What is new?
The recent update of the GMP MANUAL encompasses approx. 850 pages. In early 2011, regulatory requirements on Documentation, Computer Validation and Process Validation have been updated and the revised versions of the respective documents were in the focus of the “GMP Regulations” part of Update 11. Meanwhile, the corresponding chapters in the “GMP in Practice” part were subject to an in-depth review and represent the principal items of the present Update 12.
Vice versa, chapter 23 on Medical Devices was introduced in the “GMP in Practice” part in Update 11 as a new topic, which will now be complemented by a chapter in the “GMP Regulations” part, including EU Directives which are the underlying regulatory documents in the European region.
The contents of Update 12 are outlined below:
“GMP in Practice”
- Chapter 7.E.4: Process validation as a three stage lifecycle model
- Chapter 7.F: References
- Chapter 9.H: References
- Chapter 15.G: References
- Chapter 7: Process Validation
- Chapter 9: Computer Validation
- Chapter 15.E: Site Master File
- Chapter C: EU Directives and Guideline
- C.8.2: EU GMP Guide Part III: Quality Risk Management
- C.8.3: EU GMP Guide Part III: Pharmaceutical Quality System
- C.8.4: EU GMP Guide Part III: Internationally harmonised requirements for batch certification
- C.11: EU Directives on Medical Devices
- Chapter C: EU Directives and Guidelines
- C.6.14: Annex 14 Blood and Blood products
- C.10: Compilation of Community Procedures
- Chapter D: USA: CFR and FDA Guidelines
- Chapter F: PIC/S Guidelines
- F.2: PIC/S PI 007-6 Recommendation on the Validation of Aseptic Processes
- Chapter H Information:
- H.1: Abbreviations
- H.2: Glossary
- H.3: Adresses
- H.4: References
GMP in Practice (File 1–5)
Chapter 7 Process Validation
The entire chapter on process validation has been thoroughly revised and reorganized. It is now on the cutting edge in respect to regulatory requirements and practical implementation.
7.B Validation – a key element of quality management
The understanding of process validation has changed dramatically during the previous years. The strictly formalized obligatory act of former days has turned to become an integral part of quality management systems today, and the one-off validation approach consisting of three validation batches has advanced to become a challenging lifecycle concept. Process validation nowadays is based on science-based development and incorporates quality risk management as a key principle. This progress is reflected by the revised version of the FDA Guidance for Industry on Process Validation, which was published in January 2011. This chapter points out the direction of the latest trends with respect to process validation.
7.C Validation planning and procedure
Validation is a complex task and requires meticulous planning and management. This chapter describes different validation approaches and depicts the conditions under which they apply. Tasks and responsibilities are elucidated and the prerequisites to carry out a validation project are discussed. Last but not least the use of quality risk management for defining the adequate scope and extent of a validation study is described.
7.D Validation documentation
This chapter provides general information on the structure of validation documentation, its chronologic preparation and the requirements for archiving the documents. A key element of validation documentation is the validation masterplan (VMP) including the validation matrix. The essential elements of a VMP are discussed and special aspects such as bracketing and matrixing are explained. Each individual validation project requires a validation protocol, including instructions for testing and sampling together with the corresponding acceptance criteria. The author not only specifies the particular contents, but also addresses some challenging situations such as limited raw material availability or modifications to the validation protocol during the study. The validation plan finally includes all test results and their evaluation. The chapter is completed by detailed documentation examples for a Validation Master Plan, a validation matrix and a test plan.
7.E Process Validation and Product Lifecycle
This chapter points out how the implementation of Quality by Design establishes the prerequisites for process robustness as early as in the development stage, and shows the influence of Process Analytical Technology on the conventional approach to process validation. Another focus of this chapter is the question how to maintain the validated status. Generally a distinction has to be made between conventional revalidation – either induced by changes or performed periodically – on the one hand, and the recent approaches of continuous validation on the other.
A new subchapter has been added entitled “Process validation as a threestage lifecycle model” (chapter 7.E.4). Here the author discusses in detail the contents of the revised FDA Guidance for Industry on Process Validation. What are the main differences in the life cycle model compared to the understanding of validation to date? What new terms have been coined and which have been dropped? How are "qualification" and "validation" redefined? Beyond these questions, the author highlights future focuses such as the use of statistics, and reveals inconsistencies between the revised guideline and existing international guidance on process validation. (Dr. Christine Oechslein, Max Lazar)
Chapter 9 Computer Validation
The chapter Computer Validation has been completely revised and updated by Markus Roemer, who joined our team of authors recently. The contents and especially the innovations of the revised Annex 11 of the EU GMP Guide are discussed comprehensively in chapter 9.B Legal Aspects. The lifecycle stages of a computerized system from the project charter up to the system shutdown are in the focus of chapter 9.C System Life cycle. Within this context the author presents the socalled “V-model” and describes how to proceed in software development. An essential aspect of computer validation is the system classification according to ISPE GAMP®5, which is discussed in depth in chapter 9.D System classification and risk management. This classification is a pre-requisite for the risk-based validation approach as required by GAMP®5 and Annex 11 of the EU GMP Guide. Chapter 9.E “Validation of computerized systems” primarily deals with prospective validation, but also addresses the retrospective evaluation of legacy systems. The author explains which aspects have to be considered when establishing specifications and presents the most relevant test stages and test methods. When replacing legacy systems, the question of data migration or archiving arises.
