designations of notified bodies to ensure that they are designated only for the assessment of medical devices and technologies that correspond to their proven expertise and competence. • Ensure that all notified bodies in the context of the conformity assessment make full use of their powers given to them under the current legislation, including the powers to conduct unannounced inspections. • Reinforce market surveillance by national authorities, in particular spot checks in respect of certain types of devices. • Improve the functioning of the vigilance system for medical devices. • Support the development of tools ensuring the traceability of medical devices as well as their long-term monitoring in terms of safety and performance.


Furthermore, it was announced that the European Commission is conducting a 'stress test' intended to identify any shortcomings that have come to light as a result of the PIP case. Thus far, it appears that careful analysis is underway, which will hopefully allow effective decisions to be made without jeopardising future innovation.

References 1








Afssaps information sheet, Silicone gel breast implants from Poly Implant Prothèse Company – Information (15 July 2010); iginal/application/63285b895bc9b60c15a7 743e08432dc1.pdf Afssaps website, Information for women with PIP breast implantsQuestions/answers (26/7/2010); Afssaps report, Topical report on PIP silicone gel-prefilled implants (29 June 2011); age/original/application/39acdab9272355 84ccfa340e4a9d3896.pdf Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (OJ L 169, 12.7.1993, p. 1) ri=CONSLEG:1993L0042:20071011:EN:P DF Guidelines for Conformity Assessment of Breast Implants According to Directive 93/42/EEC Relating to Medical Devices, MEDDEV 2.5-7 rev 1 (July 1998) TÜV Rheinland® press release, Concerning latest media articles concerning Siliconefilled breast implants (29 December 2011) ess/news_2/news_5.jsp Regulatory Framework Revision Roadmap anned_ia/docs/2008_sanco_081_proposal _medical_devices_en.pdf European Commission Press Release, Medical devices: European Commission calls for immediate actions - tighten controls, increase surveillance, restore confidence (9 February 2012); .do?reference=IP/12/119&format=HTML&a ged=0&language=EN&guiLanguage=en.

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career in clinical research is a somewhat uncommon path for a pharmacist, but it is becoming more widespread in the pharmaceutical industry, Contract Research Organisations (CROs), speciality clinical supplies companies and in consulting groups. Wyndi Phillips, PharmD is Project Group Manager at Almac Clinical Services, Durham, NC, USA. Website:

Though pharmacy students are often not exposed to clinical trial research during school, they may develop an interest during postgraduate study or get exposure while working in a hospital or clinic. Pharmacists are becoming increasingly engaged in more opportunities involving the development of new drug products. Pharmacists can be a valuable resource in clinical trials as they help coordinate the research and development process and oversee the clinical supply chain. Study design

Pharmacists can assist sponsors and CROs during the study design phase by helping to ensure proper drug preparation, comparator drug sourcing, labeling and blinding of treatments to prevent bias. They are in a position to offer insight into study drug assignment and management, drug accountability and reconciliation, and data collection. Pharmacists are often involved in investigator meetings and on-site training sessions. Throughout startup and maintenance of the trial, pharmacists provide ongoing support to site personnel. Pharmacists on the clinical supplies team communicate with Interactive Response Technology (IRT) teams,

globally-situated depots, and other groups involved in study startup to ensure that the drug will be available when the first site is ready. Once the study begins, the pharmacist oversees the drug inventory throughout the world. They offer invaluable input into the design of resupply timelines and manage the inventory in a cost-efficient manner without excess overages or disruption of supply to sites. Patient focuses

The input of the pharmacist into the design of the study drug is comprehensive and patient-focused. Pharmacists understand how the drug needs to be prepared and dispensed at the study sites. Their knowledge and interaction with the clinical community results in packaging that works effectively in a clinical setting. When designing the labels to be used in a study, they consider what will offer ease of dispensing at the site and ease of use by the study participants. The review of the protocol by the pharmacists assures that it contains reasonable instructions for the preparation of the study drug at sites, and their added input results in a comprehensive clinical materials section in the protocol. Additionally, the pharmacist may

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write the dosing instructions and create pharmacy calculation worksheets to be a part of studyspecific pharmacy manuals or pocket cards to benefit the site pharmacists, nurses or physicians. The completed calculation worksheets and drug accountability logs can be returned to the unblinded study pharmacist to review for accuracy. A pharmacist in the clinical supplies group may serve as an unblinded source of information on drug preparation, dosing questions and compatibility issues to the site pharmacist. A case history

The importance of the involvement of pharmacists to the completion of a study trial is illustrated in the following example of a complex global trial involving two study programs which were divided into four Phase III, randomised trials. The programs involved different therapeutic indications for the same study drug which allowed the team to pool the drug across the four studies for a streamlined supply chain. The four trials included 39 countries, approximately 3,000 patients, different sponsor teams for each study, multiple CROs, nine depots, two IRT teams, and the clinical supplies team. The responsibilities of the study pharmacist included: • Clinical supplies management • Site pharmacist training • Development of drug related training material for sites and CROs Oversight of labeling, • packaging, and distribution of drug supply • Depot management • Sourcing of comparators and concomitant medications worldwide • Arranging and organising Qualified Person (QP) release into the European Union (EU) • Retest/expiry date management. Sourcing the comparator

One challenge of this clinical trial was the difficulty in sourcing of the comparator drug due to drug



shortages at the time of the study. Labeling the comparator drug posed problems resulting from the differences in labeling requirements of the countries participating in the study. The comparator was able to be sourced locally in only 15 of the 39 countries. The remaining countries were supplied with drug sourced either in the United States or the United Kingdom. Issues with QP release added to the complexities encountered in the sourcing of the comparator drug. Inventory management

Another supply challenge was the inventory management for the studies. Label grouping determination was hindered by an ever-changing list of participating countries, a wide time interval over which startup times occurred, and a balance of study drug located in a number of different depots. The calculation of the bulk supply of drugs actually required by each study site was difficult to ascertain with the use of weight-based dosing regimens and varying lengths of treatment based on laboratory values. There were numerous expiry and retest dates to manage as multiple lots of study drug and comparators were involved. The team pharmacist monitored all expiry and retest dates and managed the retest date extensions throughout all of the countries involved in the trial. The IRT system was set up to order study drug, not the comparator drug, as that need had not been identified at the time that the IRT specifications were finalised. The sites reordered comparator drugs by fax, based on approval from the sponsor. The clinical supplies team monitored the global inventory levels.


The study drug was provided as a bulk, open-label supply. It was the responsibility of the site pharmacist to blind the study drug against standard therapy. The dosing of both the study drug and the comparator was based on patient weight and required continual adjustments dependent upon laboratory values which were provided only to the pharmacists. The laboratory results directed the length of treatment infusions and the selection of the comparator drug. The volume required for the intravenous medication, timing of medication administration, and the dosing interval introduced issues with blinding, which were addressed by the site pharmacists in collaboration with the unblinded clinical supplies team pharmacist. The site pharmacist was responsible for maintaining the blind with all of these issues, for the duration of the therapy, which varied from 2-3 weeks for each patient. Patients were allowed to complete the therapy at home with drug supplied by a home health agency. The local home health agency was responsible for maintaining the blind and following the same procedures required of the site pharmacists. Communications

The clinical supplies team pharmacist trained the investigators and site pharmacists using interactive teleconferences, supplemented with printed materials, and acted as an unblinded source of information regarding questions on maintaining the blind. Additionally, the pharmacist provided the sites with


detailed written information on dosing, drug preparation instructions, and guidelines for dosing adjustments and the timing of blood draws for laboratory results and was available to the site on a 24-hour basis to answer any drugrelated questions.

