Section Number 部分编号 1. Scope 范围 2. Principle 通则 3. Pharmaceutical Quality System (P QS) 药物质量体系 (PQS) 4. Personnel 人员 5. Premises 设施 6. Equipment 设备 7.

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1 EU GMP Annex 1 附录一 Manufacture of Sterile Medicinal Products 无菌药品生产

2 Section Number 部分编号 1. Scope 范围 2. Principle 通则 3. Pharmaceutical Quality System (P QS) 药物质量体系 (PQS) 4. Personnel 人员 5. Premises 设施 6. Equipment 设备 7. Utilities 公用系统 8. Production and s pecific Technologie s 生产和特定技术 Document map 文件结构 General Overview 概览 Additional areas (other than sterile medicinal products) where the general principle s of the annex can be applied. ( 除了无菌药品以外 ) 其它适用该附录的领域的通则 General principles as applied to the manufacture of medicinal products. 适用于药品生产的通则 Highlights the specific requirements of the PQS when applied to sterile medicinal p roducts. 强调了无菌药品中 PQS 的特定要求 Guidance on the requirements for specific training,knowledge and skills. Also gives guidance to the qualification of personnel. 特定培训知识和技能要求指南, 还有人员资质确认指南 General guidance regarding the specific needs for premises design and also guida nce on the qualification of premises including the use of barrier technology. 关于设施设计的特定需求通用指南, 以及设施确认包括隔离技术应用的指南 General guidance on the design and operation of equipment. 设备设计和运行方面的通用指南 Guidance with regards to the special requirements of utilities such as water, air an d vacuum. 关于公用系统, 如水 空气和真空方面的特殊需求指南 Discusses the approaches to be taken with regards to aseptic and terminal sterilisa tion processes. Also discusses different technologies such as lyophilisation and Bl ow Fill Seal (BFS) where specific requirements may be required. Discusses appro aches to sterilization of products, equipment and packaging components. 讨论了无菌和终端灭菌工艺方面使用的方法, 还讨论了不同技术, 如冻干和吹灌封 (BFS), 可能需要的特殊要求 讨论了药品 设备和包装部件的灭菌方法 9. Viable and non-v This section differs from guidance given in section 5 in that the guidance here appli es to iable environmenta l ongoing routine monitoring with regards to the setting of alert limits and revie wing trend and process monit data. The section also gives guidance on the requirements of Aseptic P rocess Simulation. oring 本部分与第 5 部分的指南有所不同, 本部分适用于在持续的日常监测, 用于警戒限设适宜的环境和不适宜的环境以及过程定以及趋势数据审核 本部分还提供了关于无菌工艺模拟要求方面的指南 监测 10. Quality control ( QC) 质量控制 (QC) 11. Glossary 术语 Gives guidance on some of the specific Quality Control requirements relating to ste rile medicinal products. 给出了与无菌药品有关的一些特定质量控制要求指南 Explanation of specific terminology. 特定术语的解释

