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1、医疗器械的灭菌 微生物方法 第一部分:产品上微生物总数的估计目 次前言引言1范围2规范性引用文件-3术语和定义4总则5产品单元的选择6技术的选择7技术选择8技术的使用附录A(资料性附录) 产品上微生物总量的估计指南附录B(资料性附录) 微生物学技术确认方法指南-附录c(资料性附录)参考文献医疗器械的灭菌微生物学方法第1部分:产品上微生物总数的估计1范围ISO11737的本部分说明了应用于估计医疗器械、半成品或包装上活的微生物总数的一般标准。这种估计包括两个方面:微生物的计算和定性。注1:微生物特性的本质和限度以生物负载的预期使用目的为基础。本部分没有规定计算和鉴定病毒性或原生动物污染的要求。
2、注2:此外,本部分不用于对海绵状脑病的起因进行切除或检测,如:疯牛病、羊搔痒症及CJD。本部分不适用于对生产医疗器械的环境中微生物的监控。2.规范性引用文件 下列文件是应用本部分不可缺少的,中的条款通过GBT 19973的本部分的引用而成为本部分的条款。凡是注日期的引用文件,其现行版本版适用于本部分,凡是不注日期的引用文件,其最新版本适用于本部分。ISO 10012, 测量管理系统.测量方法和测量设备的要求ISO 13485:2003, 医疗器械 质量管理体系 用于法规的要求ISO/IEC 17025:2005, 检测和校准实验室资格的一般要求 3术语和定义 下列术语和定义适用于本部分。31
3、生物负载bioburden一件产品和或无菌阻隔系统上存活微生物的总数。ISO/TS 11139:2006, 定义2.23.2纠正 Correction 消除已发现的不合格所采取的措施。注:纠正可连同纠正措施一起实施(3.4).ISO 9000:2005, 定义 3.6.63.3correction factor 修正系数补尝从产品和/或培养基上无法完全洗脱的微生物的数值 3.4纠正措施 corrective action为消除已发现的不合格或其他不期望情况的原因所采取的措施。注 1一个不合格可以有若干个原因注 2采取纠正措施是为了防止再发生,而采取预防措施(3.9)是为了防止发生。注3纠正(3
4、.2)和纠正措施是有区别的ISO/TS 11139:2006, 定义 2.83.5培养条件 culture conditions促进微生物发芽、生长和/或繁殖所采用的生长培养基和培养方法的组合。注培养方法可包括温度、时间和其他规定用于培养的条件。ISO/TS 11139:2006, 定义2.103.6设定 establish通过理论评价确定,并经实验工作证实。 ISO/TS 11139:2006, 定义 2.173.7医疗器械 medical device制造商的预期用途是为下列一个或多个特定目的用于人类的,不论单独使用或组合使用的仪器、设备、器具、及其、用具、植入物、体外试剂或校准物、软件、
5、材料或其他相似或相关物品。这些目的是: 疾病的诊断、预防、监护、治疗或者缓解; 损伤的诊断、监护、治疗、缓解或者补偿; 解剖或生理过程的研究、替代、调节或者支持; 支持或维持生命; 妊娠控制; 医疗器械的消毒 通过对取自人体的样本进行体外检查的方式来提供医疗信息。其作用于人体体表或体内的主要设计作用不是用药理学、免疫学或代谢的手段获得,但有可能有这些手段参与并起一定辅助作用。注: 本定义由全球协调工作组制定(GHTF)。ISO 13485:20033.8微生物表征 microbial characterization 把微生物归类成主要类型的一般方法。注:列如:可根据采用的选择性培养基、菌落或
6、细胞结构形态,染色特性或其他特性,组合成各个类型。ISO/TS 11139:2006, 定义 2.253.9预防措施 preventive action为消除潜在的不合格或其他潜在不期望情况的原因所采取的措施。注 1一个潜在不合格可以有若干个原因。.NOTE 2采取预防措施是为了防止发生,采取纠正措施 (3.4) 是为了防止再发生。ISO 9000:2005, 定义3.6.43.10产品 product过程的结果注 用于灭菌的产品是实际的,是指原材料、半成品、部件和医疗保健产品。ISO 9000:2005, 定义 3.4.23.11公认的菌种保存库 recognized culture col
7、lection根据“国际公认微生物菌种保存专利与法规”布达佩斯公约建立的国际菌种保存机构。ISO/TS 11139:2006, 定义 2.383.12 回收率recovery efficiency对某一特定的技术从产品或/和培养基上获取微生物的能力的测定值。3.13样品分额 sample item portion SIP医疗器械用于试验的部分。3.14规定 specify在批准件范围内详细约定的内容。ISO/TS 11139:2006, 定义 2.423.15确认 validation为设定某可持续生产出符合预定技术规格的产品的工艺,获得、记录和整理结果的文件化程序。注5:在生物负载判定中,“
8、过程”是试验方法,“产品”是试验结果。对生物判定技术的确认包括一系列调查,来测定试验方法的有效性和重现性。ISO/TS 11139:2006, 定义 2.554质量管理体系基础4.1文件4.1.1 应规定生物负载的判定程序。4.1.2 ISO 11737本部分使用的文件和记录应经制定人员审核及批准(see 4.2.1)。文件和记录应按ISO 13485 或 ISO/IEC 17025要求进行受控.4.1.3应保存原始观察的记录、导出数据和最终报告。记录应包括取样、制备和试验人员的识别。4.1.4计算和数据转化应进行适当的校核。4.2 管理职责4.2.1 ISO 11737本部分描述的贯彻和执行
9、的职责和职权应该规定。按照ISO 13485 或 ISO/IEC 17025要求将责任分派给能胜任的人员。4.2.2如果ISO 11737的这部分的要求由几个独立的质量管理系统组织承担,应规定每部分的职责和职权。4.2.3 应具备规定试验的校核和测量所需设备的所有项目。4.3 产品的实现4.3.1 应规定采购程序。这些程序应符合ISO 13485 或 ISO/IEC 17025要求。4.3.2 符合ISO 13485 或 ISO/IEC 17025 或ISO 10012的要求建立的文件体系,应规定按照ISO 11737本部分的要求所使用的设备,包括用于检测的仪器的校核。4.3.3 应规定生物负
10、载判定(包括适宜的质量试验)所用的材料制备和灭菌方法。4.4 测量、分析和改进不合格品控制应规定检验不合格结果调查、纠正、纠正措施和玉兔方措施的程序,这些程序应符合ISO 13485 或 ISO/IEC 1702要求。5. 产品的选择5.1总则5.1.1 应建立选择和处理判定生物负载产品的程序,以保证这些产品包括包装材料和过程对常规生产具有代表性。5.1.2 如果确定生物负载所用产品是成组的,在一组中产品内含物的基本原理应该被记录(见 4.1.2),基本原理包括确认的标准来自某一组群中选择的一个产品的确定的生物负载,这一组群在整个组群中是有代表性的5.1.3 应考虑做生物负载判定的采样时间,因
