A Guide To Good Manufacturing Practices 2nd Edition
A Guide To Good Manufacturing Practices 2nd Edition
Product Type: Market Report
Published Date: November 2004
Published By: Drug & Market Development
Page Count: 386
Order Code: R294-0117
Print Copy $395
This Guide analyzes the contents of the latest versions, as of September 2004, of the Good Manufacturing Practice (GMP) rules laid down by the USA, Canada, Japan, and the European Union (EU), and the guidelines published by the World Health Organization (WHO) and the International Conference on Harmonization (ICH). It provides pharmaceutical and biological companies with assistance in complying with these rules. It is addressed particularly to the smaller companies, perhaps those with their first drug product, facing up to this additional challenge to their capabilities. Although manufacturers of medical devices are also subject to GMP compliance, these rules are outside the scope of this Guide.
The regulations and guidelines outlining GMP originated with the Food and Drug Administration (FDA) of the USA, 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. The codes are empowered by national regulations. Moves to harmonize these codes internationally have taken place, under ICH auspices. However, a recent review of the contents of the regulations from major players in the pharmaceutical industry concluded that there were far more similarities than differences in these rules. To this end, the ICH decided in the year 2000 that the only new GMP guidance that was needed was for the manufacturers of active pharmaceutical ingredients in bulk?the existing regulations for finished products were adequate. 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 Two years later, in September 2004, the Agency issued a draft guidance defining a quality systems model which is intended to enable manufacturers to establish better control over their manufacturing processes and, it is hoped, better compliance with the GMP rules. Eventually, FDA expects to modify the Code of Federal regulations to reflect this new approach to quality management in pharmaceutical manufacturing.
The objective of all GMP is to manufacture drug products that are fit for their intended use. Added to this concept, now, is that of "quality by design", i.e., that Quality should be built into the product, and testing alone cannot be relied on to ensure product quality. In order to achieve this goal, each step of the manufacturing process must be controlled, so as to maximize the probability that the finished product will meet all quality and design specifications. Compliance with GMP regulations is legislated to be the responsibility of the entire company and especially the top management. Only by having senior management initiate a full commitment to quality can a functional quality system be put in place.
Stated very simply, the cost of non-compliance with GMP is loss of business. In the case of drugs and biologicals, however, another, much more serious, consequence may be injury to a recipient of the product or even loss of life. It was the occurrence of such tragedies that resulted in the creation, first of the Food and Drug laws and then the "G-Laboratory-P", GMP and "G-Clinical-P" regulations. A manufacturer is required to report immediately to the regulatory authorities any serious adverse reaction reported from the field. Such reports may trigger an extensive review of the manufacturer's production and testing records for that product. Even without such alerts, the regulatory authorities will inspect and monitor the operations of all approved manufacturers of prescription drugs on a regular basis. Priority is given to those products which are considered to pose a high risk, e.g.: sterile, parenteral drugs. If serious non-compliance is demonstrated by such inspections, the authorities can require the recall of a single batch of a product, of all the product on the market, or even the closure of the plant, by revocation of its manufacturing license, until the company can demonstrate that the non-compliant processes have been corrected. The cost of a single product recall has been estimated at one to five million dollars.
Throughout the texts of the GMP Rules, Regulations and Guidelines published by the various regulatory authorities appears the requirement that procedures, processes and methods be written down, so that comprehensive documentation of the means and the records of manufacture and testing of a specific drug product will exist. This requirement often includes the statement, "these procedures shall be followed". Thus the creation of standard operating procedures, 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 is offered in this text. 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 also 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 manufacture. 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 USA Code of Federal Regulations #21CFR21?the principal GMP rule, 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. Where the regulations of other countries differ from those of the USA, this is explained at the end of each section.
Although it is not strictly a GMP topic, the Guide includes information on the new ICH Guideline covering the preparation of the ICH "Common Technical Document" (CTD). This was introduced as topic M4 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, e.g., Switzerland. 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 USA, 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. Eventually, this recommendation will become a legal requirement, as it already is in the other ICH partners. The intention of the M4 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 new "Six Sigma" 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 facility, including instructions for staff behavior and the handling of official citations and warning letters.
In order to ensure the maximum utility of this Guide, it contains the current texts of the major GMP regulations from the USA, Canada, Europe, Japan and the ICH. Numerous references are also given to useful Web sites, publications, conferences and consulting firms specializing in GMP compliance and training.
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