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Updates Forecast & History


GMP MANUAL Update No. 15

The recent update of the GMP MANUAL (April 2013)c encompasses approx. 650 pages. The contents of Update No.15 are outlined below:

“GMP in Practice”

New Chapters:

  • 15: Documentation
    • 15.F: Electronic Batch Recording and Batch Release (replaces 15.C.3)
    • 15.G: Document Management Systems
  • 19: Quality Unit
    • 19.E: Deviations (replaces 11.K)
    • 19.H: Complaints and Recalls

Updated Chapters:

  • 19: Quality Unit
    • 19.F: Batch Record Review (formerly 15.C.5)
    • 19.G: Product Quality Review and Annual Product Review (formerly 15.F)
  • Chapter 22: Excipients (formerly 21.C)

“GMP Regulations”

New Chapters:

  • B: National Bodies and Pharmaceutical Associations
  • C: EU Directives and Guidelines
    • C.8.5: Template for the “written confirmation” for active substances exported to the European Union for medicinal products for human use
    • C.8.5.1: Importation of Active Substances for Medicinal Products for Human Use; Questions and Answers
    • C.14: Guidelines on Good Distribution Practice of Medicinal Products for Human Use
  • E: ICH Guidelines
    • E.10.2: ICH Quality Implementation Working Group: Points to Consider (R2); ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation
    • E.11: ICH Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)
  • F: PIC/S Guidelines Chapter F.13: PIC/S PI 037-1 Recommendation: A Recommended Model for Risk-based Inspection Planning in the GMP Environment
    • F.14: PIC/S PI 038-1 Aide-mémoire: Assessment Of Quality Risk Management Implementation
    • F.15: Questions & Answers Document regarding Distribution Activities for Active Pharmaceutical Ingredients (APIs) Chapter F.16: PIC/S PI 030-1 Aide-mémoire: Inspection of Active Pharmaceutical Ingredients

Updated Chapters:

  • E: ICH Guidelines
    • E.10.1: Quality Implementation Working Group on Q8, Q9 and Q10: Questions & Answers (R4)

GMP in Practice

Chapter 15 Documentation

15.F Electronic Batch Recording and Batch Release

EBR data management system concepts can optimise processes and render them more efficient. Process risks can be reduced preventively and the observance of legal requirements is ensured right up to supporting the pharmaceutical quality system. EBR systems create relevant documents and records pursuant to the EU GMP Guide Chapter 4 and they implement the release and certification of batches in accordance with Annex 16. For this purpose, Annex 11 refers to special chapters for electronic batch certification and release. Introducing and implementing an EBR system requires systematic analysis, definition and assessment of the regulatory requirements, process-based data and product-relevant information. It is recommended that preparations be made for the conversion to an electronic system within a data-oriented transfer and project method which could include existing standards or norms. The validation and implementation strategies and periodic reviews are to be defined and communicated on a risk basis during implementation and realisation. EBR project teams must be made up of authorised and qualified experts (IT, Qualified Person, project leader, suppliers). EBR
systems or concepts are to be placed in various levels of the automation pyramid and are to be defined in keeping with project requirements.
(Markus Roemer)

15.G Document Management Systems

Various different aspects must be considered in order to transfer documentation management, including knowledge and information management, from a paper-based system into an electronic IT system. First of all, the fundamental legal stipulations and basics must be observed with regard to classifying documents as procedures (such as SOPs as specification documents) and records (such as records and reports as documents of proof). Implementation
approaches based on project management for IT projects are to be developed, building upon this foundation. Document management systems offer certain basic functions and principles. Analyses of the functional scope and definitions derived from this must be established early in the project. The initial statement “We need a document management system" should be reformulated mentally to "Which documents and records have to be managed?" These records occur as processes such as SOP management, training management, changes, deviations, production and warehouse records or records from the laboratory sector. Conversion of paper-based processes to electronic documents or forms changes, but also simplifies the methodical procedure and the handling of information and data.
(Markus Roemer)