Benefits of including a pharmacist on the supply team This example demonstrates how the use of an unblinded pharmacist on the clinical supplies team was able to assist sites in managing the challenges of individualised patient therapy while maintaining the blind. The benefit of including the pharmacist on the clinical supply team was to provide an understanding of how and why the study drug and comparator needs would vary throughout the world so that the team was in a position to better manage the inventory. The responsibilities of clinical supply team pharmacists extend from the beginning of a trial, throughout start up and maintenance, to a successfully completed study. The unique perspective of a pharmacist provides insight and solutions to drug related concerns raised by the study team or clinical sites during planning stages of the trial. Their knowledge and skills are useful in working with increasingly complex trial designs and with drug formulations that require special storage conditions or preparation. A pharmacist’s expertise on the clinical supplies team helps support a strong relationship with the clinical team and can be a valuable component of a successful drug trial.

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PHARMACEUTICAL QUALITY BY DESIGN: Accredited distance learning postgraduate course by Walkiria Schlindwein


he pressures that caused the term Quality by Design to emerge and its principles established cannot be pinpointed to any one incident, but to a series of events that influenced the changes that industry is facing in recent years. Walkiria Schlindwein, PhD is Programme Leader for the Leicester School of Pharmacy’s Postgraduate Course in Pharmaceutical quality by Design and Principal Lecturer in Pharmaceutical Technologies at De Montfort University, UK. Email: Website:

For example, IBM in 2005 produced some reviews that showed how inefficient the pharmaceutical industry was compared to other industries1 . Price Waterhouse Cooper (PWC) started to publish their 2020 series 2, which showed this industry had to start to change. The US Regulator, the Food and Drug Industry (FDA) publicly said that the industry continued to have a rather traditional approach, despite when fines were applied to companies. The International Conference on Harmonisation (ICH), which includes regulators and industries from US, EU and Japan and observers from WHO and other countries, set out in 2003 to produce some new sets of documents that would lay out a science and risk-based approach to pharmaceutical development and manufacture. The need for change was evident. The term Quality by Design, now commonly referred to by its acronym, QbD, was first defined in the ICH document Q8 (R2) – Pharmaceutical Development as 3: “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.” Equally important are the ICH Q9, Quality Risk Management 4 and ICH

Q10, Pharmaceutical Quality System 5 documents that set out the principles and tools of QbD. New distance learning course

De Montfort University’s (DMU) School of Pharmacy is supporting the industry’s new approach to quality with a new Distance Learning training course. The course is a unique collaboration between industry-leading experts, companies and academia and it comprises of over 40 recorded lectures by 29 industry experts from 15 companies. These companies include: Pfizer, AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, FMC, Lyosolutions Ltd, GEA Pharma Systems, CAMO software AS, JMP Division of SAS, Perceptive Engineering, PMcG Consulting, Lundsberg Consulting, AffinisLbD, Bruce Davis-Global Consulting and Medicines Healthcare products Regulatory Agency (MHRA). The course was validated in December 2010 with multiple start dates each year, in October, January and May. Why Quality by Design matters?

The Pharmaceutical industry is going through a period of major changes catalysed by: • Growing demand for efficiency

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• Pressure on drug prices (increase of Generic drugs) • Market access • Rising regulatory requirements • Increasing risk in R&D QbD has the potential to make a positive contribution to drug development and manufacturing in the light of these changes. Why is this course important?

This course provides: • A firm academic foundation to implementing QbD • Expert lecturers from industry who have real experience of QbD • Build a common language for academia, industry, regulators and suppliers. This highly flexible course is delivered online and can be studied in its entirety or as separate modules. All lecturers are based in industry and have hands-on QbD experience. Each module has a De Montfort University accredited academic staff member leading its delivery. The module’s assessments are conducted with rigour. Marks are internally moderated before being confirmed by an accredited external examiner and the relevant Postgraduate examination board. The course is applicable to those in large and small pharmaceutical companies, contract manufacturers, generics and consumer health, based in either R&D or manufacturing, including support functions such as regulatory, engineering and specialist technologies. It provides information on guidance notes from the International Conference on Harmonisation ICH Q8, Q9, Q10 and Q11. It covers the understanding of: • Quality Target Product Profile (QTPP), • Critical Quality Attributes (CQA), • Critical Process Parameters (CPP), • Design Space, • Control Strategy and • Continuous Improvement over the product lifecycle from R&D to manufacturing to product discontinuation.




It includes subjects such as: • Multivariate data analysis, • Quality risk management (QRM), • Experimental design, • Process analytical technology (PAT), • Real time release testing (RTRT), • Analytical methods verification, • Regulatory aspects from the Medicines and Healthcare products Regulatory Agency (MHRA). Course structure

There are a total of 4 modules that add to a total of 60 credits (Figure 1). One of the modules (optional) can be selected from a range of options in different specialised areas. Most modules are 10 credits, each of which contains 100 student learning hours. There is one module that is 30 credits, the work-based project. It is recommended that the selection of the elective module be dictated by the student’s choice of project area, where possible. The decision can be made in consultation with individual academic tutors (including any direction that might be provided by industrial line managers). Modules are combined to form a coherent pathway of study. The successful completion of 60 credits leads to the conferment of the Postgraduate Certificate in

Figure 1. Course structure showing the modules available.

Pharmaceutical Quality by Design award. Module structure

Each module is designed to be studied over 7-9 weeks, except for the project which will be around 15 weeks. At the start of each module the students will be enrolled into our website ( and BlackBoard © from where they have access to the videos and PowerPoint presentations for each lecture of the module. Figure 2 illustrates how the learning material is delivered. The video is synchronised with the PowerPoint

presentation. The PP presentations are provided as PDF files for the students to keep. These are completed away from the University, giving the student the flexibility to arrange their studies to suit. The assessment components are done electronically. Module 1 – Pharmaceutical Quality by Design: principles, tools and approaches

This module was designed to provide the fundamental concepts and tools applied to pharmaceutical product design, process design, process monitoring and continuous

Figure 2. Screen capture showing how the learning material is presented, video in synchronism with the PowerPoint presentation (first MHRA lecture by Mustafa Zaman and Gustavo Marco).


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verification based on up-to-date Quality by Design principles. Module 2 – Product & process design

The aim of this module is to understand the iterative nature of formulation and process design and the link to patient requirements for developing medicines based on quality by Design principles. Module 3 – Options

All optional modules have been designed to be in two parts. The first part is common to all of them and consists of 5 lectures that address: • 3 – Manufacturing & Advanced Process Controls. The second part contains lectures specific to a subject are (the student select one of the three options): • 3a – Inhalation/Sterile Products • 3b – Continuous Processing • 3c – Analytical Method Development Module 4 – Work-based project

This module provide each workbased student with an opportunity to consolidate their knowledge of Quality by Design applied to pharmaceutical science by carrying out a research or development project in an area directly related to their work context.


New initiatives 1 Regulatory aspects of QbD

industry experience. Students should ideally be employed within the pharmaceutical or health sectors. If your first language is not English we require a minimum IELTS score of 6.5 or TOEFL 250 (computer score) 600 (written paper). We have multiple start dates: October, January and May per year.

