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10.4 MICROBIOLOGICAL ATTRIBUTES OF NON-STERILE PHARMACEUTICAL PRODUCTS

      Few raw materials used in producing pharmaceutical products are sterile as received, and special treatment may be required to render them microbiologically acceptable for use. Strict adherence to effective environmental control and sanitation, equipment cleaning practices, and good personal hygiene practices in pharmaceutical manufacture is vital in minimizing both the type and the number of micro-organisms.

      Monitoring, in the form of regular surveillance, should include an examination of the microbiological attributes of Pharmacopoeial articles and a determination of compliance with such microbiological standards as are set forth in the individual monographs. It may be necessary also to monitor the early and intermediate stages of production, with emphasis being placed on raw materials, especially those of animal or botanical origin, or from natural mineral sources which may harbour objectionable micro-organisms not destroyed during subsequent processing. It is essential that ingredients and components be stored under conditions designed to deter microbial proliferation. Microbiological purity of the raw materials as well as manufacturing conditions, including water used for the production, should be such a degree that the microbiological purity requirements for the final product i.e. the pharmaceutical preparation, are observed to fulfill the requirements for good manufacturing practices (GMP).

      The nature and frequency of testing vary according to the product. Monographs for some articles require freedom from one or more species of selected indicator micro-organisms such as Salmonella spp., Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. For some articles, a specific limit on the total aerobic microbial count (TAMC) and/or the total combined yeasts and moulds count (TYMC) is set forth in the individual monograph. In these cases a requirement for freedom from specified indicator micro-organisms is also included. The significance of micro-organisms in a nonsterile pharmaceutical product should be evaluated in terms of the use of the product, the nature of the product, and the potential hazard to the user. Also taken into account is the processing of the product in relation to an acceptable quality for pharmaceutical purposes.

      It is suggested that certain categories of products be tested routinely for total microbial count and for specified indicator microbial contaminants, e.g. natural plant, animal, and some mineral products for Salmonella species; oral solutions and suspensions for E. coli ; articles applied topically for P. aeruginosa and S. aureus ; and articles intended for rectal, urethral, or vaginal administration for yeasts and moulds.

      Definitive microbial limits (stipulated micro-organisms and/or counts) are incorporated into specific monographs on the basis of a major criterion, i.e. the potential of the stipulated micro-organisms and/or counts, and of any others that they may reflect, to constitute a hazard in the end product. Such considerations also take into account the processing to which the product components are subjected, the current technology for testing, and the availability of desired quality material. Any of these may preclude the items from specific requirements in the “Microbial Limit Tests” (Appendix 10.2). Regardless of such preclusion, it remains essential to apply strict good manufacturing practices to assure a lowest possible load of microorganisms. “Limits for Microbial Contamination” (Appendix 10.5) is also set forth to control microbial purity in non-sterile pharmaceutical products. For herbal remedies or herbal drug preparation described in Table 2, the same criteria are applicable to both crude drugs and their preparations.

      The relevant tests for determining the total aerobic microbial count and the total combined yeasts and moulds count, and for detection and identification of designated species are given in the “Microbial Limit Tests” (Appendix 10.2). For reliable results, the personnel responsible for the conduct of the test should have specialized training in microbiology and in the interpretation of microbiological data.