日本药局方无菌制剂的微生物评估-2222

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Microbiological Evaluation of Processing Areas for SteriFra Baidu biblioteke Pharmaceutical Products
This chapter describes the methods for the control and evaluation of microbial contamination in areas used for the processing of sterile pharmaceutical products. Such processing areas are classified into critical areas and clean areas according to the required levels of air-cleanliness. A critical area is a defined space in which the airborne particulate and microorganism levels are controlled to meet grade A. The cleanliness requirements for such a space extend to the surfaces of the facilities and equipment which form or are located within the space, as well as to the supplied raw materials, chemicals, water, etc. Environmental conditions, such as temperature, humidity, and air pressure, are also controlled in this space when required. A clean area is a controlled space such that the levels of contaminants (particulates and microorganisms) in air, gases and liquids are maintained within specified limits, which are less stringent than those of grade A. When sterile pharmaceutical products are manufactured, the environment, facilities/equipment, and personnel should be routinely monitored to ensure appropriate microbiological control in the processing areas. The detection of microorganisms should be performed under normal operational conditions, using an appropriate sampling device, according to an environmental control program established previously. The sampling, cultivation, counting, and evaluation methods for airborne microorganisms, as well as those found on surfaces, should also be chosen appropriately, depending on the monitoring purpose, monitoring items, and microorganisms being detected. Sampling devices, measurement methods, media, culture conditions, frequency of monitoring, and recommended limits for environmental microorganisms shown in this chapter are for information only, and are not requirements. Definitions For the purposes of this chapter, the following definitions apply. (i) Processing areas: Areas in which actions such as cultivation, extraction/purification, weighing of raw materials, washing and drying of containers and stoppers, preparation of solutions, filling, sealing and packaging are performed, including the gowning area. (ii) Action levels: Established microbial levels (and type of microorganisms, if appropriate) that require immediate follow-up and corrective action if they are exceeded. (iii) Alert levels: Established microbial levels (and type 1.
JP XVI
Table
General Information / Microorganisms
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3 Acceptance criteria for crude drugs and crude drug preparations Category 1 Category 2 (CFU/g or CFU/mL) (CFU/g or CFU/mL) 107 104 105 103 103 Not detected Not detected
exhaustive and for a given preparation it may be necessary to test for other micro-organisms depending on the nature of the starting materials and the manufacturing process. If it has been shown that none of the prescribed tests will allow valid enumeration of micro-organisms at the level prescribed, a validated method with a limit of detection as close as possible to the indicated acceptance criterion is used. In addition to the micro-organisms listed in Table 2, the significance of other micro-organisms recovered should be evaluated in terms of: ( i ) the use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract); ( ii ) the nature of the product: does the product support growth, does it have adequate antimicrobial preservation? (iii) the method of application; (iv) the intended recipient: risk may differ for neonates, infants, the debilitated; ( v ) use of immunosuppressive agents, corticosteroids; (vi) 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 the interpretation of microbiological data. For raw materials, the assessment takes account of processing to which the product is subjected, the current technology of testing and the availability of materials of the desired quality. Acceptance criteria are based on individual results or on the average of replicate counts when replicate counts are performed (e.g. direct plating methods). When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows: —101 CFU: maximum acceptable count ＝ 20, —102 CFU: maximum acceptable count ＝ 200, —103 CFU: maximum acceptable count ＝ 2000, and so forth. Acceptance criteria for crude drugs Target limits of microbial contamination for crude drugs and crude drug preparations are shown in Table 3. Category 1 includes crude drugs and crude drug preparations which are used for extraction by boiling water or to which boiling water is added before use. Category 2 includes crude drugs which are taken directly without extraction process and
directly consumed crude drug preparations containing powdered crude drugs. In this guideline, enterobacteria and other gram-negative bacteria, Escherichia coli, Salmonella, and Staphylococcus aureus are mentioned as specified micro-organisms, but other micro-organisms such as certain species of Bacillus cereus, Clostridia, Pseudomonas, Burkholderia, Asperigillus and Enterobacter species are also necessary to be tested depending on the origin of raw materials for crude drugs or the preparation method of crude drug preparations.
Micro-organisms Aerobic bacteria Molds and yeasts Enterobacteria and other gram-negative bacteria Escherichia coli Salmonella Staphylococcus aureus
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102 Not detected