De Montfort University is delighted to welcome a distinctive series of recorded lectures from the UK Regulatory body, the Medicines & Healthcare products Regulatory Agency, MHRA. The first in the series, for the January 2012 intake, is entitled “The Regulatory Aspects of QbD: Introduction to Regulatory Affairs”, prepared by Mustafa A. Zaman and Gustavo Marco. The forthcoming lectures from the MHRA, planned for May 2012, will cover the practical aspects of a QbD submission presented from both an assessor and an inspector's point of view.


Diploma and MSc distance learning options


De Montfort University QbD team is working on the expansion of the Postgraduate Certificate qualification (60 credits) to give the students options for progression into a distance learning Diploma (120 credits) and MSc (180 credits) programmes. The validation process should be complete by the summer 2012 ready for the October 2012 intake.

We would like to thank all contributors from industry involved with the development and delivery of the course and all De Montfort University academic staff from the Pharmaceutical Technologies Group involved with the course.





Entry requirements

The course is open to graduates and postgraduates and to individuals with relevant pharmaceutical or


IBM – The Metamorphosis of Manufacturing – from Art to Science Pharma 2020: The vision, Price Waterhouse Cooper, ICH Q8 Pharmaceutical Development, rticle/quality-guidelines.html ICH Q9 Quality Risk Management, rticle/quality-guidelines.html ICH Q10 Pharmaceutical Quality System rticle/quality-guidelines.html

AAPS Graduate Student Symposium Award in Manufacturing Science and Engineering Sponsored by Bristol-Myers Squibb Co. (Deadline: May 9)

This program is designed to recognise excellence in graduate education in the fields of manufacturing science and engineering. There are no citizenship requirements for this award. All interested candidates are encouraged to apply. Your research may be submitted to only one AAPS graduate symposium committee for consideration or your submission will be disqualified from all symposia. Students must be in their final year of graduate studies leading to the doctorate degree (or will be awarded their doctorate in 2012). On the basis of submitted abstracts and summaries, two students will be selected to present their research in the Graduate Symposium at the 2012 AAPS Annual Meeting and Exposition. Selection will be made on the basis of those students judged by the committee to have provided the most outstanding contributions in the above fields through their graduate research. Each student selected will receive a complimentary registration to the 2012 AAPS Annual Meeting and Exposition, a cash award of $250, and a commemorative plaque. In addition, travel expenses will be reimbursed (up to $1,000 domestic/$1,500 international) following the meeting.

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ith its population of around 127 million people, Japan is the second largest market by sales value for both pharmaceutical products and medical devices. The sales volume in Japan is approximately 15% of the global total, compared to 50% in the USA and 27% in the European Economic Area. Japan is therefore a very significant market for healthcare products. It is also a leading player in the development and production of both medicines and devices. Dr David Jeffreys, Senior Vice President, Global Regulatory, Government Relations And Public Affairs Department, Eisai Europe Ltd, European Knowledge Centre, Mosquito Way, Hatfield, Herts AL10 9SN

The healthcare sector has been targeted as a major growth centre for the Japanese economy and increasingly Japanese companies are becoming global players, either through partnership arrangements or by establishing themselves in the US and European markets. Japan is a major player in both the International Conference for Harmonisation (ICH) being one of the 3 regions which established the ICH in 1991. As a result there has been a harmonisation of the regulatory requirements in the pharmaceutical sector between Japan and the USA and Europe. The extent of the changes within the Japanese regulatory system has been considerable over the past few years. In April 2004, the PMDA (the Pharmaceutical and Medical Device Agency) was established, which has brought about a major change in the approach to healthcare product regulation in Japan. RECENT CHANGES AND THE ESTABLISHMENT OF THE PMDA

Prior to April 2004, Japan had a somewhat different system for the evaluation and approval of healthcare products than was found in other countries. A review of the increasingly


complex Japanese regulations for the evaluation and approval of healthcare products led to the establishment of a unified single agency. The Pharmaceuticals and Medical Devices Agency (PMDA) was established on 1st April 2004 as an incorporated administrative agency with non civil servant status. This agency has many similarities to those found in Europe and other parts of the world. The new agency is responsible for providing advice and conducting reviews of quality, efficacy, and the safety of pharmaceuticals and medical devices. It now has responsibility for assessing clinical trial applications, for discussing the development of the product and evaluating the dossier as part of the approval review. It also has the responsibility for collecting, analysing and providing information on post marketing safety measures. In 2006, the Japanese government introduced a reform programme across the industrial sectors called “Innovation 25”. This identified the pharmaceutical and medical device industries as key sectors for innovation in the Japanese economy. The report highlighted the importance of the regulatory process and noted that there was a

significant “drug lag” in Japan compared to other countries. Part of this related to the shortage of resource within the regulatory process, whilst part was attributed to the relatively late conduct of phase II and phase III trials in Japan by the pharmaceutical industry. The government and the agency put in place an impressive programme of change which has paid off. New targets on performance have been agreed and there has been a significant expansion in the number of agency staff, particularly reviewers. The PMDA is currently funding much more efficiently. The agency has also explored a number of links with other South East Asian countries with a view to establishing possible exchange of assessments reports. In addition the agency has encouraged companies to incorporate Japanese subjects (where appropriate) in multi-national phase III clinical trials. This policy is allowing companies to include Japan in ‘first wave’ global dossier submissions THE DOSSIER REQUIREMENTS

As a founder member of both ICH and GHTF, Japan now has the same international requirements for the dossier as in the USA and European Union. For pharmaceutical products, Japan has adopted the common technical document (the CTD). The Japanese Agency obtains a substantial part of its income from fees just as do other agencies. These fees have to be paid with the application. Details can be obtained directly from the PMDA. ( The English language section of this website has been expanded and much information is available in English. THE REVIEW PROCESS

With the creation of the new agency, all the functions of the review process are located within the PMDA. Single teams are now allocated to handle the entire process of an application from the clinical trial stage through to approval. The agency has been recruiting and training significant numbers of additional staff. The internal reviewers undertake the

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evaluation of the dossier but have access to, and are supported by, external independent experts and by advisory committees. The PMDA review all types of pharmaceuticals, including OTC drugs. The PMDA also has responsibility for the evaluation of all medical devices. This is therefore analogous to the system adopted within the centre for devices and radiological health (CDRH) of the FDA and also the system found in Canada and Australia. This differs from the European system in that the evaluation is undertaken within the agency, whereas in Europe, the evaluation is undertaken by a Notified Body designated by the National Competent Authority. The review and the evaluation of health care products are undertaken under the provision of the pharmaceutical affairs law of Japan. It also takes into account the relevant international guidelines of ICH and international standards. OFFICES

There are currently three offices of new drug evaluation, separate office of biologics, an office for the evaluation of urgency and generic drugs, an office for the evaluation of medical devices, and an office of conformity audit. These report through to the director for the centre for product evaluation. Separately there are offices of safety and of compliance of standard reporting to the Chief Safety Officer. Within the centre for product evaluation there is also a priority review director to handle accelerated or expedited reviews. A brief review of the key features of the current regulations and the assessment procedures is set out below. In an article such as this it is difficult to cover all the details. RAPS (Regulatory Affairs Professional Society) has set up an organisation in Japan covering medicines and devices. As a result of this it has produced a comprehensive guide to regulations in Japan called Japanese Fundamentals. This can be viewed on the RAPS website (



