Cover Story. Conference Reports gmp under. on process validation. fda guidance. Q&As on cgmp. Issue 1, October/November 2008

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1 Issue 1, October/November 2008 The Journal for GMP and Regulatory Affairs Cover Story counterfeit drug products action in default? IDEAS FOR THE BETTER PROTECTION OF EU PATIENTS AGAINST THE RISK OF COUNTERFEIT MEDICINES Conference Reports gmp under reconstruction FDA s new requirements on process validation an outlook on the new fda guidance Quality by Design an interdisciplinary System from Development to Registration and Production Q&As on cgmp cgmp-compliance questions to authority officials and industry experts

2 Lead COUNTERFEIT DRUG PROD- UCTS ACTION IN DEFAULT? IDEAS FOR THE BETTER PROTECTION OF EU P A TIENTS AGAINST THE RISK OF COUNTERFEIT MEDICINES Conference Reports GMP UNDER RECONSTRUC- TION QUALITY BY DESIGN AN INTERDISCIPLINARY SYSTEM FROM DEVELOPMENT TO REG- ISTRATION AND PRODUCTION Q&As on cgmp cgmp-compliance QUES- TIONS TO AUTHORITY OFFI- CIALS AND INDUSTRY EXPERTS Issue 1, October 2008 The Journal for GMP and Regulatory l Affairs October/November 2008 Contents Editors Note Cover Story Counterfeit Drug Products Action in Default? According to the World Health Organisation s (WHO) estimates, 8-10% of medicinal products worldwide are counterfeited. Only in Europe the macroeconomic damage amounts to 30 Milliard Euros. To get a grip on this problem it is necessary that all parties affected co-operate. Ideas for the better Protection of EU Patients against the Risk of Counterfeit Medicines To fight counterfeit medicines, it will be necessary to establish a series of requirements API and medicines manufacturers have to fulfil. The European Fine Chemicals Group (EFCG) has proposed some measures and has asked the Commission and the Member States to seriously consider their implementation. Conference Reports GMP under Reconstruction During the second GMP Conference which took place in Heidelberg, Germany, in June 2007, it showed that the European Medicines Agency (EMEA) as well as the American Food & Drug Administration (FDA) intend to modernise the requirements relative to GMP fundamentally. But what has really changed since then? FDa s new requirements on process validation an outlook on the new fda guidance Industry has already been waiting for the new Process Validation Guideline as the current version has been effective since At the PAT Conference conducted in Heidelberg end of October, Jon Clark from the FDA gave an outlook on the revision. Quality by Design an interdisciplinary System from Development to Registration and Production Quality by Design is not at all only an approach limited to one area. Much rather it should be seen as a holistic system covering all phases from development to production and providing a much more thorough product and process understanding. Q&As on cgmp Volume I: Pre-filled Syringes During courses and conferences authority officials and industry experts regularly answer questions from attendees this time relative to pre-filled syringes. GMP Journal Publisher: CONCEPT HEIDELBERG GmbH rischerstraße Heidelberg, Germany HRB Mannheim Nr General Manager: Oliver Schmidt Chief Editors: Editorial Staff: Editors on this Issue Graphic Concept & Realisation: Production: Contact: Oliver Schmidt, Wolfgang Heimes Dr. Gerhard Becker, Dr. Günter Brendelberger, Dr. Robert Eicher, dr. Andreas Mangel, Sven Pommeranz, Oliver Schmidt, Wolfgang Schmitt, Axel H. Schroeder. dr. Andreas Mangel, Sven Pommeranz, Wolfgang Schmitt. Wolfgang Heimes KNOPF DRUCK MEDIA GmbH Mannheimer Straße Edingen-Neckarhausen info@concept-heidelberg.de Any reprints of text and images require specific pre-approval by the editorial office. The GMP environment is continuously experiencing profound changes. With the new GMP Journal we want to accompany this process as you can already read in this first issue. This new periodical will provide detailed information on current developments in the area of Good Manufacturing Practices (GMP), valuable background information and analyses. The Journal will not only pick up regulations from FDA, EMEA, ICH and PIC/S, though. It will also cover inspectors lectures during international conferences, reports from working groups, making it a unique source. Moreover, in no other publication you will be able to find excerpts from the FDA Warning Letters. The GMP Journal will be published twice a year (April and October) and addresses professionals in Quality Assurance, Qualified Persons and GMP Representatives in the pharmaceutical and API industry. It is free of charge and will be distributed exclusively to attendees of courses and conferences of the European Compliance Academy (ECA). If you have any comments relative to the new journal or articles, we will be looking forward to receiving your note at info@ concept-heidelberg.de. Your GMP Journal Team

