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1、GUIDE TO INSPECTIONS OF MICROBIOLOGICAL PHARMACEUTICAL QUALITY CONTROL LABORATORIES Note: This document is reference material for investigators and other FDA personnel. The document does not bind FDA, and does not confer any rights, privileges, benefits, or immunities for or on any person(s). I. INT
2、RODUCTION The Guide to the Inspection of Pharmaceutical Quality Control Laboratories provided very limited guidance on the matter of inspection of microbiological laboratories. While that guide addresses many of the issues associated with the chemical aspect of laboratory analysis of pharmaceuticals
3、, this document will serve as a guide to the inspection of the microbiology analytical process. As with any laboratory inspection, it is recommended that an analyst (microbiologist) who is familiar with the tests being inspected participate in these inspections.II. MICROBIOLOGICAL TESTING OF NON-STE
4、RILE PRODUCTSFor 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 provides little specific guidance other than The significance of mi
5、croorganisms in non-sterile 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.
6、 For example natural plant, animal and some mineral products for Salmonella, oral liquids for E. Coli, topicals for P. aeruginosa and S. Aureus, and articles intended for rectal, urethral, or vaginal administration for yeasts and molds. A number of specific monographs also include definitive microbi
7、al 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
8、 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 reporte
9、d by a hospital in Massachusetts several years ago. Therefore, each company is expected to develop microbial specifications for their non-sterile products. Likewise, the USP Microbial Limits Chapter provides methodology for selected indicator organisms, but not all objectionable organisms. For examp
10、le, 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 th
11、e 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 o
12、f 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 L
13、imits section of the Compendia.The USP currently provides for retests in the Microbial Limits section however there is a current proposal to remove the retest provision. As with any other test, the results of initial test should be reviewed and investigated. Microbiological contamination is not even
14、ly dispersed throughout a lot or sample of product and finding a contaminant in one sample and not in another does not discount the findings of the initial sample results. Retest results should be reviewed and evaluated, and particular emphasis should be placed on the logic and rationale for conduct
15、ing the retest.In order to isolate specific microbial contaminants, FDA laboratories, as well as many in the industry, employ some type of enrichment media containing inactivators, such as Tween or lecithin. This is essential to inactivate preservatives usually present in these types of product and
16、provides a better medium for damaged or slow growing cells. Other growth parameters include a lower temperature and longer incubation time (at least 5 days) that provide a better survival condition for damaged or slow-growing cells.For example, FDA laboratories use the test procedures for cosmetics in the Bacteriological Analytical Manual (BAM), 6th Edition, to identify contamination in non-sterile drug products. This testing includes an enrichmen