In Japan a clinical trial application is required for all phases of development including phase one trials. On request, the PMDA will provide face-to-face consultation and will give guidance and advice on the clinical trial for both new pharmaceuticals and medical devices. It will give advice for the development of new formulations and new indications. The advice has now been extended to cover OTC drugs and generics. CLINICAL TRIAL NOTIFICATIONS

Clinical trial notifications (CTN) are required for all stages of clinical development. No formal approval is given; rather a study can begin 31 days after submission unless the applicant receives questions or a refusal from the Agency. A trial drug or medical device can be imported into Japan once the CTN has been submitted and can then be supplied to the investigator hospital on day 31. Ethical committee approval has to be obtained separately and the Agency has to be informed of both the approval and the comments from the ethical committee. THE EVALUATION PROCESS

Under the new system, the dossier is submitted to the agency. Following submission, a review team will be constituted. The dossier will first be reviewed by the office of conformity audit which checks that all the documents and data included in the application complies with the provisions of GLP, GCP and also GPMSP (Good Post Marketing Surveillance Practice). Following this compliance review, the dossier will be evaluated by a team of reviewers to assess the safety and quality of the application. During the review process, the team will seek opinions from external experts. A separate office will consider biotechnology applications. The agency has now set target review times for the assessment process and compliance

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with these targets are published by the Agency. Once the review has been completed and a report generated, this is then shared at a meeting between the reviewers and external experts the main issues and the preliminary conclusion of the assessment are discussed. A summary of the main issues is then presented to the review meeting. This is attended by the applicant company who may be supported by specialists and by the reviewers and external experts. Following the initial review, the internal team will consider additional information and clarification submitted by the applicant. A second expert discussion will then take place between the reviewers and the external experts and a revised or updated report will be generated along with the summary of all the discussions. This will be provided together with a set of recommendations to the MHLW (the Ministry of Health Labour and Welfare), which will then consider whether the application should be approved. For complex and difficult applications advice may be sought from the Pharmaceutical Affairs and Food Sanitation Council. This is a formal body established under the Japanese Pharmaceutical Affairs Law. GMP AUDIT SERVICE AND QUALITY MANAGEMENT REVIEW

PMDA is now responsible for undertaking good manufacturing practice audits. The agency conducts these as both on site and document reviews. The agency will review on a regular basis manufacturing facilities within Japan and will conduct audits on those domestic sites that require manufacturing licences. The agency will also undertake accreditation of overseas manufacturing sites where this is appropriate and not covered by reciprocal accreditation agreements. The agency will undertake a



specific, product focused audit on the manufacturing facility for new pharmaceuticals, new medical devices and vaccines and any facility manufacturing high risk medical devices. The agency undertakes a similar product specific audit to that undertaken by the EMEA for centralised applications.


Careful consideration should be given to the ICH E5 Guideline (Ethnic factors in acceptability of foreign clinical data). For a successful drug development programme, it is necessary to have data in Japanese patients. Japan usually requires a full or appropriate phase 1 development programme on EVALUATION OF QUASI-DRUGS Japanese subjects. If a phase I and a The Japanese pharmaceutical affairs phase IIa study in the programme law has a definition of a have been undertaken in Japanese pharmaceutical product which is subjects, then it is possible to very similar to those in the proceed directly to a Japanese legislation of the USA and the phase III study, although this may be European Union. There is in influenced by the stage and extent addition a class of agents known as of development outside Japan. If a “quasi-drugs” which are evaluated phase IIb study has been performed by the PMDA in Japan. These in Japanese patients then it will be agents provided that they did not possible to discuss with the Agency CLINICAL DATA make a medical claim, would be whether phase III data generated in REQUIREMENTS FOR JAPANESE regarded as cosmetics in both an EU/US programme can be REGISTRATION Europe and the United States. They augmented by a bridging study. When considering developing a range from deodorants, Data obtained in non resident drug for use in Japan a series of depilatories, medicated soap, Japanese subjects can be issues need to be considered. These dentifrices and insect repellents. considered by the Agency but include possible pharmacogenetic In Japan the quasi-drugs have to patients who have lived outside differences due to polymorphisms, be approved by the PMDA before Japan for more than 4 years would different pharmaco-dynamic they are marketed, a dossier has to not usually be accepted as part of responses and differences in be submitted and address the the Japanese data. Such patients receptive sensitivity. relevant efficacy safety and quality. must be first generation Japanese Clearly there is a subjects. boundary between Exceptions to the more is important to discuss with the rigorous these products and over phase III the counter medicines. development can occur Japanese Authorities any particular issues. This is a unique with the use of an Under the new system such consultation is adequate bridging study category of products to the Japanese market and phase IIb data, or for both possible and welcomed. and it is important for oncology products where an applicant to check conditional approvals may The effect of diet and food need whether they would be classified be granted by the Agency or if there to be considered along with dose under this group in Japan, whereas are adequately powered Japanese tolerance. they would be available as general centres as part of a multi-national There are well documented consumer products in other markets. multi-centred development differences in the reporting and in programme. the tolerance of adverse event GENERIC DRUGS The health ministry in Japan and reactions between western and Generic drugs take a much the Agency are seeking to Japanese populations, which need smaller proportion of the market in encourage companies to include Japan than in the USA and Europe. to be carefully considered. Japanese subjects where Generic substitution is slowly being There may also be significant appropriate in major phase III introduced into Japan with plans for differences in comparator therapies international trials. Clearly this may a significant increase. In most and interventions which need to be not be possible for several classes of markets the introduction of generics determined in advance of drugs because of different is dependent on the exclusivity constructing a clinical protocol. pharmacogenetic, Differences in the prevalence and period provided to the innovative pharmacodynamic and dosing nature of a disease being studied drug and its period of patent issues, but for several types of drug and the relevance of historical protection. In Japan there is no it is possible to include Japan in the comparisons need to be explored. global development programme. specific period of exclusivity. There is however a first renewal (or reevaluation) of the authorisation. This normally takes place after six years. A generic application cannot be considered until this first evaluation has taken place. On occasions a second re-evaluation may be required. If so the generic will not be considered until after the second evaluation. On occasions this can be an important provision because whilst some applications are approved in Japan, significantly ahead of those in other countries, it is the case that many applications will be submitted to Japan later then any other markets because of the requirements for additional phase three studies to be performed on Japanese subjects.


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The Agency is particularly willing to discuss such programmes. This is an important development which needs to be closely watched as part of a global drug approval strategy. Increasingly companies wish to pursue a single global development programme and to make simultaneous global filings. To facilitate this, it is recommended, that where marketing conditions are appropriate, the phase I programme for Japan is commenced at the same time as, or shortly after, the phase I development programme for the USA and Europe. This then allows an early discussion with PMDA and the option of including a significant number of Japanese subjects in a worldwide development programme. POST MARKETING SAFETY

Japan has adopted the post marketing safety requirement of ICH and GHTF. This has made matters


very much easier for companies as they now have a single set of global requirements. The Agency has developed a system for disseminating safety information to health care professionals within Japan. There is an interesting and unique system for the surveillance of new medicines. In October 2001, the EPPV (early post-marketing phase vigilances) programme was introduced in Japan. This programme has many similarities to the black triangle scheme operated by the Committee on the Safety of Medicines in the United Kingdom. The EPPV requires that medical institutions expeditiously report on the occurrence of serious ADRs for new products during the first six months after their launch. Within two months of the end of the vigilance period a full report on the adverse event experience has to be submitted to the Agency for consideration.


