cGMPs / QRM Process

From Harmonization to Inspections: An FDA Update

A talk with FDA's CDER Office of Compliance's Division of Manufacturing and Product Quality about the state of regulatory harmonization, enforcement, and priorities for the future.

PhM: Looking broadly at ICH, WHO and other efforts, what were the most significant gains seen in harmonizing pharma regulation last year? Please comment on specific programs/progress with the EU and with Japan involving cGMPs and plant inspections? For finished drugs? API's and excipients?

FDA: In June 2009, ICH published ICH Topic Q8, Q9 and Q10, Note for Guidance on Pharmaceutical Development, Quality Risk Management, Pharmaceutical Quality System, Questions and Answers. This document answers questions about the current working procedures of the ICH Quality Implementation Working Group’s (Q-IWG) implementation of the guidelines of Q8, Q9, and Q10.

The Q-IWG is currently developing a training program for workshops that will be held in the three ICH regions that cover the ICH Guidelines Q8, Q9, and Q10. The aim of the workshops is to achieve globally consistent implementation of ICH Guidelines Q8, Q9, and Q10. This training program will consist of case studies representing the four phases of the life cycle of a pharmaceutical product. The workshops are tentatively scheduled for Brussels in June 2010, Washington, D.C. in October 2010, and Tokyo in November 2010.

Under the EMEA/TGA/FDA API Pilot Program, in 2009 the FDA increased collaboration with the European Medicines Agency (EMEA) and Australia’s Therapeutic Goods Administration (TGA) in a number of ways. For example, FDA shared API establishment information with the EMEA and TGA and identified sites of common interest for leveraging or joint inspections. FDA performed joint inspections of API manufacturers—two with EMEA and one with TGA. FDA also conducted four joint inspections of drug product manufacturers with the EMEA in 2009. FDA additionally enhanced our cooperation and leveraging with EMEA and TGA through regularly scheduled teleconferences and sharing of inspectional information.

PhM: Is FDA now officially part of PIC/S? What work is being done to harmonize plant cGMP inspections in order to share data and avoid gathering of redundant information?

FDA: PIC/S has indicated their plan to make a decision on FDA’s membership in 2010. In previous years, the FDA participated in PIC/S annual meetings and working group meetings (including the API expert working group) to discuss topics of mutual interest. Upon admittance, FDA would like to pursue activities with PIC/S that advance harmonization.

PhM: Japan has often seemed to go its own way in clinical and in other areas. Yet, two years ago, its top regulators had affirmed commitment to step up reviews and adapt to global regulations. Has there been any change, and are there plans for increased outreach/collaboration between FDA and Japanese regulatory agencies?

FDA: The U.S. and Japan collaborate closely on quality issues at ICH, including the recent Q8, Q9, and Q10 documents, the Implementation Working Group, and currently on Q11. We will continue to explore further opportunities for collaboration between our regulatory authorities.

PhM: What are the greatest challenges that remain to achieving full harmonization?

FDA: The goals of FDA’s harmonization efforts are to pool regulators’ resources in developing standards for public health protection; enhance global consistency; and minimize impediments to providing safe and effective treatments to patients. Resolving differences in regulatory approaches will be a challenge, but will be optimized if harmonization venues like ICH, PIC/S, and others continue their work on important issues.

PhM: What are your top priorities for this year with regard to harmonization of cGMP-type regulations/inspections?

FDA: FDA will continue its work on updates to the CGMP regulations for finished drug products, which will be in more accord with international regulatory approaches and the medical device QSR system. Regarding inspections, we will continue to collaborate with our global regulatory partners to further enhance cooperation and leveraging.

PhM: Regarding enforcement and compliance, are the pharmaceutical inspectorate training programs being continued?

FDA: Yes. Pharmaceutical Inspectorate (PI) training programs continue. The next PI training course is being held this month (March 2010).

PhM: What steps are being taken to bring inspection and review teams closer?

FDA: We are formalizing our knowledge management relating to product-specific inspections in order to integrate the approach for review, inspection, and compliance evaluation of the manufacturing site. CDER’s Office of Compliance has implemented a formal process, the Knowledge Transfer Program, to share CDER review and GMP knowledge with the Office of Regulatory Affairs inspection team prior to conducting the inspection. This exchange of knowledge includes specific areas of coverage for the pre-approval inspection and may include:

  • evaluation of possible data integrity issues
  • manufacturing process (e.g., proposed batch record), equipment, facility, and scale-up
  • product sensitivities or complexity call for special attention

The transfer may occur via a formal memo, pre-inspection briefing, or CDER participation on the inspection.

PhM: Will process validation guidance be finalized?

FDA: We expect to finalize this guidance in 2010.

PhM: Regarding excipients: While third-party inspections/voluntary standards are being discussed, EU is said to be planning to establish cGMP-type requirements. What is FDA considering?

FDA: U.S. law requires excipient manufacturers and firms that hold excipients to adhere to principles of CGMP. FDA advocates the use of appropriate excipient CGMP standards by qualified auditors, including those that are members of an independently accredited excipient auditing body. It is essential that drug product manufacturer provide oversight that ensures that their excipient suppliers follow CGMP standards and supply consistent materials. Consistent drug product manufacturing and quality depends upon obtaining such high quality materials from qualified manufactures.

Although FDA has not promulgated any explicit regulations directly applicable to excipients, we have used the general principles of drug product CGMP and quality systems approaches to interpret CGMP for excipient manufacturing and distribution. Under the National Technology Transfer and Advancement Act, the FDA may consider any voluntary guideline as a potentially applicable standard. We generally regard established well-accepted voluntary excipient standards such as the IPEC guidelines, as largely providing appropriate advisements. IPEC guidelines are already being applied voluntarily by excipient manufacturers and by drug product manufacturers when auditing excipient manufacturing sites.

To participate in the global drug market, foreign excipient manufacturers should be aware of the need to adopt and follow the same standards as their compliant counterparts, without waiting for regional laws to go into effect.

PhM: Any plans to revise/modernize cGMP requirements or guidance?

FDA: We are developing several guidance documents in the CGMP area, and are hoping to finalize the process validation guidance.

+++Since we last connected with FDA's Compliance Office last year there have been some personnel changes. Former Deputy Director Joe Famulare is since employed at Roche/Genentech, and Jennifer Devine now holds the Deputy Director position.

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