The proceeding of computer validation is illustrated by means of numerous practice-oriented examples. Within the system life-cycle, validation is followed by the operation of computerized systems (chapter 9.F). This stage requires all relevant SOPs to be issued and the corresponding training measures to be accomplished. With view to data security, authorized access has to be managed and provisions for data backup and archiving have to be defined. The development of contingency plans is also an important aspect of security. Change management plays a central role in mastering the challenge of keeping a system in a validated status. Another approach here is the periodic review of the systems. The relocation of activities to external service providers and the corresponding requirements are in the focus of chapter 9.G. Here you will also find an example of a service level agreement and a detailed questionnaire for auditing of suppliers and service providers. (Markus Roemer)
Chapter 15 Documentation
15.E Site Master File
The revised version of the PIC/S Explanatory notes for pharmaceutical manufacturers on the preparation of a site master file (PIC/S PE 008-4) includes additional topics such as risk management and supplier qualification. On the other hand, the formal requirements for the preparation of a Site Master File have been simplified. What does this situation mean in practice for companies which have already issued a Site Master File or companies who are faced with this task for the first time? How is the new Site Master File designed and which information should be included? To what extent may already existing parts be used again and what kind of information should be added? These questions were in the focus of the actual review of this chapter, which provides a lot of valuable advice and practical tips for designing a Site Master File in form and content. (Cornelia Wawretschek)
GMP Regulations (File A–C)
Chapter C EU Directives and Guidelines
C.6.14 EU GMP Guide Annex 14 Blood and Blood Products
Annex 14 to the EU GMP Guide has been revised in the light of Directive 2002/98/EC and relevant implementing directives setting standards of quality and safety for the collection and testing of human blood and blood components for all uses, including the manufacture of medicinal products. The revision was published in March 2011 and will come into operation on 30 November 2011.
C.8 EU GMP Guide Part III GMP related Documents
The creation of a new Part III to the EU GMP Guide, entitled “GMP related Documents”, started in early 2011 with the Explanatory Notes on the preparation of a Site Master File (see Update 11). In the meantime, ICH Q9 Quality Risk Management and ICH Q10 Pharmaceutical Quality System have been allocated to Part III as additional documents by the European Medicines Agency (EMA), each annotated with a preface. You will find the EMA preface in chapters C.8.2 and C.8.3, whereas the core documents (ICH Q9 and Q10) are still located in chapter E ICH Guidelines. Chapter C.8.4 Internationally harmonised requirements for batch certification provides a new document which was published on 01 June 2011 by the EMA. This document describes the content of batch certificates for medicinal products and contains explanatory notes and a glossary.
C.10 Compilation of Community Procedures
In July 2011 the European Medicines Agency published Revision 13 of the Compilation of Community Procedures on Inspections and Exchange of Information. Several changes were made in the chapter Procedures related to GMP Inspections, which is subject of chapter C.10 of the GMP MANUAL:
The Community Procedure Conduct of Inspections of Pharmaceutical Manufacturers or Importers was completely revised and extended by an additional Annex 3.The Community Procedure Exchange of Information on Manufacturers and Manufacturing or Wholesale Distribution Authorisations between Competent Authorities in the EEA has been withdrawn.The title of the Procedure for dealing with serious GMP non-compliance or voiding/suspension of CEPS […] has been corrected (read or instead of for).All documents have undergone an editorial update of the cover sheets. These revisions gave rise to re-edit chapter C.10 completely and to foresee individual subchapters for each Community Procedure, thus facilitating future updates of the respective documents.
C.11 EU Directives on Medical Devices
In the context of European medical device regulations, several EU directives represent the statutory provisions which have to be put into national legislation by the EU member states. The chapter EU Directives on Medical Devices, which is introduced with the present update, provides the most important directives, i.e. directive 90/385/EEC on active implantable medical devices, directive 93/42/EEC on medical devices and directive 98/79/EC on in vitro diagnostic medical devices. This chapter provides the regulatory background on the subject of medical devices as described in chapter 23 Medical Devices in the GMP MANUAL (see Update 11).
Chapter D USA: CFR and FDA Guidelines
Chapter F PIC/S Guidelines
F.2 PIC/S PI 007-6 Recommendation on the Validation of Aseptic Processes
On 01 January 2011 the PIC/S published an updated version of the Recommendation on the Validation of Aseptic Processes, PIC/S PI 007-6. In this revision, amendments were made to chapters 5.2.2 and 5.2.3 concerning the selection of growth medium.
Chapter H Information
The content of chapter A has been updated and relocated to chapter H.
The Abbreviations (H.1) and the Glossary (H.2) have been completely revised and considerably extended. Now, more than 700 abbreviations from daily pharmaceutical routine are deciphered, and the glossary provides over 900 definitions of GMP terms which are of relevance within the Pharmaceutical Industry. Most of the definitions originate from the glossaries which are part of the international regulatory documents published within the “GMP Regulations” part of the MANUAL (with reference). Some definitions are practical terminology (italics, without reference).