The pharmaceutical regulatory system in Japan has undergone extensive change in the last few years as a result of the ICH initiative. At the same time, Japan has reorganised its control system so it is now very similar to those found in other major markets. This process of harmonisation has been a great achievement. It has accelerating the development of the global health care industry. An article such as this can never cover all the details and therefore it is important to discuss with the Japanese Authorities any particular issues. Under the new system such consultation is both possible and welcomed. A full version of this article is available in the form of a Supplement to the Clinical Research Manual published by Euromed Communications

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THE FALSIFIED MEDICINES DIRECTIVE Impact on wholesalers by Monika Derecque-Pois


ith the adoption of the European Falsified Medicines Directive, the pharmaceutical sector is at a critical point in the development of coding and serialisation systems in Europe. While the main force of the Directive is very much welcomed by GIRP, the umbrella organisation of pharmaceutical full-line wholesalers in Europe, some aspects of the brand new legislation need to be defined further as they present significant concerns to the sector and could have an adverse impact on the current speed of delivery of medicines to Europe’s pharmacies. Monika Dereque-Pois is Director-General of the European Association of Pharmaceutical Full-line Wholesalers (GIRP), Brussels, Belgium. Email: Web:

Harmonised pan-European safety features

The Directive on Falsified Medicines introduces mandatory, harmonised pan-European safety features in the form of tamper evident packaging and a unique identifier to be applied to all prescription medicines, subject to possible exclusions based on a risk assessment. The European Commission is tasked with defining, in Delegated Acts, the mechanics of how this system will work. First consultations are expected to be launched at the beginning of 2012 with adoption scheduled for 2014. The Delegated Acts will define the characteristics and technical specifications of the “unique identifier” allowing identification of individual packs, and the accessibility of national product databases or repositories that allow verification of each dispensed pack. GIRP believes that the information content as well as the data carrier needs to be harmonised at European level. In the light of the very limited space on a one dimensional code and the high costs and relatively low reliability of


RFID tags on medicinal products, GIRP opts for the adoption of a 2 dimensional matrix code which as a minimum includes the national identification number, the batch number and the expiry date in addition to the randomised serial number. In partnership with other pharmaceutical supply chain stakeholder organisations – the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Group of the European Union (PGEU), GIRP is working to jointly promote the development of an efficient, workable and cost effective product verification system that is to be run by stakeholder organisations on a non-profit basis. The system proposed by the stakeholders is composed of a European central hub connected to a series of national or regional data repositories that serve as the verification platforms which pharmacies and other registered users including an interface for wholesale distributors to check a product’s authenticity.

Impact for wholesale distributor

The new Directive insists, “wholesale distributors must verify that the products they have received are not falsified by checking the safety features on the outer packaging”. Whereas the detailed procedure on how this requirement should be fulfilled in practice will only be covered in the “Delegated Acts” it causes a lot of concern as it can potentially have major negative implications, not only for wholesale distributors but also for manufacturers, pharmacies and patients. If significant individual pack scanning is involved it presents major practical and costly challenges to the smooth operation of the distribution chain and will severely impact the speed of delivery of vital medicinal products to pharmacies and ultimately to patients. Today, the average European delivery time is 2-4 hours and we do not think it is necessary to let patients wait longer through unnecessary procedures. For this reason GIRP urges the European Commission when drafting the Delegated Acts to take account of the need for proportionate, pragmatic and workable solutions for all stakeholders concerned. In particular, rather than a systematic process of checking all medicinal products received by wholesale distributors, GIRP proposes the ‘selective, risk based’ verification of the authenticity of medicines in forwards logistics. This would be the case for medicinal products obtained by wholesale distributors from sources other than the marketing authorisation holder or a person who is authorised by the marketing authorisation holder to supply these products. Concerning backwards logistics wholesale distributors should verify the authenticity of all returned medicines before putting them back to saleable stock. GIRP strongly believes that a point of dispense verification system with a wholesalers interface to verify the authenticity of medicines in case of doubt is the most efficient and cost effective way to protect patients

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from receiving falsified medicinal products. It is also the most proportionate solution for meeting the requirements of the Directive as it does not compromise the delivery process of medicinal products and most importantly it ensures that patients can trust that they receive only genuine products through the legal supply chain. Ongoing and next steps

A stakeholder-developed proposal for complying with the terms of the Directive by a result orientated process should be welcomed by the European Commission. GIRP together with its stakeholder partners will propose to the European Commission a system that ensures verification of product authenticity by professionals at the point of dispense and provide a modern technology solution that will ensure patient safety. To this effect 10 key principles have been developed between the stakeholder associations and we are currently working on getting all involved stakeholders on board as well as on conceptualising the framework for the stakeholder led organisation for governing the proposed system. Ten core principles to protect patients from falsified medicines. EFPIA/PGEU/GIRP Joint Position Paper, March 2011.


authenticity. However, a product verification system can only secure the content of the pack if it remains sealed at all times. Using tamper evident packaging makes it clear whether the pack has been opened or tampered with and is therefore an essential complement to a product verification system. • EFPIA and PGEU consider that safety features should be applied to all prescription medicines to ensure the same level of security. Therefore if a risk-based approach for prescription medicines is pursued, exemptions should be based on therapeutic categories, narrowly defined (e.g. ATC 4 level), rather than individual products to minimise the risk to patient safety. 2. Guaranteeing continuity of protection throughout the entire supply chain:

• As regards the obligations on the repackager to replace mandatory safety features, the original pack serial number should be cancelled in the database by the repackager and a new number provided. The original and new numbers must be linked in the database to enable the product to be tracked in case of recalls or other safety issues.

1. Combining tamper-evident packaging with a unique serial number:

3. Ensuring a single coding and identification system on each pack across the EU:

• EFPIA, PGEU and GIRP support

• Given the movement of

the requirement in the falsified medicines directive that the safety features should consist of a unique serial number placed on each pack together with packaging that would reveal if a pack has been opened or tampered with. • Checking a unique, randomised, serial number placed on each pack against a central database at the point of dispensing is currently one of the most secure ways to verify product

medicines across national borders, any effective coding and identification system must be able to exchange information between Member States. There should therefore be a harmonised standard coding system across the EU. • In order to ensure that the coding system facilitates other functionalities such as reimbursement, the EU harmonised standards should allow for the incorporation of

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relevant national codes. • EFPIA and GIRP propose using a two-dimensional code (i,ii) containing a unique serial number to encode all selected products. This code can be verified against a database. This means that pharmacists can rapidly verify the status of each pack before dispensing it to the patient. As well as the serial number, the code would store the expiry date along with product identification (including national code) and batch numbers, providing additional patient safety enhancements. 4. Ensuring product verification database systems can work together across the EU:

• In addition to using a common standard for pack identification in Europe, all national database systems must also be able to work together and exchange information in order to allow any pharmacist, and wholesaler where deemed necessary, in any Member State to check whether the pack has been dispensed before, irrespective of its country of origin. • There should be sufficient flexibility to implement national or regional solutions within an overall EU technical framework. • National database systems should meet equivalent quality assurance requirements. • Without this interoperability, counterfeiters would be able to exploit gaps between national systems to insert falsified medicines into the legitimate supply chain. 5. Verifying every serialised pack at pharmacy level:

• It is everyone’s responsibility in the supply chain to ensure that medicines delivered to patients are safe and genuine. • Pharmacy level verification at the point of dispensing with an interface for wholesalers is a



robust and cost-effective way to improve patient protection. However, unless every individual serialised pack is verified at the point of dispensing, patients will not benefit fully from the safety features. The unique serial number can only provide protection against counterfeits if it is routinely checked against a central database and the status changed on the database to ‘dispensed’ when the product is handed to the patient. Systems should be configured so that pharmacists can undertake checks when medicines enter pharmacy stock, as well as at point of dispensing. Since the technical challenges of point of dispensing verification vary across the EU, pharmacists may initially adopt a system of verification when medicines enter the pharmacy, until such time as any technical issues with regard to point of dispensing verification have been resolved. The process of verification in the pharmacy should be virtually instantaneous in order to ensure efficient pharmacy workflow and the avoidance of delays. In order to ensure that products are verified in one scanning action, verification software should be integrated with existing pharmacy software. The process of verification at the wholesale level should allow products to be checked during forward logistics as well as for returning medicines and without changing the status on the database. Stakeholders shall work together to define standard procedures for exceptional events such as verification failure, system failure etc.

