An Overview of cGMP Policies for Quality Management

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Over the last 25 years there have been fewer FDA inspections and significant changes in government regulations and drug manufacturing processes. With technological advances in pharmaceutical sciences and manufacturing technologies, a risk-based approach to regulation and efforts towards global harmonization, the new regulatory initiatives for FDA compliance will impact greatly.

The guiding principles behind the implementation and FDAs initial actions to initiate GMP reappraisal include - Guiding Principles

• Risk-based orientation - Although, the FDA has been implementing risk-based programs, a more systematic and rigorous risk-based approach to cover all pharmaceutical products and production will be developed. The FDA must provide the most effective public health protection, by matching its level of effort against the magnitude of risk
• Science-based policies and standards - Advances in pharmaceutical sciences and manufacturing technologies over the last two decades have been incorporated in an ongoing manner into FDA's approach to product quality regulation. But the fundamental nature of these advances dictates a thorough evaluation of the science base, to ensure product quality regulation, incorporate up-to-date science, and encourage further advances in technology
• Integrated quality systems orientation - Over the past decade, various innovative approaches have been developed towards manufacturing quality, and these principles will be evaluated for applicability. cGMP requirements and related pre-approval requirements will be evaluated according to applicable principles, and interaction of the pre-market CMC review process along with the application of cGMP requirements will also be evaluated as an integrated system
• International cooperation - FDA will collaborate with other regulatory authorities worldwide, since globalization of pharmaceutical manufacturing requires a global approach to regulation
• Strong Public Health Protection - FDAs achievement in regulating drug product manufacturing for public health protection will get strengthened by these initiatives. It will not interfere with the strong enforcement of existing regulatory requirements, even as examinations and revisions are ongoing for these programs.

Review of warning letters
The FDA general counsel has begun reviewing all warning letters for potential legal problems; since this will help identify possible program inconsistencies and resolve those before warning letters are issued. Also FDA centers provide scientific and technical review of all drug cGMP warning letters issued from field offices. Since innovative manufacturing and control technologies are adopted in the pharmaceutical industry, it is important that FDA regulate them in a consistent way but the center's review of warning letters will help assure that FDA responds to any deficiencies in a consistent manner as well.

21 CFR Part 11 Implementation
CDER (Center for Drug Evaluation and Research) will have the lead responsibility for implementing 21CFR Part11 and the responsibility will be shifted from ORA (Office Of Regulatory Affairs) to CDER. FDA is embarking on a re-examination of part 11 as it applies to all FDA regulated products and may revise provisions of part 11 as a result of that re-examination. The draft guidance explains that while this re-examination is under way, they intend to exercise enforcement discretion with respect to certain part 11 requirements.

Discussion
FDA will meet with manufacturers, pharmaceutical scientists, and other involved groups to discuss scientific concerns and explore innovative approaches.

Dispute resolution
FDA plans to develop a technical dispute resolution process consisting of technical experts who will participate in an ongoing forum for addressing manufacturing concerns and perceived inconsistencies between centers. This transparent process will be easier to understand and use. In addition, it will make it easier to raise scientific and technical issues early on to avoid misunderstandings and reduce inconsistent agency action. In addition, sharing the outcome of technical and scientific issues/disputes should provide greater clarity about regulatory requirements and facilitate the development and revision of guidance documents. Further, dissemination of the results, both internally and externally, should preclude future disputes on the same and related subjects.

Manufacturers can improve production processes
The FDA will encourage manufacturers to improve production processes by reviewing manufacturing changes that require the FDA's prior review and approval. They also aim to expand the use of comparability protocols and other procedures that help document product quality and safety that reduce FDA oversight.

Improving plant-inspection processes
In February 2002, CDER's systems-based GMP inspection pilot program was expanded to cover International and US drug establishment inspections. The GMP inspection program was designed to enhance oversight of manufacturer's quality control systems, and required that inspections focus on a few key production systems to determine whether the operation was under control.

Since FDA is expected to explore additional ways of improving manufacturing oversight, it was proposed that CDER drug product specialists accompany field inspection teams. This was very particular in the case of visits to sites that produced innovative products or those that had experienced manufacturing difficulties. FDA plans to enhance the operations of Team Biologics (FDA established framework for a partnership between ORA and CBER (Center for Biologics Evaluation and Research)), and future initiatives include the establishment of dedicated cadres of pharmaceutical inspectors similar to Team Biologics. Also a special field force assigned to pharmaceutical inspections trained extensively about guidance policies and better equipped to handle more complex or problematic products and organizations.

Enhance FDA expertise
The FDA seeks to enhance its expertise by training of agency staff on new scientific approaches and innovative pharmaceutical manufacturing technology. They will also hire more employees with expertise in pharmaceutical engineering and industrial pharmacy, and leverage expertise from external sources.

Other Initiatives

The "Pharmaceutical cGMPs for the 21st Century" initiative will include additional intermediate and long-term steps.

The initiative is being overseen by an agency steering committee with representatives from the Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), Center for Veterinary Medicine (CVM), Office of Regulatory Affairs (ORA), and the Office of the Commissioner (OC). Janet Woodcock, M.D., Director of CDER, is the chairperson of the steering committee.

According to Dr. Woodcock, "FDA expects to complete and publish a comprehensive implementation plan for this cGMP initiative by mid-year. These initial accomplishments are the first steps toward achieving FDA's goals for a 21st-century regulatory system for pharmaceutical manufacturing designed to protect the public health and to ensure that safe and effective drugs are available to the American public."

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