3 Conference Reports 9 gmp under reconstruction Sven Pommeranz During the 2 European GMP Conference in Heidelberg, Germany, in the summer of 2007, the European Medicines Agency (EMEA) as well as the US Food & Drug Administration introduced their road map for the coming years to attendees of the conference. What was then supposed to change, and what has really been changed since then? The changes in Europe In Europe, for instance, risk management has been gaining in importance in the meantime. In addition to the implementation of ICH Q9 (Quality Risk Management) as Annex 20 of the EC GMP Guide, the subject also found its way into the European authority SOP Compilation of Community Procedures (key word risk based inspections). It is also supposed to be included in part II of the EC GMP Guide (GMP for APIs). Another important issue is Dedicated Facilities, affecting items 5.18/5.19 and 3.6 of the EC GMP Guide. Besides a concept paper there have been several drafts relative to dedicated facilities. Key elements of the first drafts were: Indication of types of products (Cytotoxics and Cytostatics, Betalactam antibiotics, Radiopharmaceuticals, BCG vaccines and so on) for which dedicated and selfcontained facilities should be mandatory Types of products which according to a risk analysis could be produced on a campaign working basis Factors to be considered within the risk analysis In January 2008, the EMEA published an interim report on the current state of revision. This report states that the GMP/GDP Inspectors Working Group is unanimous that there will be a list of substances for which a dedicated facility is mandatory. For other products it is supposed to be possible to base this decision on a risk analysis depending on the physico-chemical risk. The drafting group is currently developing a table intended to define a high physicochemical risk in more detail. Apparently it is planned to submit the revised GMP Guide chapters to the European Commission at the end of 2008; public consultation can be expected to start at the beginning of But there are also further plans for changes, which are currently either in a draft phase or already finalised. Finalised are Annex 1 (Sterile Products): The revised version will come into operation in March 2009 and March 2010 ( Capping ). The changes relate more strongly to EN/ ISO and to the FDA Aseptic guide. Annex 3 (Radiopharmaceuticals) and Annex 7 (Herbal Products): The revised guides will also become effective on 1 March In a draft stage are currently revisions of Annex 2 (Biological Products) Annex 6 (Medicinal Gases) Annex 11 (computerised systems) Annex 13 (Investigational medicinal products) and Annex 14 (Blood Products). The changes in Annex 11 will also affect chapter 4 of the EC GMP Guide (Documentation). A draft is available already. Moreover, chapter 5 of the European GMP Guide is currently also being revised. Changes are concentrating on Qualification of suppliers: Until now the GMP Guide (chapter 5.26) referred only to the testing of starting materials. Now this obligation is to be extended to include active pharmaceutical ingredients (APIs) with a note that only APIs are to be used that are produced according to GMP. To achieve harmonisation between all member states, the requirements on testing of starting materials will also be revised. There is also a new draft regarding Variation Regulations :

4 10 An important goal of the regulation is to further decrease the overall number of variations procedures. It is supposed to enable the competent authorities to concentrate on those changes that will in fact impact quality, safety or efficacy. For certain, less severe changes it is planned to introduce a system with annual reports - similar to the system already established in the US. These changes will not have to be approved in advance and should be notified within a 12 months period after their implementation. This would also mean a tremendous relief for the pharmaceutical industry, especially with regard to changes concerning the continuous improvement of manufacturing processes. In addition there are a number of new requirements concerning the classification of changes. It is also supposed to be possible to propose a reference authority for changes to multiple authorisations. Under certain conditions changes can be grouped and submitted to the authorities in a single notice. And what is new in the US? In the Federal Register, the FDA informed about changes to the cgmp rules for medicinal products on 8 September These changes will come into force on 8 December Next to a summary, the announcement includes a total of seven further parts: The most interesting ones are parts 1 to 3: Background, the summary and the comments on the original draft document with FDA s answers. In the summary, the FDA announced that the changes are just one part of the entire revision process for updating the cgmp rules. In a later passage, these changes are announced as efforts to harmonise the cgmp rules with other FDA regulations (the text mentions the Quality Systems Regulation for medical devices) and other GMP regulations (explicit mention of EC GMP). The changes mainly affect aseptic processing, the implementation of the 4-eyes principle, the use of asbestoscontaining filters. Minor changes without relevance for the contents complement the main changes mentioned. The part titled Background explains the history that led to the now finalised changes. Regarding aseptic manufacture, the following paragraphs have been changed: (b) changes concern the validation of the aseptic process for the prevention of microbiological contaminations (a) refers to the sterilisation /sanitisation of equipment (d)(6) affects the microbiological tests performed prior to the use of primary packaging materials (c) validation of depyrogenisation of primary packaging materials and (a) bioburden tests within the framework of in-process controls Especially the changes to (b) are meant to harmonise the FDA requirements with Annex 1 to the