Chapter 19 Quality Unit

19.E Deviations

In spite of qualified equipment, trained employees and validated processes, the daily routine in pharmaceuticals is rife with situations in which prescribed workflows are not observed or processes fail to deliver the expected results. For this reason it is important to specify how such deviations are to be handled. As a rule, deviations must be observed, their root causes investigated and actions documented in the Failure Investigation Report. Deviation management is directly linked to the risk management system and has interfaces to other elements of Quality Management such as CAPA, PQR or Management Review. The author discusses the basic requirements for deviation management and describes a workflow for systematic processing of deviations. There are numerous tasks in the context of deviation management and responsibilities have to be defined clearly. Instructions for investigating deviations are provided as a comprehensive list of questions. The failure investigation report should include a description of the deviation, the root cause(s) found, the actions taken and an overall evaluation of the impact on product quality. Deviations must be regularly evaluated with regard to their content. For this purpose it is advisable to use a database. The results of the statistical analysis are usually included in the Management Review. The deviation system itself has also to be checked regularly for system effectiveness. This is usually part of self-inspections and the results are also part of the Management Review. The chapter rounds up with some examples taken from daily work.
(Dr. Christian Gausepohl)

19.F Batch Record Review

The Batch Record Review is an examination of the batch records that is independent of their creation and takes place at the end of the production process. It is usually conducted by the Quality Unit. The obligation to perform such a review is anchored both in the CFR and in the EU GMP Guide. The BRR is used to determine whether the batch records comply with both regulatory and the internal business requirements. The Batch Record Review is thus an important prerequisite for the batch certification and for the release of the finished drug product by the Qualified Person. Since the accountabilities and workflows in conducting the Batch Record Reviews are not clearly specified in the regulations, the pharmaceutical company must define this in detail in an internal SOP. The scope of a Batch Record Review is not a binding stipulation either and therefore it must be individually defined for a particular company. A checklist with relevant questions is provided as work aid for performing a Batch Record Review.
(Dr. Nicole Kordek)

19.G Product Quality Review and Annual Product Review

Product Quality Reviews (PQR) for Europe and Annual Product Reviews (APR) for the USA are aids that play a crucial part in the evaluation of processes, process environments and of the product as well. The key aspects of PQR and APR are presented and compared to each other. The contents of the reviews are then discussed in detail. As a prerequisite of creating the review, quality descriptors and their respective data sources have to be identified. Data collection and data handling is another challenging aspect of PQR/APR. Evaluating the data gathered actually constitutes the core task of the APR/PQR. Changes and deviations as well as the respective actions taken have to be evaluated carefully and their impact on the validation status and the consistency with the marketing authorisation has to be checked. Practical advice is given for creating the review, concerning document structure and data presentation. The chapter rounds up with a sample SOP for creation of a PQR and documentation examples for a PQR.
(Dr. Christian Gausepohl)

19.H Complaints and Recalls

In principle, the quality of pharmaceutical products should always be ensured by validation of the production process and final quality control. However, in practice, this will never be 100 % possible. One reason for this is that production always entails certain unforeseeable events; another reason is that only a very specific quantity of samples of the commercial product is subjected to quality control prior to release. Therefore, it is possible that complaints may reach the manufacturing company by way of the marketplace. In the case of complaints a fundamental distinction has to be made between complaints with medicinal product risks (responsibility of the Qualified Person for Pharmacovigilance) and complaints related to product quality without medicinal risks (responsibility of the Quality Unit). A system must be established that regulates the assessment of the complaint and the workflow for its further processing within the company. If the complaint is justified and a major quality defect is confirmed, a recall must be initiated. The competent supervisory authorities must be included in the process. All actions necessary for this must be defined and drills simulating an emergency must be conducted from time to time. Together with the Trend Analysis, the Product Quality Review and the Management Review, processing and evaluating complaints make an important contribution to the continuous monitoring of product quality and therefore represent an essential element of a modern quality management system.
(Dr. Heinrich Prinz)

Chapter 21 Active Pharmaceutical Ingredients / Chapter 22 Excipients

In times of growing awareness of the importance of product and process understanding, GMP for active and inactive ingredients becomes more and more important. This understanding is mirrored by growing regulatory focus on GMP for APIs and excipients.

