FDA Changes CGMP Rules (21 CFR 210/211)

In the Federal Register, the FDA informed about changes to the CGMP rules for medicinal products on 8 September 2008. These changes will come into force on 8 December 2008. Next to a summary, the announcement includes a total of seven further parts: The most interesting ones are parts 1 to 3: Background, the summary and the comments on the original draft document with FDA's answers.

In the summary, the FDA announced that the changes are just one part of the entire revision process for updating the CGMP rules. In a later passage, these changes are announced as efforts to harmonise the CGMP rules with other FDA regulations (the text mentions the Quality Systems Regulation for medical devices) and other GMP regulations (explicit mention of EC GMP).

The changes affect mainly aseptic processing, the implementation of the 4-eyes principle, the use of asbestos-containing filters. Minor changes without relevance for the contents complement the main changes mentioned. The part titled "Background" explains the history that led to the now finalised changes. We described this background in detail in the GMP News of 13 December 2007 and 9 April 2008. Apart from few exceptions, the items listed in the latter news (then still published as "proposals") will be implemented after all.

Regarding aseptic manufacture, the following paragraphs have been changed: § 211.113(b) (the changes concern the validation of the aseptic process for the prevention of microbiological contaminations), § 211.67(a) (refers to the sterilisation /sanitisation of equipment), § 211.84(d)(6) (affects the microbiological tests performed prior to the use of primary packaging materials), § 211.94(c) (validation of depyrogenisation of primary packaging materials) and § 211.110(a) (bioburden tests within the framework of in-process controls). Especially the changes to § 211.113(b) are meant to harmonise the FDA requirements with Annex 1 to the EC GMP Guide.

The ban on asbestos-containing filters resulted in changes to §§ 210.3(b)(6) and 211.72. As a reaction to comments on the first revision draft, the passage "the use of an asbestos-containing filter is prohibited" has now been included. Furthermore, the update to the state of the art regarding the loss of fibres in filters and the indication of the pore size reflect.

The changes regarding the implementation of the 4-eyes principle ("verification by a second individual") refer to the use of computerised systems instead of a second pair of eyes. This affects a whole number of paragraphs, e. g. § 211.68 has been extended by a section (c) now allowing the use of a computerised system instead of a second individual. Of course, this also has consequences for other paragraphs requiring this 4-eyes principle: §§ 211.101(c) and (d) (charge-in of components and containers), § 211.103 (calculation of yields), § 211.182, (equipment cleaning and maintenance), § 211.188(b)(11) (batch production and control records). For which reason they will also be adapted.

The "minor changes" concern §§ 211.82(b), 211.84(c)(1) and (d)(3), as well as 211.160(b)(1). The changes serve the purpose of clarification without affecting the contents.

Some of the comments by industry on the original draft and FDA's answers to them that resulted in this final version are also quite interesting. Among other things, the industry reminded the FDA of their fear that the Agency's reviewers and GMP inspectors might lack clarity and consistency in their understanding of the new changes. The FDA replied that it understands this fear and intends to respond to it with adequate training of the group of persons in question.

Four comments prevented among others even the revision of 21 CFR 211.48(a) ("Plumbing"). The original requirement that potable water must be up to EPA (Environmental Protection Agency) standards was intended to be changed in order to harmonise it with other regulations (e. g. those of the EU). The wording should be "safe for human consumption". However, according to the comments, this wording was not prescriptive enough. Within the framework of further updates of the CGMP rules, this question regarding water relating to water qualities used as a component in medicinal products will be taken up again.

The excerpt from the Federal Register can be found here.

Sven Pommeranz
On behalf of the European Compliance Academy (ECA)

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