6. Maximising all the potential benefits of mass serialisation:

• Using mass serialisation provides benefits over and above improved counterfeiting prevention. Maximising these should help to encourage widespread use of



identification systems and assist all stakeholders. • The coding system enables the pharmacist to automatically read the batch number, serial number and expiry date, significantly enhancing patient safety and improving product recall procedures. • The system may also facilitate the provision of additional services to patients by pharmacists. 7. Focusing on securing patient safety and protecting patient privacy:

• Verification systems are for preventing counterfeits, not for accessing individual pharmacy data. • Manufacturers do not seek, and will not have access to, individual patient/prescribing profile information. • Transactional data belongs to the pharmacist, or in relation to wholesaler verification, to the wholesaler. However, relevant stakeholders will need to see certain data to help investigate when there is a verification failure, a product recall or a level of unusual activity related to a specific serial number, in accordance with national circumstances. • Any additional use of transactional data would need to be agreed between the stakeholders in accordance with national circumstances.

verification process, we are committed to working together to establish an efficient, viable and effective system to protect patients against the threat of counterfeit medicines. • The establishment and management of product verification systems should be undertaken by relevant stakeholders. For the governance of product verification systems, EFPIA, PGEU and GIRP favour the setting up of independent nonprofit organisations to be jointly managed by relevant stakeholders, building on the current coding environment in the various countries and meeting the needs of patients and all players in the supply chain. • Each stakeholder will be severally responsible for the system. 10. Involving other stakeholders

• EFPIA, PGEU and GIRP welcome the involvement of other relevant stakeholder organisations which play an active role in the pharmaceutical supply chain in the further elaboration of the product verification system at point of dispensing. Together we can ensure a strong and comprehensive system to take forward the fight against counterfeiters.

Notes: (i)

8. Using safety features that are simple, robust and costeffective:

Data matrix ECC 200 does not endorse a particular technology at this stage

(ii) PGEU

• The product verification solution proposed should meet the criteria of being practical, affordable and accessible. Unnecessarily complex and costly solutions should be avoided. 9. Working Together in the Interests of Patient Safety:

• As key stakeholders in the

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Implementation in Sweden by Anita Finne-Grahnén



n July 2011 the European Commission (EC) published a directive from the European Parliament and the Council of Ministers (Directive 2011/62/EU1) with the aim to prevent falsified medicines entering the legal supply chain and reaching patients. It introduces harmonised safety and strengthened control measures across Europe by applying new measures. Anita Finne-Grahnén is Director of LIF, the Swedish Association of the Pharmaceutical Industry. Email: Web: and

What is new?

The Pharmaceutical Directive 2001/83/EC is changed so that prescription-only medicines must bear safety features that allow verification of authenticity and identification through the entire distribution chain of every single pack. Non-prescription medicines will normally not bear safety features. The Commission will after a risk assessment publish a list of prescription-only medicines that due to a low frequency of falsified product reporting will be exempted from safety features (White list). They will also publish a corresponding list of the nonprescription medicines that will need safety features due to risk of falsification (Black list). The products must also bear a device allowing verification of whether the outer packaging has been tampered with. Repackaging (e.g. for parallel import) will still be possible, but if safety features on the original package are removed or covered, either fully or partially, they will have to be replaced by equivalent safety features. There has to be a repository set up by the manufacturing authorisation holders. This repository shall include information on the safety features, enabling the verification of the authenticity and identification of medicinal products.

The costs of the repository system shall be borne by the manufacturing authorisation holders of medicinal products bearing the safety features. The illegal sale of medicinal products to the public via the Internet is an important threat to public health as falsified medicinal products may reach the public in this way. In order to meet this threat the Commission shall decide on a logo to be put on legal websites for the public to be able to identify websites that are legally offering medicines. Websites offering medicines for sale at a distance to the public should be linked to the website of the competent authority concerned. In addition, the Commission should, in cooperation with the Agency and Member States, run awareness campaigns to warn of the risks of purchasing medicinal products from illegal sources via the Internet. Member states will still be free to ban Internet sales of medicines. Timelines

The Directive has to be transposed into national law by 1 January 2013. Many requirements are to be decided in Delegated Acts.(i) For safety features the following are to be decided: 1. Characteristics and technical specifications of the unique identifier with due consideration

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to the cost-effectiveness of the safety features. Lists of products or product categories that shall/shall not bear the safety features, established on the basis of a riskbased evaluation. Procedures for the notification to the Commission, and subsequent evaluation, concerning products to be included in the lists in 2. Modalities for the verification of the safety features by the manufacturers, wholesalers, pharmacists and the authorities. Provisions on the establishment, management and accessibility of the repositories system.

There are no timelines for the publication of Delegated acts, but the EC has made it probable that this will occur in 2014. In the Directive, it is stated that the abovementioned points shall enter into force 3 years after the publication of the Delegated acts (6 years after publication for some countries that already have product verification). The logo for Internet pharmacies shall enter into force 12 months after publication of the Delegated Acts. Pilot in Sweden

In 2009 EFPIA(ii) made a pilot study in Sweden together with Apoteket AB, the only pharmacy chain in Sweden at that time 2. The aim was to approach the issue of product verification in line with the EC’s suggestions on a new directive and to test a practical and effective solution for relevant stakeholders (manufacturers, pharmacists, wholesalers). The solution should be able to fully integrate with their existing operations and be based on common standards and mature technology. Twenty-five pharmacies in the greater Stockholm area participated in the pilot. Fourteen manufacturers provided a total of 25 different products (110,000 packs). Special routines for ordering and delivery to the pilot pharmacies were developed. Changes in the pharmacy software to allow only one scanning were done. The pharmacies involved informed and



educated their staff before the pilot, that had an operational phase of 4 months, could be started. The pilot showed that the model works in practice. The system availability and the performance allowed work to be done without any significant additional effort. The system was easy to use when fully integrated. The main lessons learnt were that a system must provide correct answers and that the system should be customised to the existing pharmacy workflow, the work processes, the local conditions and the regulatory requirement. The presence of more than one code on the pack causes confusion at pharmacy level. The pilot also showed that the necessary data segregation and security could be technically ensured. European level

