EP 5.1.4 非无菌制剂和药用物质的微生物质量标准(中英文).doc

01/2011:501045.1.4. MICROBIOLOGICAL QUALITY OF NON-STERILE PHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE (1)非无菌制剂和药用物质的微生物质量The presence of certain micro-organisms in non-sterile preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient.在非无菌制剂中如果存在某些微生物，可能会降低或抑制药物的治疗活性，可能会对病人健康有潜在不良影响。Manufacturers therefore have to ensure a low bioburden of finished dosage forms by implementing current guidelines on Good Manufacturing Practice during the manufacture, storage and distribution of pharmaceutical preparations.因此，生产商应在药品生产、存贮和销售过程中遵守现行GMP指南，来保证制剂的微生物在一个较低的水平。Microbial examination of non-sterile products is performed according to the methods given in general chapters 2.6.12 and 2.6.13. Acceptance criteria for non-sterile pharmaceutical products based upon the total aerobic microbial count (TAMC) and the total combined yeasts/moulds count (TYMC) are given in Tables 5.1.4-1 and 5.1.4-2. Acceptance criteria are based on individual results or on the average of replicate counts when replicate counts are performed (e.g. direct plating methods).非无菌产品微生物检查应依据通则2.6.12和2.6.13中指定的方法进行。非无菌制剂的细菌数（TAMC）和霉菌酵母菌总数（TYMC）可接受标准见表5.1.4-1和表5.1.4-2。可接受标准是基于单个计算结果或多个计数（例如碟式直接计数法）结果的平均值。When an acceptance criterion for microbiological quality is prescribed it is interpreted as follows:可接受标准的解释如下101CFU: maximum acceptable count = 20;101CFU:：最大可接受计数结果=20102CFU: maximum acceptable count = 200;102CFU:：最大可接受计数结果=200103CFU: maximum acceptable count = 2000, and so forth.103CFU:：最大可接受计数结果=2000，依此类推Table 5.1.4.-1 includes a list of specified micro-organisms for which acceptance criteria are set. The list is not necessarily 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.表5.1.4-1包括控制菌清单及其可接受标准。清单并未列出制剂需要检验的全部控制菌，需要检测的菌种业依起始物料和生产工艺而定。Table 5.1.4-1. Acceptance criteria for microbiological quality of non-sterile dosage forms表5.1.4.-1非无菌制剂微生物可接受标准Route of administration给药方式TAMC总细菌计数(CFU/g or CFU/mL)TYMC霉菌和酵母菌总数(CFU/g or CFU/mL)Specified micro-organisms控制菌Non-aqueous preparations for oral use口服非水制剂103102Absence of Escherichia coli (1g or 1 mL)大肠杆菌不得检出（1g或1ml）Aqueous preparations for oral use口服水型制剂102101Absence of Escherichia coli (1g or 1 mL)大肠杆菌不得检出（1g或1ml）Rectal use直肠给药103102Oromucosal use口腔粘膜给药Gingival use齿龈给药Cutaneous use皮肤给药Nasal use鼻给药Auricular use耳给药102101Absence of Staphylococcus aureus (1 g or 1 mL)Absence of Pseudomonas aeruginosa (1 g or 1 mL)金黄色葡萄球菌不得检出（1g或1ml）铜绿假单胞菌不得检出（1g或1ml）Vaginal use阴道给药102101Absence of Pseudomonas aeruginosa (1 g or 1 mL)Absence of Staphylococcus aureus (1 g or 1 mL)Absence of Candida albicans (1 g or 1 mL)铜绿假单胞菌不得检出（1g或1ml）金黄色葡萄球菌不得检出（1g或1ml）白色念珠菌不得检出（1g或1ml）Transdermal patches (limits for one patch including adhesive layer and backing)贴皮给药（限度指一贴，包括贴剂和其贴衬）102101Absence of Staphylococcus aureus (1 patch)Absence of Pseudomonas aeruginosa (1 patch)金黄色葡萄球菌不得检出（1贴）铜绿假单胞菌不得检出（1贴）Inhalation use (special requirements apply to liquid preparations for nebulisation)吸入给药（特殊要求适用于喷雾给药液体制剂）102101Absence of Staphylococcus aureus (1 g or 1 mL)Absence of Pseudomonas aeruginosa (1 g or 1 mL)Absence of bile-tolerant gram-negative bacteria (1 g or 1 mL)金黄色葡萄球菌不得检出（1g或1ml）铜绿假单胞菌不得检出（1g或1ml）胆汁耐受革兰氏阴性菌不得检出（1g或1ml）*Special Ph. Eur. provision for oral dosage forms containing raw materials of natural (animal, vegetal or mineral) origin for which antimicrobial pretreatement is not feasible and for which the competent authority accepts TAMC of the raw material exceeding 103 CFU/g or CFU/mL欧洲药典对含有自然原料（动物、植物或矿物）经过抗微生物前处理的口服制剂的特殊条款不可行，对于这类制剂，有资质的药监当局接受原料TAMC结果超过103CFU/g或CFU/mL104102Not more than 102CFU of bile-tolerant gram-negative bacterial (1 g or 1 mL)Absence of Salmonella (10 g or 10 mL)Absence of Escherichia coli (1 g or 1 mL)Absence of Staphylococcus aureus (1 g or 1 mL)*胆汁耐受革兰氏阴性菌不得过102CFU（1g或1ml）沙门氏菌不得检出（10g或10ml）大肠杆菌不得检出（1g或1ml）金黄色葡萄球菌不得检出（1g或1ml）*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.如果实验表明上述测试无法对上述微生物水平进行有效的计数，则应选择一个经过验证、检测限尽可能接受上述可接受标准的方法In addition to the micro-organisms listed in Table 5.1.4.-1, the significance of other micro-organisms recovered is evaluated in terms of:除了在表5.1.4-1中列出的微生物，应根据以下情况对所发现的其它微生物进行评价Use of the product: hazard varies according to the route of administration (eye, nose, respiratory tract);产品给药途径：危害性根据给药方式不同（眼给药、鼻给药、呼吸道给药）Nature of the product: its ability to support growth, the presence of adequate antimicrobial preservation;产品特性：其是否有助于微生物增长，是否有足够的微生物抑制剂Method of application;使用方法Intended recipient: risk may differ from neonates, infants, the debilitated;目标受者：新生儿、婴儿、体虚者Use of immunosuppressive agents, corticosteroids;免疫抑制剂、糖皮质激素的使用Presence of disease, wounds, organ damage.是否有其它病症、伤口、器官损害Where warranted, a risk-based assessment of the relevant factors is conducted by personnel with specialized training in microbiology and 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.如果可以保证微生物质量，应由经过微生物和微生物数据解释方面专业培训的人员对相关因素进行风险评估。对于原料，评估应考虑产品所经过的处理，现行检测技术和所需质量的物料是否可以获得。Table 5.1.4-2. Acceptance criteria for microbiological quality of non-sterile substances for pharmaceutical us