11、为生物负载判定会随时间而改变。52样品份额(SIP)假如生物负载被证明均匀地分布在产品上或/和产品内,SIP可以从产品的任意部分挑选。否则SIP应由产品的多部分组成,随便地选择,其制成产品的每种材料适当的代表。如果生物负载的分布已知,那么SIP可以选择产品的一部分,该部分对灭菌过程具有挑战性,SIP能以长度、质量、体积或表面积计算出。表 1 SIP计算举例Basis for SIP产品Surface area表面积Implants (non-absorbable)植入(非吸收的)Mass质量Powders粉末GownsImplants (absorbable)植入(可吸收的)Length长度T
12、ubing (consistent diameter)管(外径一致)Volume体积Fluid in water cup在水杯中的液体)注:如适用,规定灭菌过程的确认和常规控制要求的标准应提供样品份额的适宜性指标。6.1.2Removal of microorganisms 微生物的消除6.1.2.1For an identified product where removal of viable microorganisms is part of the method, the efficiency of removal shall be considered and the outcome
13、s of this consideration recorded (see 4.1.3). Consideration shall, at least, be given to:对于确定的产品消除存活的微生物是一部分方法,应考滤消除的效率和记录的考虑的结果,至少应考虑:a) ability of the technique to remove microorganisms;(见4。1。3),消除微生物技术的能力b) possible type(s) of microorganism and their location(s) on product;微生物的可能类型和在产品上的位置c) effe
14、ct(s) of the removal technique on the viability of microorganisms;对于存活微生物消除技术的效果d) the physical or chemical nature of product under test.在试验状态下产品的物理和化学性质6.1.2.2For an identified product for which removal of viable microorganisms is not part of the method, the efficiency of enumeration of microorgani
15、sms shall be considered and the outcomes of this consideration recorded (see 4.1.3). Consideration shall, at least, be given to:对于确定的产品消除产品上的存活微生物的方法不包括在本部分中,列举微生物的效率应考虑,并且记录考虑的结果(见4。1。3)至少应考虑以下方面:a) possible type(s) of microorganism and their location(s) on product;微生物的类型和在产品上的位置b) the physical or
16、chemical nature of the product to be tested;试验产品的物理、化学性能c) aggregates of cells forming single colonies due to in-situ culturing.在原处培养的单克隆细胞合计6.1.2.3If the physical or chemical nature of product is such that substances can be released that adversely affect either the number or the types of microorgan
17、ism found, then a system shall be used to neutralize, remove or, if this is not possible, minimize the effect of any such released substance. The effectiveness of such a system shall be demonstrated.如果产品的物理和化学状态其物质能被释放出来,反作用在发现的一个或一种类型的微生物上,那么使用中和、消除系统,如果这些是不可能的,那么这种释放的物质的作用应降低到最小化NOTEAnnex B descri
18、bes techniques that may be used to assess the release of microbicidal or microbiostatic substances.附录B描述了用于评定微生物或微生物物质释放的技术6.1.3Culturing of microorganisms微生物的培养Culture conditions shall be selected after consideration of the types of microorganism likely to be present. The results of this considerat
19、ion and the rationale for the decisions reached shall be recorded (see 4.1.2).选择培养条件然后考虑微生物可能存在的类型,考虑的结果和达到结果的基本原理应该纪录(见4.1.2).6.1.4Enumeration of microorganisms微生物列举The technique for enumeration shall be selected after consideration of the types of microorganism likely to be present. The results of
