REGULATORY COMPLIANCE GUIDE SERIES (GxP Guides)

Excerpt of Good Manufacturing Practice Guide

This Guide analyzes the contents of the current versions of the Good Manufacturing Practice (CGMP) rules and guidances laid down by the US, the European Union (EU), Canada, and Japan, the guidelines published by the World Health Organization (WHO), and the International Conference on Harmonization (ICH).

The regulations and guidelines outlining GMP originated with the Food and Drug Administration (FDA) of the US and have been in operation in their current form since 1978. Other countries, including Canada, Japan, Australia, Switzerland and the members of the European Union, have published similar codes, empowered by national regulations. In 2002, however, FDA announced a review of current GMP regulations with the aim of bringing compliance into the 21st century. Two years later, in September 2004, the Agency issued its Final Report on the GMP Initiative entitled Pharmaceutical cGMPs for the 21st Century – A Risk-based Approach. This defined a quality systems model intended to enable manufacturers to establish better control over their manufacturing processes and better compliance with the GMP rules. This approach was formalized by the issue of the ICH Guidance Q10, Pharmaceutical Quality System, in 2008 and its adoption by FDA in 2009. Eventually, the FDA expects to modify the Code of Federal Regulations (CFR) to reflect this new approach to quality management in pharmaceutical manufacturing.

Throughout the texts of the GMP Rules, Regulations and Guidelines published by the various regulatory authorities, the requirement that procedures, processes and methods be written down is a recurring theme, so that comprehensive documentation of the means and the records of manufacture and testing of a specific drug product exist. This requirement often includes the statement, “these procedures shall be followed”. Thus the creation of standard operating procedures (SOP), and their observation, is a GMP legal requirement. This Guide provides standard formats for this type of documentation. The writing of clear, easily followed SOPs is an art which must be acquired by those responsible for this task, so assistance in that area is offered in this guide. A list of the minimum set of SOPs needed in the average GMP facility is given. It is derived directly from the sections list of the main US GMP regulation, so as to ensure that all procedures required to be written are covered.

The most critical areas of GMP compliance, as they have been identified by regulatory authorities worldwide, are validation, records, environmental monitoring, equipment failures and failures to conduct adequate investigations of out-of-specification results and deviations. The validation concept has been extended beyond that of validating processes to ensuring that test methods used to determine critical characteristics of the drug are validated. Also, the regulations governing the manufacture of investigational products for clinical testing are requiring validation of facilities and critical processes such as sterilization and viral clearance.

Validation therefore lies at the heart of the application of GMP to drug manufacturing. The Guide deals exhaustively with this topic. Examples are given that serve to illustrate the types of problem that may be encountered in cleaning, process and test method validation, with suggested ways to resolve these problems. The examples deal with systems and equipment that are used in the manufacture of many drug types, but especially biopharmaceuticals, which may present more difficulties to the validation engineer than synthetic drugs.

The chapters of this Guide dealing with compliance take their order of contents from the content pages of the US Code of Federal Regulations #21CFR210-211—the principal GMP rules, and 21CFR600, the general regulations for the production of biologicals. Each topic is covered in turn, with emphasis being placed on the most critical requirements.

Although it is not strictly a GMP topic, the Guide includes information on the ICH Guideline covering the preparation of the ICH “Common Technical Document” (CTD). This was introduced in 2001 and has been adopted by all partners in ICH, as well as Canada, Australia and certain European countries not part of the European Union. Previous to the adoption of the CTD, all countries had their own format for new drug applications and a company seeking to register a product for sale in more than one would be required to submit the application in each country’s format, thus leading to considerable duplication of effort, with a corresponding waste of time, energy and money. In the US, the Code of Federal Regulations 21CFR314 contains rules on the content and format of new drug applications (NDAs). On the adoption of the CTD, FDA published a “strong recommendation” that all NDAs, abbreviated NDAs (ANDAs) and Biological License Applications (BLAs) should be in the CTD format, effective July, 2003. The intention of the CTD guidelines is to create a common format for the presentation of all technical information which must appear in submissions for approval to market a drug and to have this format acceptable by all partners to ICH. The Guide explains how this format is used in practice to present the manufacturing and testing data generated under GMP.

All manufacturers of pharmaceutical products, biologics, diagnostics and devices controlled by the FDA and similar overseas authorities are subject to facility inspections, both before approval of a new product and routinely thereafter. In addition, the manufacturer is now required to perform regular self-inspections to ensure that GMP compliance is current throughout the facility. This Guide provides a set of forms suitable for such self-inspections, using as a format the FDA’s “Six Systems” approach. There are also recommendations for dealing with external inspections, at the planning, implementation and follow-up stages. There are sections dealing with the key factors of the inspection of all types of manufacturing facilities, including instructions for staff behavior and the handling of official citations and warning letters.

In order to ensure the maximum utility of this Guide, numerous references to Web sites, publications and conferences specializing in GMP compliance and training are provided at the end.

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