proposedrevisionin21cfrpart211

The Food and Drug Administration (FDA) is amending certain regulations as the first phase of an incremental approach to modifying the current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. On Dec 4, 2007, the FDA published changes to FDA's drug GMP regulation (Part 211). This is the first step of a phased approach to modernize GMPs. The revised text will be effective from April 17, 2008, if no significant comments are received before February 19, 2008.

Based on the CGMP Working Group’s analysis, FDA decided to take an incremental approach to modifying parts 210 and 211. This is the first increment of modifications to parts 210 and 211

The major highlights for this revision being the following:

A. Plumbing – This rule deletes from § 211.48(a) the current requirement of adherence to a specific U.S. Environmental Protection Agency (EPA) water standard.

B. Aseptic Processing - The amendment to several regulations relates to aseptic processing to clarify the regulatory requirements to reflect currently accepted industry practice as well as, in some cases, to harmonize with international regulatory standards. The revision to § 211.113(b) applies specifically to validation of aseptic processes, but the revisions to the other four sections discussed, to both aseptic and other types of processes and operations. For example - Section 211.67(a) Equipment cleaning and maintenance is being revised to add the phrase ‘‘and/or sterilized’’ after the word ‘‘sanitized’’ in the current regulation. This change updates the terminology to reflect the fact that, in the context of sterile drug products, the appropriate form of sanitization would be sterilization.

(c) Such automated equipment used for performance of operations addressed by §§ 211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the requirements included in those sections for the performance of an operation by one person and checking by another person if such equipment is used in conformity with this section and one person verifies that the operations addressed in those sections are performed accurately by such equipment.

Paragraph (b) of § 211.113 Control of microbiological contamination is being revised to include validation of aseptic processes for drug products that are purported to be sterile. The current regulation mentions only validation of sterilization processes, not aseptic processes.

C. Asbestos Filters –The current regulations require manufacturers, before using asbestos-containing filters, to submit proof to FDA that an alternative filter will or is more likely to result in product contamination. Therefore, §§ 210.3(b)(6) and 211.72 are being revised to remove an outdated regulation permitting limited use of asbestos-containing filters. This revision also provides consistency with international standards. This revision removes from the definition of ‘‘non-fiber releasing filter,’’ the statement that ‘‘All filters composed of asbestos are deemed to be fiber-releasing filters’’; because the revised regulation does not permit any use of asbestos-containing filters. Thus, this sentence is no longer necessary.

D. Verification by second individual. - Under the current CGMP regulations, several regulations include requirements that certain activities be performed by one person and checked as specified by a second person. Section 211.101(c) requires that each container of component dispensed for use in manufacturing be examined by a second person to assure that it was released by the quality control unit, that the weight or measure is correct as stated in the batch production records, and that the containers are properly identified. The others being Section 211.101(d), Section 211.103, Section 211.182 and finally, § 211.188(b)(11) requires that batch production and control records shall include identification of the persons performing and directly supervising or checking each significant step in the operation.

FDA specifically noted that the use of automated systems is permitted under section 211.68 and that the requirement of 211.101 would be met if the second individual verifies that the automated system is working properly. Thus, in this situation, the first individual is replaced by a machine or other automated process, and only one person is necessary to verify that the automated system is functioning as intended.

The revisions will clarify long-standing interpretation and policy that verification by a second individual may not be necessary when automatic equipment is used under § 211.68. Rather, in these situations, only one person is needed to verify that the automated equipment is functioning adequately. In cases where there is an operator for the automated equipment, the verifying individual may be, but is not required to be, the operator. Thus, FDA is amending §§ 211.101(c) and (d), 211.103, 211.182, and 211.188(b)(11) to indicate that the use of automated equipment under § 211.68 may eliminate the need for verification by a second individual and that in those situations only one person is needed to verify that the automated equipment is functioning properly. In addition, section 211.68 is also being amended to provide a consistent clarification of this point.