20、 this consideration and the rationale for the decisions reached shall be recorded(see 4.1.2).选择列举的技术然后考虑微生物的类型。考虑的结果和达到结果的基本原理应该纪录(见4.1.2).6.2Microbial characterization of bioburden生物负载的微生物特征6.2.1Appropriate techniques for microbial characterization of bioburden shall be selected.选择生物负载的微生物描述的适当的技术N
21、OTEMicrobial characterization is necessary to detect a change to product microflora that might affect some aspect of the use of the bioburden data (e.g. establishing a sterilization process).微生物的描述是必要的对于发现产品的一个变化的微生物群,那可能影响一些表面的生物负载资料的使用(建立一个灭菌过程)6.2.2Microbial characterization shall be accomplished
22、 using one or more of the following:微生物描述应用一下一个或更多个完成a)staining properties;着色性b)cell morphology;细胞形态c)colony morphology;群体形态d)use of selective culturing;使用的培养方法e)biochemical properties;生物化学性质f)genetic sequence data for which there is an adequate data base.遗传序列资料,对此有适当的资料库7Validation of method for de
23、termining bioburden确定生物负载方法的确认7.1The method for determining of bioburden shall be validated and documented.生物负载的确定方法应被确认和文件化7.2Validation shall consist of the following:确认有以下内容组成a)assessment of the adequacy of the technique for removal of microorganisms from product, if removal is part of the method
24、;从产品上消除微生物的适当的技术评估,如果消除是方法的一部分。b)determination of the recovery efficiency in order that a correction factor be derived;回收率的测定以便于推断纠正因子c) assessment of the adequacy of the enumeration of microorganisms, including culture conditions and microbiological counting techniques;适当的微生物列举评估,包括培养条件和微生物计算技术。d)a
25、ssessment of the suitability of the technique(s) of microbial characterization.微生物表述技术的适宜性评估8Routine determination of bioburden and interpretation of data生物负载的确定程序和数据资料8.1Routine determination of bioburden shall be performed employing documented sampling plan(s) defining sample size and sampling fre
26、quency.生物负载的确定程序应文件规定采样计划,定义样品规格和采样频率。8.2Determination of bioburden shall be performed using a method specified for a product or group of products (see 5.1.2).对于一个产品或一组产品使用规定的方法进行生物负载的确定。8.3Microbial characterization of bioburden shall be performed to a degree dependent on the purpose for which the
27、data derived from the determination of bioburden are to be used (see 6.2).进行生物负载的微生物描述度量依赖于来源于使用生物负载的确定的推断数据If, on microbial characterization, isolates are recovered that are not part of the normal microflora, consideration should be given to assessing the properties of these isolates.假如,涉及微生物描述,隔离种
28、群被恢复,那不是普通的生物群,应考虑这些隔离种群的性质评估。8.4If bioburden data are to be used to establish the extent of treatment of a sterilization process, any requirements applicable to the use of bioburden data, specified in the appropriate standard for the development, validation and routine control of the sterilization
29、process, shall be met.若生物负载的资料用于建立灭菌程序涉及的程度,一些必要的条件应用于使用的生物负载数据,在适当的标准中规定灭菌过程的发展、确认和常规控制,应满足.8.5Acceptable limits for bioburden on or in a medical device shall be specified. This specification shall be based on previously generated data. If these limits are exceeded, action shall be taken (see 4.4).
