The Harmonization of the Microbial Limits Tests - Pharmaceutical Technology

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The Harmonization of the Microbial Limits Tests

Pharmaceutical Technology

The importance of identifying all isolates from either or both Total Plate Count testing and enrichment testing will depend upon the product and its intended use. Obviously, if an oral solid dosage form such as a tablet is tested, it may be acceptable to identify isolates when testing shows high levels. However, for other products such as topicals, inhalants or nasal solutions where there is a major concern for microbiological contamination, isolates from plate counts, as well as enrichment testing, should be identified.

Why is microbial contamination of concern? To understand, we must consider the history on this matter. As early as 1942, USP had a test for the "Bacteriological Examination of Gelatin" (12). But, most nonsterile medications in the United States were not required to assay for microbiological quality attributes until the introduction of the "Microbial Limits Tests" in 1970 (13). In the late 1960s, several outbreaks of disease were traced back to pathogen-contaminated medications, which prompted increased attention to the microbial content of nonsterile drugs (14). Later in the 1980s, a series of articles described contamination by P. cepacia (currently Burkholderia cepacia) (15, 16) and its survival in disinfectants (17–21). This concern led to the addition of requirements in the 21 CFR to ensure that no objectionable organisms are in product released to market.

The compendial concern

As early as 1982, the USP is on record for verifying that the demonstration of "absence of objectionable microorganisms" is not the intent of the chapter. In a one-page Stimuli to the Revision Process (22), the microbiology committee of the time states:

The tests described in the Microbial Limits Tests ‹61› were not designed to be all-inclusive, i.e., to detect all potential pathogens. To accomplish this, an extensive text on laboratory detection of microorganisms would be required. The procedures in USP were designed to detect the presence of specific "index" or "indicator" organisms. Nevertheless, the present chapter does not preclude the detection of Ps. Cepacia - the organism requires subsequent differentiation. The chapter does not provide specific methods for this, nor does it provide procedures for detecting thousands of other potentially pathogenic organisms. Individual monographs include requirements for limits on total aerobic counts and/or absence of one or more of the four selected "indicator" organisms. The chapter on Microbial Limits Tests provides methods to assure that one may test for those microbial requirements in the individual monographs.

Against this background, we now examine the short harmonized Chapter ‹1111›, which consists of two tables and a few paragraphs. A significant passage in this chapter reads:

In addition to the microorganisms listed in Table I [Table I is entitled "Acceptance Criteria for Microbiological Quality of Nonsterile Dosage Forms"], the significance of other microorganisms recovered should be evaluated in terms of the following:

  • The use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract).
  • The nature of the product: does the product support growth? does it have adequate antimicrobial preservation?
  • The method of application.
  • The intended recipient: risk may differ for neonates, infants, the debilitated.
  • Use of immunosuppressive agents, corticosteroids.
  • The presence of disease, wounds, organ damage.

Where warranted, a risk-based assessment of the relevant factors is conducted by personnel with specialized training in microbiology and in the interpretation of microbiological data. For raw materials, the assessment takes account of the processing to which the product is subjected, the current technology of testing, and the availability of materials of the desired quality.

The harmonized chapter does not provide instruction beyond this level, but do not overlook this "new" recommendation. Merely showing the absence of specified organisms is not sufficient to demonstrate the microbial quality of a nonsterile product.


The US Pharmacopeia and the US Food and Drug Administration are in agreement about the question of the microbial quality of nonsterile pharmaceuticals: the product must be safe for use. The internationally harmonized chapters provide a strong framework for this assurance.


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