The EFPIA solution on product verification at the point of dispensing is an end-to-end system. It allows pharmacists to check a unique identification code on each individual pack when it is dispensed to the patient 3. These codes are generated and applied by manufacturers using a 2D data matrix barcode, which contains a unique serial number. The unique randomised code is presented in combination with additional information in machine-readable form (product code, batch number and expiry date). On a European level there have been discussions between stakeholders. During 2011 EFPIA, together with its partners (GIRP(iii) & PGEU (iv), the Wholesalers and Pharmacists at EU Level), have agreed a Memorandum of Understanding (MoU) which outlines the proposed solution and steps for implementation including: – Unique Identifier for medicinal products – Modalities for verifying the safety features – Provisions on the establishment, management and accessibility of the repository system – Lists of products to be covered by the safety features



EIPG Survey: The Unique Identifier for Medical Products Directive 2011/62/EU introduces obligatory 'safety features' to allow verification of the authenticity of medicinal products for human use ('unique identifier'). The European Commission has published a consultation document on the Delegated Act on the Detailed Rules for the Unique Identifier. EIPG would like to know your opinion on the proposals in this document (available at terf_par_trade/safety_2011-11.pdf Take the EIPG Survey at

Based on this MoU, EFPIA, PGEU and GIRP have created a common document named ”Ten Core Principles to protect patients from falsified medicines”4. The latest partner is EAEPC (v), which represents parallel importers at EU level. Implementation in Sweden

Product verification should be coordinated throughout Europe or on a regional level. It is important to avoid a lot of different systems, which are not compatible with each other. Costs for product verification will arise at different stages. The manufacturers will have to finance the development and management of the repositories, the registration of the products and also the labelling of the safety features on every package. Systems at pharmacy level will have to be adapted and that includes costs for introduction, validation, quality assurance and purchase of equipment (scanners). These costs will be borne by the pharmacies. Sweden has a highly developed infrastructure and it will probably be easier to implement the systems than in a lot of other European countries. This will impose that Sweden ought to be able to take advantage of the systems other than just to prevent falsified medicines. The costs for development could be easier to

bear if the parties see many other advantages. Patient safety has to be increased and by such a system machine-readable expiry dates and batch numbers can be obtained. This will enhance traceability and lead to simplified recalls and simplified warehousing. We are presently discussing if the costs for our companies is lower with a national system or a regional system (such as the Nordic one). The respective Nordic pharmacy systems and article registers are different and a joint solution has to be properly evaluated before decisions and deeper involvement of the national stakeholders. Pros and cons must be taken into account and we can then decide which way to move. References 1




Directive 2011/62/EU of the European Parliament and of the Council ol-1/dir_2011_62/dir_2011_62_en.pdf EFPIA Product Verification Project ( D=559&DocID=8770) EFPIA: Coding & Identification of Products: towards safer medicines supply ( D=566) EFPIA-GIRP-PGEU: Ten Core Principles to protect patients from falsified medicines ( D=559&DocID=12357)

Notes (i)

Delegated acts – The law-makers can give the EU Commission the option to supplement or amend (which means decide) certain non-essential elements of the EU law or framework law by delegating authority. The Lisbon Treaty introduces delegated acts as a special category of law in addition to EU directives and regulations. Delegated acts have also supremacy over national laws and national constitutions although they are to be approved in an organ where all member states are not represented ( (ii) EFPIA – European Federation of Pharmaceutical Industries and Associations (iii) GIRP – The European Association of Pharmaceutical Full-line Wholesalers (iv) PGEU – The Pharmaceutical Group of the European Union (v) EAEPC – European Association of EuroPharmaceutical Companies

european INDUSTRIAL PHARMACY March 2012

• Issue 12

book review Computer Validation: A Common Sense Guide by Teri Stokes, Ph.D. Reviewed by Ellis Daw With the title “Computer Validation, A Common Sense Guide” my first thought was this book had to be a challenge to write, especially if the content lived up to the promise. While the requirement for Computer Validation has existed for the industry more than 25 years, in practice it is still often seen as a subjective and challenging activity – the intent of the book is to provide a practical approach for the process. The main topics of this book of over 340 pages include a history of the regulations, explanations of the numerous roles and their responsibilities and required activities for successful outcomes, a large number of example documents, and principles and guidance from an author who has more than 20 years experience. It begins by providing a clear and insightful summary of the regulations and guidance that have shaped CV practices. Every major influence on current practice is covered, from FDA’s Blue Book guidance in 1983 to the very recent reissue of EU GMP Guide Annex 11 in 2011. The aims and expectations of regulatory authorities are well summarised into common themes and the first chapter ends with a useful summary of principles that bring sharp clarity to the common intent of regulators worldwide. Several chapters are devoted to explaining the roles required for successful computer validation. The first role is that of managers and expectations for sponsorship and active engagement with the projects are described. The book gets across the key message that validation is a process that must be strongly supported by management, from the identification of a need for a system through to its archival when the system is replaced or redundant. The guidance to management rightly conveys that computer validation cannot be achieved by a single person as a one-time activity; it is a lifecycle activity that must be supported by the organisation throughout the life of the system. The book describes the typical validation activities from identifying the team, development of requirements for the system, dealing with suppliers including auditing of practices, testing, managing the infrastructure requirements and completing the validation package. Useful guidance is given on building reusable packages that can be repeated for

european INDUSTRIAL PHARMACY March 2012

installations of similar systems. As the activities are described, detailed roles and responsibilities are identified for the activities. Some of these are too fragmented, e.g. seven roles are identified for formal testing and this granularity could confuse less experienced readers – who appeared to be the key target audience. Another example is the testing role of “Witness” whose responsibility is focused on ensuring test materials are prepared and collected properly rather than actually witnessing any activity – this and the follow-on impact of so many role acronyms in the example documents is a bit confusing. To its credit the book mentions that people can perform multiple roles and these can be combined or split to fit the size and scope of the system. There is a logical flow and value to the real life examples provided throughout the book and readers of all skill levels should find useful bits to apply to their own projects. There are some odd suggestions such as printing different parts of the document set on different colour paper and keeping documentation in envelopes. It took several encounters with the term “Test Envelope” for me to realise the author was describing the retention of documents in an envelope rather than introducing some testing standard or concept. A disappointment is that the book provides very little in the way of risk management guidance to focus validation activities. Every practitioner struggles with the areas of focus, level of detail in which the effort should be conducted and how to vary the intensity of specifications, testing and other controls. Given the revision of Annex 11 in 2011, with its expectation for the extent of validation and data integrity controls to be based on a risk assessment, I had expected guidance on varying the approach to match the level of risk. However, the coverage of risk analysis is limited to example forms with yes/no questions to determine if validation is required. Simple advice on where and how to focus computer validation on the functionality most critical to patient safety would have been a valuable addition. In conclusion, this is a worthwhile book that conveys a lot of practical experience and guidance for anyone involved in computer validation. Overall, the book delivers on its title as a common sense guide. Ellis Daw, is Director of Quality Applications Shared Service at GlaxoSmithKine, Research Triangle Park, North Carolina, U.S.A. Published by Biopharm-Guides ( ISBN: 933722-54-1. 36 pages. Price $22.

• Issue 12


regulatory review United States of America FDA rule requiring manufacturers to report interruptions in production of critical drugs

FDA has issued an interim final rule that will help prevent prescription drug shortages. The rule requires manufacturers that are the only producer of certain critical drugs to report to FDA all interruptions in manufacturing of products. USP New General Chapter <1083> "Good Distribution Practices – Supply Chain Integrity"

This new chapter will be published in the Pharmacopeial Forum – March-April edition for comment. It will focus on packaging technologies (tamper proof evidence) and on identification and serialisation technologies (2D Barcode or RFID). It also covers the regulations that should be developed for re-packaging and the measures to be taken against illegal Internet pharmacies.