30、可接受的在医疗器械上或内的生物负载的限度应规定,这个规定基于前期产生的资料。如果这些限度超标,应采取措施(见4.4)8.6Data derived from determination of bioburden obtained over a period of time shall be used to identify trends. Acceptable limits shall be reviewed and revised as necessary.通过前期获得的生物负载测定的推断资料被应用于确定趋势,观察可接受的界限并进行必要的修正。8.7The application of st
31、atistical methods to define sample size, sampling frequency and/or acceptable limits shall conform to ISO 13485.应用统计方法说明样品大小,取样频度或/和接受限度符合ISO 13485.。9Maintenance of the method of determination of bioburden生物负载确定方法的维护9.1Changes to the product and/or manufacturing process产品和/或生产流程的改变Changes to product
32、 and/or manufacturing processes shall be reviewed to determine whether they are likely to alter bioburden. The results of the review shall be recorded (see 4.1.2). If there is potential for alteration of bioburden, specific determinations of bioburden shall be performed to evaluate the extent and na
33、ture of any change.评价产品和/或生产流程的改变,确定是否可能是变化的生物负载。评价的结果应记录(见4.1.2),如果有可能改变生物负载,进行明确的生物负载确定,并估计变化的程度和种类。9.2Changes to the method of determination of bioburden生物负载确定方法的变化Any change to a routine method of bioburden determination shall be assessed. This assessment shall include:生物负载确定的常规方法的任何改变应评定,这种评定包括
34、:a) evaluation of the effect of the change on the outcome of determination;评价于确定结果的改变的影响b) establishment of the recovery efficiency of the method following the change.建立以下变化方法的回收率NOTEThe assessment of the change could indicate that the previous validation and recovery efficiency are still applicable
35、.变化的评价指出先前的确认和回收率仍然适用。9.3Revalidation of the method of determination of bioburden生物负载确定方法的再确认The original validation data (see 7.2) and any subsequent revalidation data shall be reviewed at specified intervals in accordance with a documented procedure. The extent to which revalidation is to be under
36、taken shall be determined. The outcome of the review and any revalidation undertaken shall be recorded (see 4.1.3).确认的原始资料(见7.2)和一些后来再确认资料应按照文件规定的时间间隔再评价。进行再评价的范围应确定,评价的结果和进行得再确认应记录(见4。1。3)Annex A(informative)Guidance on determination of a population of microorganisms on product确定产品上微生物数量的指南NOTEFor
37、ease of reference, the numbering in this annex corresponds to that used in the normative part of this partof ISO 11737.为了参考简单,本附录的编号与ISO 11737用于本部分的相符合A.1 Scope概述This annex contains guidance on the implementation of the requirements specified in this part of ISO 11737. The guidance given is not inte
38、nded to be exhaustive, but to highlight important aspects to which attention should be given.本附录包含ISO 11737本部分规定要求的执行,所给指南没有规定是详尽的,但关心的最重要的方面应给出。Methods other than those given in this annex may be used, but these alternative methods should be demonstrated as being effective in achieving compliance w
39、ith the requirements of this part of ISO 11737.除了本附录给出的方法被使用外,对于其他可供选择的方法应被论证This annex is not intended as a checklist for assessing compliance with the requirements of this part of ISO 11737.本附录不包含评价符合本部分ISO 11737要求的清单 。A.2 Normative references参考标准The requirements of documents included as normative
40、 references are requirements of this part of ISO 11737 only to the extent that they are cited in a normative part of this part of ISO 11737; the citation may be to an entire standard or limited to specific clauses.参考文件包含参考标准作为本部分ISO 11737要求,只是本部分ISO 11737标准引用的程度;该引用可能是标准的全部也可能限于规定的条款A.3 Definitions定
41、义No guidance offered.没有指南提供A.4 Quality management system elements质量管理体系要素NOTEIt is not a requirement of this part of ISO 11737 to have a full quality management system, but the elements ofa quality management system that are the minimum necessary to control the determination of bioburden as used in
42、the validation and monitoring of medical devices to be sterilized are normatively referenced at appropriate places in the text(see, in particular, Clause 4). Attention is drawn to the standards for quality management systems (see ISO 13485) thatcontrol all stages of production or reprocessing of med
43、ical devices. National and/or regional regulations for the provision of medical devices might require a complete implementation of a full quality management system and the assessment of that system by a third party.A.4.1 Documentation文件In ISO 13485, the requirements in the documentation section rela
44、te to the generation and control of documentation (including specifications and procedures) and records.Computers may be used in laboratories for direct and indirect collection, processing and/or storage of data. Both the hardware and software used for such applications should be controlled.ISO 1173
45、7-1:2006(E)The computer system in use should be identified, both in terms of hardware and software, and any changes ineither of these aspects should be documented and subject to appropriate approval.If calculations are performed by electronic data processing techniques, the software (e.g., spreadsheet calculations) should be valid