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This article first appeared in the PMF Newsletter of June, 2006 and is protected by copyright to PMF. It appears here with permission.
We have to note from the outset that USP and FDA frequently are interested in the same thing. From the vantage point of USP, there is a need to have a test for sterility, for antimicrobial efficacy, for Antibiotic/ Vitamin Potency, for Bacterial Endotoxin, for Microbial Limits etc. The need for these tests is not driven by any concern over “Good Manufacturing Process” (GMP). It is governed by the USP monographs found in the National Formulary (NF). If there is a monograph that requires a test for antimicrobial efficacy, then chapter <51> Antimicrobial Effectiveness Test” is the referee test used to demonstrate that characteristic.
FDA has similar, but separate concerns. Where the requirements are identical, the referee chapters in USP (those numbered under <1000>) are enforced. However, there are situations where the FDA’s concerns are not covered by a USP referee test method. One such situation is with the CFR requirement that medicines be “free of objectionable microorganisms.” 21CFR 211.113 under the section “Control of microbiological contamination. (a)” 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 “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.”
So, here we have a problem. The USP monograph for a product (as provided in the current National Formulary) may require “Absence of Pseudomonas aeruginosa.” There is a test in the Microbial Limits chapter to demonstrate the absence of Pseudomonas aeruginosa. However, although this test may be required to demonstrate compliance with the monograph requires as laid out in NF it does not meet the FDA concern that any organism in the final product be acceptable to the product and the target population (i.e. are not “objectionable”).
FDA will enforce the GMP requirement that if your product approval to market submission contained a statement that you would test the finished product by the Microbial Limits Tests that in fact you must do that. This is purely a GMP concern. However, the Agency has been absolutely clear on the concern over objectionable microorganisms in the product, and that fact that testing to the USP chapter might be necessary, but it is not sufficient to demonstrate microbial quality. In fact, in the 1993 instructional guide for inspections of QC Microbiology Labs (1) the FDA states:
“For a variety of reasons, we have seen a number of problems associated with the microbiological contamination of topical drug products, nasal solutions and inhalation products. The USP Microbiological Attributes Chapter <1111> provides little specific guidance other than “The significance of microorganisms in nonsterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential hazard to the user.” The USP recommends that certain categories be routinely tested for total counts and specified indicator microbial contaminants. For example natural plant, animal and some mineral products for Salmonella, oral liquids for E. Coli [sic], topicals for P. aeruginosa and S. Aureus [sic], and articles intended for rectal, urethral, or vaginal administration for yeasts and molds. A number of specific monographs also include definitive microbial limits.
As a general guide for acceptable levels and types of microbiological contamination in products, Dr. Dunnigan of the Bureau of Medicine of the FDA commented on the health hazard. In 1970, he said that topical preparations contaminated with gram negative organisms are a probable moderate to serious health hazard. Through the literature and through our investigations, it has been shown that a variety of infections have been traced to the gram negative contamination of topical products. The classical example being the Pseudomonas cepacia contamination of Povidone Iodine products reported by a hospital in Massachusetts several years ago.
Therefore, each company is expected to develop microbial specifications for their nonsterile products. Likewise, the USP Microbial Limits Chapter <61> provides methodology for selected indicator organisms, but not all objectionable organisms. For example, it is widely recognized that Pseudomonas cepacia is objectionable if found in a topical product or nasal solution in high numbers; yet, there are no test methods provided in the USP that will enable the identification of the presence of this microorganism.
A relevant example of this problem is the recall of Metaproterenol Sulfate Inhalation Solution. The USP XXII monograph requires no microbial testing for this product. The agency classified this as a Class I recall because the product was contaminated with Pseudomonas gladioli/cepacia. The health hazard evaluation commented that the risk of pulmonary infection is especially serious and potentially life-threatening to patients with chronic obstructive airway disease, cystic fibrosis, and immuno- compromised patients. Additionally, these organisms would not have been identified by testing procedures delineated in the general Microbial Limits section of the Compendia. . . .
Microbiological testing may include an identification of colonies found during the Total Aerobic Plate Count test. Again, the identification should not merely be limited to the USP indicator organisms.
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 this a concern? To understand this we have to go back to the 1970’s. USP had a test for the “Bacteriological Examination of Gelatin” as early as 1942 (2). However, most non-sterile medications in the US were not required to assay for microbiological quality attributes until the introduction of the Microbial Limits Tests in 1970 (3). In the late 1960’s several outbreaks of disease were traced back to pathogen contaminated medications, and this prompted increased attention to the microbial content of non-sterile drugs (4). Later in the 1980’s there was a series of articles appearing in the literature describing contamination by P. cepacia (currently Burkholderia cepacia) (5, 6) and its survival in disinfectants(7 – 11). This lead to the addition of requirements in the 21 CFR to ensure that there are not objectionable organisms in product released to market (see above). Add to this the knowledge that the USP “Absence of Pseudomonas aeruginosa” assay will not identify presence of B. cepacia (as discussed).
The USP is on record as early as 1982 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 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…
In conclusion, the Microbial Attributes and Microbial Limit Tests chapters accomplish their intent. If a manufacturer needs particular tests for any specific organisms that are potential problems in a process or a final product, the quality control microbiologist can provide specific detection procedures. Many such procedures are published in several laboratory texts on microbiology.”
On the question of the microbial quality of non-sterile pharmaceuticals, the USP and the FDA are in agreement – the product must be safe for use. The NF monograph requirements for absence of specific organisms is a minimal requirement, and should not be taken as proof that the product is suitable for sale from a microbiological perspective.
The manufacturer is responsible for the quality and safety of the product marketed, and it is the clear expectation of FDA (as described in CFR) that this will include a determination of the microbial safety – i.e. the “absence of objectionable microorganisms” from the product. These positions have been publicly stated for decades and should not come as a surprise to anyone. The harmonized microbial limits tests only address the “absence of specified microorganisms” and leave the determination of the “absence of objectionable microorganisms” in the capable hands of each company’s appropriately educated and well-trained microbiology group.
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