Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach
A science and risk-based approach to product quality regulation incorporating an integrated quality systems approach



FDA oversees the quality of drug products* using a two-pronged approach involving review of information submitted in applications as well as inspection of manufacturing facilities for conformance to requirements for current Good Manufacturing Practice (cGMP). These two programs have served the country well by helping to ensure the quality of drug products available in the US. Now, as we approach the 25th anniversary of the last major revision to the drug cGMP regulations, it is time to step back and evaluate the currency of these programs so that:

To these ends, FDA is undertaking an initiative, "Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach."

Merging Science-Based Risk Management with an Integrated Quality Systems Approach

Over the last two decades, significant changes in the environment of pharmaceutical regulation have occurred and have resulted in incremental adjustments in FDAs regulatory approach to product quality. These changes include:

The cumulative impact of these changes has been greater than the sum of the parts, and warrants a systematic reappraisal of FDAs approaches to product quality regulation. The following principles will guide implementation of the reappraisal:

Risk-based orientation In order to provide the most effective public health protection, FDA must match its level of effort against the magnitude of risk. Resource limitations prevent uniformly intensive coverage of all pharmaceutical products and production. Although the agency has been implementing risk-based programs, a more systematic and rigorous risk-based approach will be developed.

Science-based policies and standards Significant advances in the pharmaceutical sciences and in manufacturing technologies have occurred over the last two decades. While this knowledge has been incorporated in an ongoing manner into FDAs approach to product quality regulation, the fundamental nature of the changes dictates a thorough evaluation of the science base to ensure that product quality regulation not only incorporates up-to-date science, but also encourages further advances in technology. Recent science can also contribute significantly to assessment of risk.

Integrated quality systems orientation Principles from various innovative approaches to manufacturing quality that have been developed in the past decade will be evaluated for applicability, and cGMP requirements and related pre-approval requirements will be evaluated according to applicable principles. In addition, interaction of the pre-market CMC review process and the application of cGMP requirements will be evaluated as an integrated system.

International cooperation The globalization of pharmaceutical manufacturing requires a global approach to regulation. FDA will collaborate with other regulatory authorities, via ICH and other venues.

Strong Public Health Protection The initiative will strengthen the public health protection achieved by FDAs regulation of drug product manufacturing and will not interfere with strong enforcement of the existing regulatory requirements, even as we are examining and revising our approach to these programs.

To accomplish the reappraisal, FDA will carry out the following broad actions:


The following immediate steps are planned:

Intermediate Steps

Long term Steps


Current regulations (21 CFR Parts 210, 211, 600 and 610) appear to provide a degree of flexibility to allow the agency to shift the emphasis to a science-based, risk management approach. However, an evaluation of the comments from the May 1996 proposed drug cGMP amendments will continue and consideration will be given to revising these regulations and others (e.g., 21 CFR 11) in the future. In addition, efforts currently underway to revise existing regulations (e.g., 21 CFR 600-610) to allow for more flexibility will continue.