At the backdrop of this development, chapter 21 Active and Inactive Ingredients will be completely revised and prospectively figure as two separate chapters:

  • 21 Active Pharmaceutical Ingredients
  • 22 Excipients

In a first step, the part on excipients has been updated with inclusion of some of the current GMP approaches for excipients detailed in the EXCiPACT ™ Certification Standards for GMP and GDP and the forthcoming US national standard for GMP for excipients (ANSI NSF 363). A new section highlighting recent developments with regard to joint auditing and certification of excipient suppliers is also included. As a whole, the chapter draws heavily on the documents and guides issued by the International Pharmaceutical Excipient Council (IPEC). The author provides a critical discussion of the Joint IPEC-PQG GMP Guide for pharmaceutical excipients and outlines its implementation in a drug firm. Furthermore, safety and precedence of use issues for new and marketed excipients are discussed. A large number of excipients are described in compendial monographs. The procedure to introduce excipients to a pharmacopoeia, the contents of a monograph and the advantages offered by a compendial description are illustrated. Finally, the differences in forwarding information about excipients to the regulatory authorities within the three regions USA, Europe and Japan are explained.
(Iain Moore, Ph.D.)

GMP Regulations

Chapter B National Bodies and Pharmaceutical Associations

The development, production (including Quality Control) and distribution of drug products are integral parts of a comprehensive regulatory structure consisting of legislation, rules and regulations, guidelines and standards. In terms of their interpretation and enforcement, the elements of this structure are governed by the appropriate government authorities. The most important government authorities together with their roles, responsibilities and organisation will be introduced in the following chapters:

  • B.2 Government Authorities in Europe
  • B.3 Government Authorities in the United States (FDA, Food and Drug Administration)
  • B.4 Government Authorities in Asia

For companies operating on an international scale, the density of existing regulations often causes problems, since the regulations are not globally uniform. To improve this situation, internationally operating organisations are endeavouring to harmonise regulations; bilateral trade agreements with third countries (e.g. Mutual Recognition Agreement, MRA) are intended to facilitate trade in goods. You will find information on this in the following chapters:

  • B.5 International Cooperation (MRAs)
  • B.6 International Organisations

Chapter C EU Directives and Guidelines

C.8 EU GMP Guide Part III – GMP related documents

C.8.5 Template for the “written confirmation” for active substances exported to the European Union for medicinal products for human use in accordance with Article 46b(2)(b) of Directive 2001/83/EC
Directive 2011/62/EU amending Directive 2001/83/EC, the so-called “falsified medicines directive”, introduces EU-wide rules for the importation of active substances. According to this, active substances shall only be imported if, inter alia, the active substances are accompanied by a written confirmation from the competent authority of the exporting third country which confirms that the standards of good manufacturing practice and control of the plant manufacturing the exported active substance are equivalent to those in the Union. The template for this written confirmation is set out in annex of the document which was published first in July 2012 and has been revised in January 2013. This document has been allocated to Part III of the EU GMP Guide.

C.8.5.1 Importation of Active Substances for Medicinal Products for Human Use; Questions and Answers
In parallel with the publication of the above mentioned template for the “written confirmation”, the European Commission published a Q&A-document on this topic. This document sets out frequently-asked “questions and answers” regarding the new rules for the importation of active substances for medicinal products for human use. The views expressed in this questions and answers document are not legally binding. This document which was published first in July 2012 has been updated twice and is now available as Version 3.0 as of January 2013.

C.14 Guidelines on Good Distribution Practice of Medicinal Products for Human Use
On 8 March 2013 the European Union published the Guidelines on Good Distribution Practice of Medicinal Products for Human Use in its Official Journal. These guidelines lay down appropriate tools to assist wholesale distributors in conducting their activities and to prevent falsified medicines from entering the legal supply chain. The final version shows some modifications compared to the draft guideline. The GDP Guideline will enter into force on 8 September 2013.

