E7-23271. Current Good Manufacturing Practice; Amendment of Certain Requirements For Finished Pharmaceuticals; Withdrawal

AGENCY:

Food and Drug Administration, HHS

ACTION:

Proposed rule; withdrawal.

SUMMARY:

The Food and Drug Administration (FDA) is announcing the withdrawal of a proposed rule published in the Federal Register of May 3, 1996 (61 FR 20103) (the May 1996 proposed rule). The May 1996 proposed rule would have amended certain requirements of the current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. These proposed changes would have clarified certain manufacturing, quality control, and documentation requirements and would have updated the requirements for process and methods validation. In light of more recent scientific and technical advances and evolving quality systems and risk management concepts, FDA concludes that, at this time, it is appropriate to withdraw the May 1996 proposed rule and newly evaluate the issues raised in that proposal.

DATES:

The proposed rule is withdrawn on December 4, 2007.

FOR FURTHER INFORMATION CONTACT:

Mary Malarkey, Center for Biologics Evaluation and Research (HFM-600), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-6190, or

Dennis Bensley, Center for Veterinary Medicine (HFV-140), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-827-6956, or

Frederick Blumenschein, Center for Drug Evaluation and Research (HFD-326), Food and Drug Administration, 11919 Rockville Pike, Rockville, MD 20852, 301-827-9022.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of May 3, 1996 (61 FR 20103), FDA proposed to amend certain requirements of the CGMP regulations for finished pharmaceuticals in parts 210 and 211 (21 CFR parts 210 and 211) to clarify certain manufacturing, quality control, and documentation requirements so that the regulations would more accurately reflect the prevailing CGMP. FDA received approximately 1,500 comments on the proposed rule. (See section III of this document, Comments on the May 1996 Proposed Rule).

After publication of the May 1996 proposed rule, FDA began to reconsider its approach to regulation of CGMP, consistent with changes occurring in other industries and in other countries. This change in approach is summarized in the following paragraphs.

In August 2002, FDA announced a significant new initiative to enhance and modernize regulation of pharmaceutical manufacturing quality, the Pharmaceutical CGMPs for the 21st Century initiative (21st Century initiative). As a part of the 21st Century initiative, FDA created a CGMP Harmonization Analysis working group to analyze internal and external CGMP requirements, including those related to quality systems. The working group performed a formal analysis of parts 210 and 211 compared with other regulations, such as the FDA Medical Device Quality System Requirements, the FDA Food Hazard Analysis and Critical Control Points requirements, and the drug GMPs of the European Union, to identify the differences and consider the value of adding or changing the current regulations in light of these more recently developed and related product manufacturing standards.

Based on the working group's analysis, the agency decided that a different approach to revising the CGMP regulations was appropriate, and has decided to withdraw the proposed rule.

II. New Approach to Revising FDA's CGMP Regulations

The emphasis of the new approach to CGMP arising from the 21st Century Initiative will be to encourage timely detection of and response to emerging adverse trends or indications that product quality has been compromised, to provide further clarity and modernize the regulations, and to harmonize various aspects of parts 210 and 211 both internationally and with other agency regulations.¹

The agency has determined that the current CGMP regulations (parts 210 and 211) provide a degree of flexibility that will permit the agency to continue to modernize its approach to regulation of CGMP. The agency has also concluded that, as stated in the final report on the 21st Century initiative, given this new approach to regulation of pharmaceutical CGMP, it would be preferable to revise the CGMP regulations in an incremental fashion, rather than using the comprehensive approach taken in the May 1996 proposed rule. After careful consideration, FDA concludes that at this time, it is appropriate to withdraw the May 1996 proposed rule and newly evaluate the issues raised in that proposal in the context of more recent scientific and technical advances and quality systems and risk management concepts.

We plan to revise the CGMP regulations using a more incremental approach. As part of the FDA's incremental approach to revising our CGMP regulations, we are publishing a direct final rule (and a companion proposed rule) elsewhere in this issue of the Federal Register that will, when finalized, clarify and modernize certain provisions in parts 210 and 211. That direct final rule and proposed rule include some of the minor changes to CGMP that were originally proposed in 1996.

III. Comments on the May 1996 Proposed Rule

FDA received approximately 1,500 comments on the May 1996 proposed rule from 116 pharmaceutical companies, attorneys, consultants, trade associations, and generic companies. The most significant topics on which FDA received comments are summarized as follows:

• Approximately 298 comments addressed the proposed new section on process validation (§ 211.220). The volume and variety of comments and suggestions indicated to FDA that the new section, as proposed, did not provide the clarification intended.
• Approximately 102 comments were directed at the proposed changes to § 211.110 on sampling and testing of in-process materials and drug products, which would have added new in-process sampling and validation requirements with respect to blend uniformity. The bulk of these comments questioned the need for additional testing and sampling requirements in § 211.110, because other sections of the current rule already require scientifically sound sampling plans and representative samples.
• Approximately 112 comments discussed proposed revisions to § 211.192 on the production, control, and laboratory review, and investigation of discrepancies. The May 1996 proposed rule required written procedures to be established for the review of certain records and investigation of unexplained discrepancies. Many of these comments recommended that these investigations and reviews should be used to proactively prevent (potential) future problems rather than being used only to retroactively identify manufacturing discrepancies.
• A number of comments to the rule were submitted by the compressed medical gas industry, which communicated concerns regarding the applicability to the compressed medical gas industry of the proposed changes to CGMP.
• Approximately 70 comments were received regarding the proposed new § 211.240 on control of chemical and physical contaminants. Many of the comments stated that the rule should be revised to better describe how contaminants will be identified and to provide allowances for threshold levels or limits of contaminants.

Overall, the comments were constructive, informative, and addressed nearly every area of the May 1996 proposed rule. Although we do not plan to publish specific responses to each of these comments, we will take these comments into account as we proceed to make incremental changes to parts 210 and 211.

IV. Withdrawal of the Proposed Rule

For the reasons described in this document, FDA is withdrawing the proposed rule published on May 3, 1996 (61 FR 20103).

Dated: November 26, 2007.

Jeffrey Shuren,

Assistant Commissioner for Policy.

Footnotes

1. See Pharmaceutical CGMPs for the 21st Century—A Risk Based Approach; Final Report, September, 2004; available at http://www.fda.gov/​cder/​gmp/​gmp2004/​GMP_​finalreport2004.htm.