GMP in Practice (File 1–3)

File 1

Chapter 1 Pharmaceutical Quality System (PQS) The pharmaceutical industry’s understanding of “Quality“ has consistently developed from the concept of Quality Control in the 80ies to a Pharmaceutical Quality System as outlined recently in the ICH Q10 Guideline. This paradigm change was the catalyst to rewrite Chapter 1.
The Author describes the main elements of a PQS such as management responsibility and resource management, explains the relationship between the various stages of the manufacturing process and the PQS, and highlights the importance of evaluation activities. A separate subchapter is dedicated to processrelated aspects. A number of methods for process mapping are presented, and the importance of key performance indicators to manage processes and measure process improvements is discussed. Furthermore, the author gives advice on how to implement a PQS both from an organizational point of view and concerning the document hierarchy. Finally he proposes a structure for a PQS Quality Manual and gives an excellent overview on the correlation between GMP requirements and ISO 9001:2000. (Author: Lothar Hartmann, Ph.D.)

File 2

Chapter 11 Production Globalization within the pharmaceutical industry requires global supply chains and cooperation with logistic service providers around the world in order to be able to deliver pharmaceutical products wherever and whenever they are needed. But distribution and transport are complex processes, comparable to a chain with many links which is difficult to control.

• Chapter 11.N Transportation The author of the new subchapter discusses the challenges related to transportation and defines the resulting requirements for logistic service providers. She describes measures to control the cargo conditions in general and introduces various devices that can be used to monitor the ambient conditions during transport. A separate subchapter is dedicated to cold chain distribution. Different temperature ranges are characterized and standard temperature profiles presented which are intended for evaluation and testing purposes in order to make the cold chain more reliable. The chapter concludes with an outline of a risk-based approach to transportation, based on a suggestion of the Chemical Manufacturers Association. (Author: Nicola Spiggelkötter, Ph.D.)

File 3

Chapter 18 Inspections The questionnaire for preparing GMP-inspections was extended by more than 170 questions relating to the following topics:

• computer validation (Author: Thomas Halfmann)
• storage and transport (Author: Rainer Kutsch)

The newly added questions provide further support in preparing internal and external audits.

Chapter 20 Continual Improvement Methods This chapter is extended by two new subchapters on SPC and PAT.

• Chapter 20.C Statistical Process Control (SPC) is a tool used to monitor, analyze and improve the variability of a process. The author explains the different types of variation, discusses the shortcomings of descriptive statistical methods and introduces various types of control charts. Based on examples, he shows how to set up and to interpret control charts. Furthermore the differences between SPC and APC (Automated Process Control) as well as their common objectives and prerequisites are discussed. The author also addresses the variation of the measurement system as part of the total variation. The concept of Process Capability as a tool for process evaluation is explained in detail. The chapter continues with a summary of the objectives and benefits of SPC and provides guidance on implementation of the method. Some examples of successful implementation of SPC in the pharmaceutical industry complete this chapter. (Author: Rolf Staal)
• Chapter 20.D Process Analytical Technology (PAT) is a system for designing, analyzing, and controlling manufacturing through timely measurements of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. There has been considerable growth in the use of PAT in pharmaceutical manufacturing in recent years. The authors describe the role of PAT in Process Development as well as routine manufacturing and point out the opportunities of this method to support evolving quality systems such as Continuous Quality Verification and Real Time Release Testing. PAT is also of key importance to enabling new manufacturing paradigms like Continuous Manufacturing, Advanced Process Control or Lean Manufacturing. Regulatory perspective and guidances on PAT are presented, including regulatory submission requirements for PAT. A separate subchapter deals with the PAT instrumentation, addressing the supplier’s quality system as well as instrument robustness. The application of PAT in a GMP environment implies system qualification, software and method validation, data interpretation and management, training and change control. The chapter concludes with a number of potential applications and real-life examples of successful implementation. (Authors: John O’Sullivan, Ph.D., Seamus O’Neill, Ph.D. et.al.)

GMP Regulations (File 4–5)

File 4

Chapter C EU GMP Guide

• Chapter C.6.6 Annex 6 Manufacture of Medicinal Gases was revised as a consequence of the restructuring of the GMP Guide and the need to modify the requirements of Part II of the Guide for applicability to medicinal gases. There was a need to define more clearly what should be considered as a starting material as opposed to a bulk pharmaceutical product. The opportunity was also taken to update the annex in general. The revised annex was adopted by the European Commission in January 2010 with a deadline for coming into operation until 31 July 2010.
• Chapter C.6.13 Annex 13 Investigational Medicinal Products has also been revised in order to reinforce the principle of independence between production and quality control functions in cases where the number of personnel involved is small. Changes were made to sections 36 and 37 to supplement, for investigational medicinal products, the guidance for reference and retention samples given in annex 19. An additional note has been introduced to clarify the meaning of “reconstitution” as referred to in article 9.2 of Directive 2005/28/EC. The content of the Batch Certificate referred to in Art. 13(3) of Directive 2001/20/EC, agreed following a separate public consultation, has been added as an attachment. A few editorial changes have been made to sections not consulted upon in the interests of updating references and consistency with terminology used throughout the GMP Guide. The revised annex was adopted by the European Commission in January 2010 with a deadline for coming into operation until 31 July 2010.

The entire chapter C.6 was re-edited with each annex now having its own pagination. This will facilitate future updates for individual annexes.

File 5

Chapter E ICH Guidelines

• Chapter E.8 Pharmaceutical Development The ICH guideline Q8 Pharmaceutical Development was revised in August 2009 and is now coded as ICH Q8(R2). You receive the actual version with this update.
• Chapter E.10.1 Quality Implementation Working Group on Q8, Q9 and Q10: Questions & Answers The benefits of harmonizing technical requirements across the ICH regions can only be reached if the various Q-ICH guidelines are implemented and interpreted in a consistent way across the three regions. The Implementation Working Group (IWG) is tasked to develop questions and answers to facilitate the implementation of existing guidelines. In October 2009 a document entitled Quality Implementation Working Group on Q8, Q9 and Q10: Questions & Answers was published. The main topics of this document are
  
  • Quality by Design,
  • Pharmaceutical Quality System,
  • Knowledge Management and
  • Software Solutions.

A separate chapter covers the impact of ICH new quality guidelines on GMP
inspection practices.

Chapter F PIC/S Guidelines

• Chapter F.7 PIC/S PI 028-1 We have added the PIC/S Guideline PI 028-1 Aide-mémoire GMP Inspection related to Packaging as well.
  The increased number of the defects of medicinal products occurred due to deficiencies in the process of labeling and packaging, which is recognized as one of the risk factors that may affect the quality of the final product, has drawn inspectors’ attention towards the need for identifying and clarifying the critical aspects of this specific stage of inspection. The Aide-mémoire was compiled in order to have a uniform interpretation of the provisions of the current GMP guide concerning packaging of medicinal products and prevention of mix-up.

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