Chapter E ICH Guidelines

E.10.1 Quality Implementation Working Group on Q8, Q9 and Q10: Questions & Answers (R4)

In order to facilitate the implementation of the Q8/Q9/Q10 guidelines, the ICH Experts have developed a series of Q&As. In the current version (R4) a new question was added in section 2.1 “Design Space”, concerning the evaluation of outer limits of the Design Space during validation.

E.10.2 ICH Quality Implementation Working Group: Points to Consider (R2); ICH-Endorsed Guide for ICH Q8/Q9/Q10 Implementation

The ICH Quality Implementation Working Group (Q-IWG) has prepared “Points to Consider” covering topics relevant to the implementation of ICH Q8(R2), Q9 and Q10, which supplement the existing Questions & Answers (chapter E.10.1) and workshop training materials already produced by this group. They should be considered all together. The “Points to Consider” are based on questions raised during the ICH Q-IWG training workshop sessions in the three regions. The “Points to Consider” are not intended to be new guidelines, but to provide clarity to both industry and regulators and to facilitate the preparation, assessment and inspection related to applications filed for marketing authorizations.

E.11 ICH Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

This guideline describes approaches to developing and understanding the manufacturing process of the drug substance, and also provides guidance on what information should be provided in Module 3 of the Common Technical Document (CTD). It addresses aspects of development and manufacture that pertain to drug substance, including the presence of steps designed to reduce impurities. In addition, ICH Q11 provides further clarification on the principles and concepts described in ICH Guidelines on Pharmaceutical Development (Q8(R2)), Quality Risk Management (Q9) and Pharmaceutical Quality System (Q10) as they pertain to the development and manufacture of drug substance. This guideline is applicable to drug substances as defined in the Scope sections of ICH Guidelines Q6A and Q6B, but might also be appropriate for other types of products following consultation with the appropriate regulatory authorities. The guideline does not apply to contents of submissions during the clinical research stages of drug development.

Chapter F PIC/S Guidelines

F.13 PIC/S PI 037-1 Recommendation: A Recommended Model for Risk-Based Inspection Planning in the GMP Environment

The purpose of this PIC/S Recommendation is to provide a simple and qualitative Quality Risk Management tool that may be of use to Inspectorates to prioritize sites for inspection when planning the frequency and scope of GMP Inspections. The document sets out a simple and flexible methodology that is based upon the concept of rating manufacturing sites on the basis of an estimated risk that they may pose to patients, consumers, animals and users of medicines. The methodology also takes into account the risk to product quality. The document provides a simple two-page quality risk management worksheet that is designed to be completed by Inspectors immediately following an inspection at the site. The approach pre-supposes that every manufacturer will be inspected at least once every three years.

F.14 PIC/S PI 038-1 Aide-mémoire: Assessment of Quality Risk Management Implementation

The purpose of this PIC/S Aide-mémoire is to assist GMP inspectors in the assessment of QRM implementation in industry during regulatory inspections. Parts of this document may also be useful (with suitable modification) during other GxP inspections where similar principles of QRM also apply. QRM aspects should be an integrated part of the planning and content of all GMP inspections (including for final products as well as for active pharmaceutical ingredients). The existence of this separate Aide-Memoire document does not suggest that specific inspections for QRM systems are performed.

F.15 Questions & Answers Document regarding Distribution Activities for Active Pharmaceutical Ingredients (APIs)

The document is intended to provide guidance to inspectors when inspecting areas relating to two topics:

  • Supply Chain & Distribution and
  • Repackaging & Relabelling operations.

This list of Questions and Answers were agreed by inspectors of the PIC/S Expert Circle of APIs at a meeting in Dublin, Ireland in May 2010.

F.16 PIC/S PI 030-1 Aide-mémoire: Inspection of Active Pharmaceutical

Ingredients It is recognised that due to their background and experience the majority of GMP inspectors are more familiar with the inspection of finished products. Therefore, to assist inspectors not specialised in the inspection of API manufacturers this document has been developed to provide training and guidance for the preparation and performance of such inspections. This Aide-Mémoire should also contribute to a harmonised approach for inspections of API manufacturers between the different PIC/S Members.

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