EC GMP Guide. The ban on asbestos-containing filters resulted in changes to 210.3(b)(6) and As a reaction to comments on the first revision draft, the passage the use of an asbestos-containing filter is prohibited has now been included. Furthermore, the update reflects the state of the art regarding the loss of fibres in filters and the indication of the pore size. The changes regarding the implementation of the 4-eyes principle ( verification by a second individual ) refer to the use of computerised systems instead of a second pair of eyes. This affects a whole number of paragraphs. For example, has been extended by a section (c) now allowing the use of a computerised system instead of a second individual. Of course, this also has consequences for other paragraphs requiring this 4-eyes principle: (c) and (d) charge-in of components and containers), (calculation of yields , equipment cleaning and maintenance (b)(11) batch production and control records for which reason they will also be adapted. The minor changes concern (b), (c)(1) and (d)(3), as well as (b)(1). The changes serve the purpose of clarification without affecting the contents. Some of the comments by industry on the original draft and FDA s answers to them that resulted in this final version are also quite interesting. Among other things, the industry reminded the FDA of their fear that the Agency s reviewers and GMP inspectors might lack clarity and consistency in their understanding of the new changes. The FDA replied that it understands this fear and intends to respond to it with adequate training of the group of persons in question. Four comments prevented among others even the revision of 21 CFR (a) ( Plumbing ). The original requirement that potable water must be up to EPA (Environmental Protection Agency) standards was intended to be changed in order to harmonise it with other regulations (e. g. those of the EU). The wording should be safe for human consumption. However, according to the comments, this wording was not prescriptive enough. Within the framework of further updates of the cgmp rules, this question regarding water relating to water qualities used as a component in medicinal products will be taken up again. Alike its European counterpart, the US authority also pays more attention to quality risk management. For the FDA the 2006 Quality System Guidance serves as a bridge between the cgmp Regulations from 1978 and the quality systems for the 21st century. While cgmp is more concerned with the technical aspects of pharmaceutical man-

5 11 ufacturing, modern quality management puts greater emphasis on: Risk analysis Risk management Preventive actions Continual improvement. 5. Quality Control responsibilities (211.22) 6. Stability ( ) 7. Batch release testing ( ) 8. Record review/investigation ( ) 9. Complaint investigation ( ) The industry is also paying close attention to the next steps regarding the Draft Guidance Process Validation. The bottom line of the (still) valid Process Validation Guideline from 1987 is its focus on full-scale-replication. In the FDA s view, the Compliance Policy Guide 7123c.08 is an interim step towards the new Validation Guidance. It no longer requires process validation prior to approval. But process validation has to be completed prior to distribution. According to the authority, validation will be regarded as a life cycle approach in the revised Process Validation Guidance including the following three steps: 1. Design (development phase) 2. Confirm/Qualification (commercialisation phase) and 3. Monitor and Assess (maintenance phase) And manufacturers can define the number of runs themselves scientifically based. Requalification and revalidation are part of the maintenance phase. Life cycle will also mean that development leads to process understanding and to the corresponding sources of variability. The FDA also revised some Guidances to Industry, e.g. regarding beta-lactam Penicillin Contamination and Penicillin detection and GMPs for Phase I IND Clinical Supplies. Enforcement Trends of the FDA Trends concerning Realisation of Inspections The FDA performs about 200 foreign FDA inspections every year. In 2005, 204 inspections were conducted. In 100 cases, the authority observed deficiencies of so-called moderate significance, i.e. deficiencies which the concerned firms commonly take care of themselves. Twelve inspections led to further measures by the FDA such as regulatory actions in form of warning letters, seizure or injunction. The analysis of the inspections shows the following most frequently objected cgmp deficiencies: 1. Lab controls ( ) 2. Validation of production and process controls( ) 3. Cleaning equipment (211.67) 4. Batch production records ( ) Remarkable: The most frequent cgmp deficiencies during foreign inspections. The red dot marks the deficiency s position in According to the FDA, typical cgmp problem areas identified during foreign inspections were: 1. Having and following sound lab SOPs; documenting results, testing stability 2. Investigating complaints/issues fully 3. Following production SOPs 4. QC not exercising real oversight 5. Validating manufacturing processes properly The analysis of the objected GMP deficiencies show old acquaintances. An overview of the GMP deficiencies at drug and API manufacturers sites furthermore showed that old friends such as Failure/OOS Investigations, Equipment Cleaning and Cleaning Validation, Lack of/inadequate SOPs top the list.

