Destin A. LeBlanc

Cleaning Validation Technologies

Technical Consulting Services

MARCH 1998

Do pharmaceutical manufacturers need to have written procedures for preventing growth of objectionable microorganisms in drug products not required to be sterile? What does "objectionable" mean, anyway?

Reference: 21 CFR sections 211.113(a) Control of Microbiological Contamination, and 211.111 Time limitations on production [subpart F- Production and Process Controls]

Yes, the CGMP regulations do require these written procedures. 21 CFR 211.113(a) specifies that appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, be established and followed. This means that even though a drug product is not sterile, a firm must follow written procedures that proactively prevent contamination and proliferation of microorganisms that are objectionable.

The meaning of "objectionable" has several facets that need to be evaluated on a case by case basis by each drug manufacturer. The primary meaning relates to microbial contaminants that, based on microbial species, numbers of organisms, dosage form, intended use, patient population, and route of administration, would adversely affect product safety. Of course, most objectionable would be organisms that pose a threat of patient infection or mortality.

Microorganisms may be "objectionable" by virtue of other problems. For example, microbial content that adversely affects product stability, would be objectionable. Likewise, microorganisms that react with, or potentially damage the integrity of, the container closure system (fermentation creating gaseous pressures that explode a container would be an extreme, though legitimate, example), would be objectionable. Similarly, microbial content that interferes with analytical methods, or active ingredient bioavailability, would be objectionable.

For new drugs, the above considerations will likely have been addressed during the new drug review process and may result in microbial specifications for the end product.

Establishing production time limits is an example of a control to prevent objectionable microorganisms. Per 21 CFR 211.111, when appropriate, time limits for the completion of each phase of production must be established and followed. Where a firm finds it necessary to hold a bulk topical or liquid product for several months until it is filled, the firm might establish a holding time limit to prevent microbial build up that would be objectionable. Validation and control over microbial content of purified water systems used in certain topical products are also examples of such procedures.