Europe Revised guidance on genotoxicity testing of medicines

Damage to the DNA, or genotoxicity, is an important consideration for developers of medicines and medicines regulators, because it has the potential to cause irreversible changes to genes and even cancer. EMA has published a revised guideline on how pharmaceutical companies should test their medicines for damaging effects on the DNA. The guideline, effective June 2012, follows the core ICH guideline. It is expected to improve the assessment of the risks of human medicines, to reduce the number of animals used in the testing and to improve the efficiency of the medicine development process. EMA work programme 2012

EMA will focus on implementing


new pharmacovigilance legislation and also on supply shortages of medicines caused by insufficient GMP compliance. Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry

This guideline describes the regulatory requirements for MAA and variation applications submitted for medicinal products for human or veterinary use, which include the use of NIRS. Enhancing GMP inspection cooperation between the EMA and FDA

As the latest step in increased collaboration between EMA and the FDA, an initiative is in place to share work on inspections of manufacturing sites in each other's territories. From January 2012, they may rely on each other's inspection outcomes rather than carrying out separate inspections in duplicate, enabling: • Better use of inspection resources • Reduce the burden of inspections for medicines manufacturers • Shift inspection capacity to other regions The most likely impact will be in the area of routine postauthorisation/surveillance inspections. Delegated Act/detailed rules for a unique identifier for medicinal products and its verification. The Commission is under an obligation to adopt delegated acts setting out the details relating to the unique identifier including: • Characteristics and technical specifications • The modalities for verification • Establishment, management and accessibility of the repositories system in which information on the safety features is to be contained

by Malcolm Holmes • Lists containing the medicinal products or product categories which, shall, or shall not bear the safety features • The procedures for the notification of medicinal products by the national authorities to the Commission, as regards medicinal products (not) at risk of falsification. An impact assessment will be made of the characteristics of the unique identifier, the detailed procedures for verification, and the repositories system. Delegated Act principles and guidelines of GMP for active substances

Member States must take appropriate measures to ensure that manufacturers of active substances on their territory comply with GMP. A Concept Paper has been released with a view to preparing the delegated act.

International PIC/S recommended model for risk-based inspection planning in the GMP environment

This PIC/S Recommendation sets out a simple and flexible Quality Risk Management tool that may be used by Inspectorates when planning the frequency and scope of GMP inspections. EMA & EC extend confidentiality arrangement with Japan

The EMA and the European Commission have extended their confidentiality arrangement with the Japanese medicines regulatory authorities for a year. For further information on these and other topics please refer to the websites of relevant regulatory bodies and to “GMP Review News” published by Euromed Communications. To subscribe to this monthly news service contact

european INDUSTRIAL PHARMACY March 2012

• Issue 12

news from the EIPG Bureau Meeting

The format and agenda for the 2012 General Assembly to be held on 5-6th May in Lisbon were drafted. Education and financial matters were discussed, as was the revision to the Statutes. Professional Qualifications Directive

On 19 December 2011, the European Commission adopted a legislative proposal for modernising Directive 2005/36/EC on the recognition of professional qualifications. Its proposals for accelerating the update of the minimum training requirements through “delegated acts”, introducing professional cards, amendments to language knowledge and the proposals on partial access have been discussed with representatives of the European community and hospital groups and the European faculties of pharmacy. Innovative Medicines Initiative

EIPG responded to comments on the summary documents on Continuing Professional Development produced from the meeting in Manchester. EMTRAIN launched the on-course®: on 14 February 2012. Everyone is kindly invited to start using on-course® and register as course seeker. Also, please register

if you are a course provider and enter your programmes. Currently, EMTRAIN contains > 1500 European Master courses and around more than 700 CPD courses. PhD programmes and courses are to be added in the near future. EIPG Comments on Technical Documents

In December, EIPG submitted comments on the EMA “Revised Guidelines on Good Distribution Practices”. In January, EIPG submitted comments on the “Concept paper on Revising Annex 16 of the Guide to Good Manufacturing Practice: Certification by a Qualified Person and Batch Release”. Both documents are on the EIPG website under “Position Papers” Draft Technical Documents Pending Comment

The European Commission has published a concept paper for a Unique Identifier for medicinal products for human use and its verification (available at terf_par_trade/safety_2011-11.pdf Deadline for comments to EIPG is 31st March 2012.

EIPG would like to know your opinion on the proposals in this document. A survey is being conducted by Claude Farrugia and is available at: The European Commission has issued a concept paper for public consultation on the principles and guidelines of good manufacturing practice for active substances in medicinal products for human use. See EIPG website under “News”. Deadline for comments to EIPG is 1st April 2012. The European Medicines Agency has published a draft of a Scientific guideline: Reflection paper on the use of starting materials and intermediates collected from different sources in the manufacturing of biological medicinal products. See EIPG website under “News” Deadline for comments to EIPG by 1st August 2012. Any comments can be made via and I will pass them to the person drafting the response. Jane Nicholson, Executive Director EIPG

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european INDUSTRIAL PHARMACY March 2012

• Issue 12


events MARCH 19-21 March 2012 – Amsterdam, The Netherlands Bio-Europe Spring 2012 28-29 28-29 March 2012 – London, UK Advanced in nanomedicine for oral and non-oral drug delivery

26-27 April 2012 – Cambridge, UK Risks, requirements, tests and traceability: A model for computerised system validation 26-27 April 2012 – Amsterdam, The Netherlands Open Innovation in Pharmaceutical R&D


17-19 April 2012 – Reading, UK Good Manufacturing Practice

13-17 May 2012 – Cambridge, UK Advanced Level Workshop on Pharmacokinetic – Pharmacodynamic Data Analysis

18-19 April 2012 – London, UK Pharmaceutical Portfolio & Product Lifecycle Management

15-17 May 2012 – Manchester, UK Best Practice for the Analytical Laboratory

18-19 April 2012 – Prague, Czech Republic BioProcess International European Conference & Exhibition

17 May 2012 – London, UK Advances in Raman Spectroscopy in Pharmaceutical Analysis

23-27 April 2012 – Glasgow, UK Qualified Person & Professional Development Training 24-25 April 2012 – Cambridge, UK Systems audit

22-24 May 2012 – Islington, UK Biomarkers World

JUNE 3-5 June 2012 – Lisbon, Portugal 53rd Annual General Meeting GIRP

APRIL 16-17 April 2012 – London, UK Asthma & COPD

22-23 May 2012 – Cambridge, UK The practical application of QRM tools and techniques

21-22 May 2012 – Berlin, Germany Pharma Outsourcing & Procurement Summit 2012 21-25 May 2012 – Manchester, UK Effective Pharmaceutical Audits and Self-Inspections

18-22 June 2012 – Frankfurt am Main, Germany Achema 2012 20 June 2012 – Cambridge, UK Dissolution testing for the pharmaceutical industry 25-28 June 2012 – Barcelona, Spain IWPCPS-14 –International Workshop on Physical Characterization of Pharmaceutical Solids ct.cfm

SEPTEMBER 24-26 September 2012 – Dusseldorf, Germany 11th Annual Biological Production forum 2012



european INDUSTRIAL PHARMACY March 2012

• Issue 12

european Industrial Pharmacy Issue 12 (March 2012)  

European Industrial Pharmacy is the electronic journal of the European Industrial Pharmacists Group (EIPG). The journal contains articles, n...

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