6 12 Moreover, the main reasons for drug recalls indicated by the analysis (data from October 2005 to September 2006) also provide a real good insight: Sub-potent (single-ingredient drugs) Defective container Impurities/degradation Lack of assurance of sterility cgmp deviations (not specifically identified) Correct labeled product in incorrect package Microbial contamination of non-sterile products (tied with) Non-Sterility Failed USP Dissolution Requirements Stability Super-potent (single-ingredient drug) Developments with an impact in Europe as well as in the US On 4 June 2008, the International Conference on Harmonisation (ICH) adopted the Step-4 version of the Guideline ICH Q10 Pharmaceutical Quality System, and now it has also made the document available to the public. With this, the guideline is now harmonised in Europe, the US and Japan. The authorities in the three regions, i.e. the EMEA/European Commission in Europe, the FDA in the USA and MHLW in Japan, are now required to include this regulation in their respective legislative/ordinance procedures. Co-operation between the European and the American authorities EMEA and FDA are also supposed to be intensified. As a result of a meeting held under the auspices of the Transatlantic Economic Council, a co-operation at the level of administrative practices and guidelines was agreed. The new cooperation covers four different areas: Quality and inspection Pharmacovigilance Scientific collaboration Guidelines, format harmonisation and electronic submission Conclusion A lot has happened in the area of GMP since the GMP Conference was conducted in 2007 and not everything found the support from the industry. For instance, changes regarding the subject Capping in the Annex 1 are still in discussion. Further, the planned changes with regard to the Annexes and the chapters 3, 4 and 5 of the EC GMP Guide will lead to discussions. Industry hopes for easement from the revision of the Variation Regulation though. Regarding FDA everyone is waiting for the revision of the Process Validation Guideline. It will also be interesting to see in the EU as well as in the US how industry will implement ICH Q10. And it further remains to be seen what the announced intensified co-operation between EMEA and FDA really will look like. FDA s new requirements on process validation An Outlook on the New FDA Guidance (Part i) Oliver Schmidt At the PAT Conference 2008, which was organised jointly by the University of Heidelberg and the European Compliance Academy (ECA), Jon Clark from the FDA gave an outlook on the upcoming new FDA Process Validation Guidance. The new Guidance will replace the current version of The new approach of Process Validation considers validation as a series of activities taking place over the life of a product or process. Its key goal is hence to achieve process understanding. As a consequence the overall validation is not complete but ongoing. It requires a comprehensive process design to identify and mitigate significant sources of variability. The Process Validation may also incorporate risk management and recognises that more knowledge will be gained during commercial distribution. This is a fundamental change from the traditional three batches validation. In his presentation Jon Clark mentioned that the life cycle approach to Process Validation consists of three elements: Process Design Process Qualification and Continued Process Verification Process Design assures that the commercial process is defined based on knowledge gained through development and scale-up activities. Process Qualification consists of two aspects: Design of facilities including qualification of equipment and utilities and performance qualification. During his talk he defined the criteria for the Performance Qualification Protocol. This document specifies the manufacturing conditions, controls, testing and the expected outcomes. It should therefore include operating parameters, processing limits and component (raw material) inputs, the data to be collected and when and how these