The Harmonization of the Microbial Limits Tests - Pharmaceutical Technology

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The Harmonization of the Microbial Limits Tests


Pharmaceutical Technology


USP ‹1111› "Microbial Quality": a new compendial consideration of "other organisms"


Table IIIb: Absence of specified microorganisms.
Chapter ‹1111› "Microbial Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use" is a relatively short section that has a significant impact. For the US reader, the allowance for twice the specification in observed results is significant. But, this is not the major change.


Table IIIc: Absence of specified microorganisms.
Before the introduction of the harmonized Chapter ‹1111›, USP was only interested in specified organisms. These organisms are specified in monographs. But, FDA has been concerned about objectionable organisms. The "Control of Microbiological Contamination (a)" section of 21 CFR 211.113 states, "Appropriate written procedures, designed to prevent objectionable microorganisms on drug products not required to be sterile, shall be established and followed." This is reinforced by 21 CFR 211.165 which states in the section "Testing and release for distribution... (b) There shall be appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms."


Table IV: Nutritive, selective, and indicative properties of media.
Thus, industry has had a problem. The USP monograph for a product (as provided in the current National Formulary [NF]) may require the "Absence of Pseudomonas aeruginosa." A test in the "Microbial Limits" chapter demonstrates the absence of P. aeruginosa. Although this test may be needed to demonstrate compliance with the monograph requirements laid out in the National Formulary, it does not meet FDA's concern that all microorganisms in a nonsterile product should be acceptable to the product and the target population (i.e., are not "objectionable").

The FDA concern

If a company's product approval to market submission states it will test the finished product by the "Microbial Limits Tests," FDA will enforce the good manufacturing practices (GMPs) requirement that it must do so. This is purely a GMP concern. Nonetheless, the agency has been absolutely clear about its concern over objectionable microorganisms in the product and that testing to the USP chapter might be necessary, but it is not sufficient to demonstrate acceptable microbial quality. In fact, in the 1993 instructional guide for inspections of quality-control microbiology laboratories (11), FDA points out several issues that have occurred by particular contaminants of nonsterile medicines that compromised patient health. The document notes that the USP provides methods for specific organisms, but not all objectionable organisms and FDA strongly recommends all organisms be identified to determine which are acceptable and which are objectionable. This section of the guidance concludes:


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