FDA's Pharmaceutical Quality Initiatives: Implementation of a Modern Risk-based Approach - Pharmaceutical Technology

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FDA's Pharmaceutical Quality Initiatives: Implementation of a Modern Risk-based Approach
The US Food and Drug Administration announced its Pharmaceutical GMPs for the 21st Century initiative six years ago. This article reports on the outcome of a recent workshop on this topic and the action plan set forth.

Pharmaceutical Technology

Pharmaceutical Quality Initiatives Workshop, 2007

In early 2006, under the auspices of the CPQ, a workshop planning committee was established with key leaders from the pharmaceutical industry and FDA. Industry representatives encompassed a broad range of expertise and experience in the fields of drug, biologic, and biotech discovery, manufacturing, GMPs, and quality assurance. FDA representatives included key leaders from diverse pharmaceutical quality programs (GMP, compliance, new drug, biologic and generic quality assessment, and postmarketing surveillance). The planning committee's goal was to develop a workshop program to highlight the agency's pharmaceutical quality initiatives and continue forging a common vision for a scientific risk-based regulatory process. As noted, the workshop, co-sponsored by AAPS and ISPE and held Feb. 28-Mar. 2, 2007 provided a forum for regulated industry, other stakeholders, and the public to comment on progress made in implementing the intiatives and to assess future needs and implementation challenges. The following sections summarize the work of 10 breakout sessions held during the three-day workshop. The reports were prepared and presented by industry lead moderators based on discussions with participants from industry, FDA, and the public. These reports are not endorsed by FDA and do not represent FDA's position on issues discussed.

Quality-by-design breakout reports CMC pilot program. The concept of QbD, while not new to the pharmaceutical industry, has presented implementation opportunities and challenges to both industry and regulators. To facilitate QbD implementation for innovator products, FDA established the CMC pilot program in 2005 as part of the Pharmaceutical Quality Assessment System. The information obtained from this pilot has enabled FDA and industry to interact and identify key challenges and opportunities tied to QbD implementation. This breakout session focused on lessons learned, to date, from the pilot program. Participants discussed best practices, regulatory submissions, and review of QbD-based applications. They reached consensus on a number of topics, as outlined below.

Type of QbD information:
  • Knowledge-rich submissions are the backbone of QbD submissions
  • The focus of the submission should be on the content and not on the volume of information provided
  • A summary of the risk assessment performed on the product/process/facility as related to the product profile (safety, efficacy, and quality) should be included
  • A clear rationale for the identification of critical quality attributes and critical process parameters as well as noncritical process parameters should be included
  • Design of experiments (DOE) to understand the process and/or product should be performed and provided as should information regarding edge of failures, if available
  • Further efforts toward the characterization of active pharmaceutical ingredients (APIs) and raw materials and the impact of their variability on the process and/or product performance should be studied and provided
  • A control strategy based on product and/or process understanding should be developed and provided. The control strategy should then be managed using a plant quality system.

Presentation of QbD information:

  • Information can be provided to the regulatory agency within the current ICH common technical document, specifically in the quality format section and in various sections where logical and with proper links as needed.
  • Industry and regulatory authorities emphasized the importance of a pharmaceutical development report that is rich in scientific content.

Challenges and opportunities. Workshop participants expressed that there is a fine balance between information necessary for the submission versus that which can be retained at the manufacturing site. In addition, there was concern about getting more questions related to QbD, which may result in approval delays. Regulatory authorities expressed the desire for a comprehensive quality overall summary (QOS) that would be systematic and rich in technical content. They also emphasized that a mechanism should be available for providing QbD information for currently marketed products.

Some participants were not certain whether regulatory flexibility would truly result from a QbD approach. A business case, therefore, may be difficult to establish for some companies or for some products.

In terms of experience coming out of the CMC pilot program, breakout session participants discussed the necessity for some form of a CMC regulatory agreement or CMC postapproval management plan (PMP) to demonstrate that there is a clearly defined regulatory benefit for industry to adopt the QbD approach (see section on "Regulatory Agreement" for more details). Noted benefits of the program, to date, included enhanced communication between FDA and industry, quick resolution of questions, a multi-disciplinary approach to review, and greater information-sharing.

To facilitate QbD implementation, participants suggested other mechanisms. Specifically, for the implementation of QbD in programs submitted outside the CMC pilot program umbrella, there was consensus around the need for discussions between regulatory authorities and the sponsors during development of the program. Suggested timeframes for such discussions were the end of Phase-2 or mid-Phase 3.

Risk-based flexible regulatory approaches and regulatory agreements. QbD approaches to pharmaceutical development have been advocated by FDA and industry. Submission of such enhanced QbD information in a new drug application (NDA) or biologic license application (BLA) toward the establishment of design space will enable the applicant to propose flexible regulatory approaches for postapproval manufacturing changes. A resultant risk-based regulatory flexibility can be expected such that movement within the approved design space will not require traditional postapproval regulatory submissions. This workshop breakout session focused on possible flexible regulatory approaches, ways to document this flexibility, and types of information to be submitted. Companies and regulators involved with the CMC pilot program shared their experiences during the session.


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