3 1 Scope 范围 The manufacture of sterile medicinal products covers a wide range of product types, (sterile active substance through to finished dosage form), batch sizes (single unit to multiple units),processes (from highly automated systems to manual processes), primary packaging materials and technologies (e.g. biotechnology, classical small molecule manufacturing and closed systems). This Annex provides general guidance that should be used for all sterile medicinal products and sterile active substances, via adaption, using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination associated with microbes is prevented in the final product. 无菌药品的生产涵盖多种产品类型,( 从无菌活性成分至最终的制剂成品 ), 批量 ( 从单个单位到多个单位 ), 工艺 ( 从高度自动化系统到人工操作 ), 内包装材料及技术 ( 例如, 生物技术, 小分子生产以及密闭系统 ) 本附录提供了适用于所有无菌药品和无菌活性成分的通用指南, 使用质量风险管理 (QRM) 的原则适当调整, 以确保能够防止最终产品中的微生物 颗粒和与微生物有关的热原污染 The intent of the Annex is to provide guidance for sterile medicinal products. However some of the principles andguidance, such as contamination control strategy, room qualification,classification, monitoring and gowning, may be used to support the manufactureof other products that are not intended to be sterile (such as certain liquids,creams, ointments and low bioburden biological intermediates) but where the controlof microbial, particulate and pyrogen contamination, to reduce it as far aspossible, is considered important. 本附录的目的是为无菌药品提供指导 然而, 有些原则和指导, 例如污染控制策略, 房间确认, 洁净级别, 监测和更衣, 也可被用于支持其他不需要无菌, 但其微生物 颗粒和热原污染的控制被认为很重要的产品的生产, 以尽可能减少它们的污染 ( 例如某些液体制剂, 膏剂, 软膏剂以及低微生物负荷的生物中间体 ) 2 Principle 原则 The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological,particulate and pyrogen contamination. The following key areas should beconsidered: 无菌药品的生产需符合特殊的要求以降低微生物, 颗粒及热原的污染风险 应考虑以下关键区域 : a. Facility, equipment and process design must be optimized qualified and validated according to Annex 11 andannex15 of EU GMP. The use of appropriate current technologies should beimplemented to ensure protection and control of the product from potential extraneous sources of particulate and microbial contamination such aspersonnel, materials and the surrounding environment. 设施, 设备及工艺的设计须按照 EU GMP 附录 11 和附录 15 中的要求进行最有效的确认和验证 应适当应用最新的技术以确保保护和控制产品中潜在的外来颗粒和微生物的污染, 例如人员, 物料及周边环境 b. Personnel must have appropriate skills, training and attitudes with a specific focus on the principles involvedin the protection of sterile product during the manufacturing, packaging anddistribution processes. 人员须具备在生产 包装及发运过程中与保护无菌药品的原则相适应的技能, 培训及态度

4 c. Processes and monitoring systems for sterile product manufacture must be designed, commissioned,qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge. 无菌药品的生产和监控系统须由具有适当工艺 工程以及微生物知识的人员进行设计 使用 确认和监控 Processes, equipment, facilities andmanufacturing activities should be managed in accordance with QRM principles that provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Risk assessments should be used to justify alter native approaches to those specified in this Annex only if the sealternative approaches meet or surpass the intent of this Annex. 工艺 设备 设施及生产活动应基于 QRM 的原则进行管理, 该原则提出了一个前瞻性的方法用于识别 科学评估及控制潜在的质量风险 只有当这些可选择的方法满足或优于本附录的目的时, 风险评估方可被用于判断本附录中所明确的那些可选择的方法 Quality Assurance is particularlyimportant, and manufacture of sterile products must strictly follow carefullyestablished and validated methods of manufacture and control. A contaminationcontrol strategy should be implemented across the facility in order to assessthe effectiveness of all the control and monitoring measures employed. Thisassessment should lead to corrective and preventative actions being taken asnecessary. 质量保证尤其重要, 无菌药品的生产必须严格遵循仔细建立的以及经过验证的生产和控制方法 一个污染控制策略应在整个设施内被实施以便评估所有采用的控制以及监测方法的有效性 该评估应能在必要时引入纠正和预防措施 The strategy should consider all aspects ofcontamination control and its life cycle with ongoing and periodic review andupdate of the strategy as appropriate. 该策略应考虑所有污染控制的因素, 在其生命周期内应具有持续性和周期性的审核, 并在必要时更新该策略 Contamination control and steps taken tominimise the risk of contamination from microbial and particulate sources are aseries of successively linked events or measures. These are typically assessed, controlled andmonitored individually but these many sources should be consideredholistically. 所采取的用于降低来自微生物和微粒来源的污染风险的污染控制和步骤是一系列连续关联的事件或措施 这些事件或措施应被单独地进行评估 控制和监测, 但有些来源可进行整体考虑 The development of such strategies requiresthorough technical and process knowledge. Potential sources of contaminationare attributable to microbiological and cellular debris (e.g.pyrogens/endotoxins) as well as particulate matter (glass and other visible andsub-visible particles). 该策略的开发需要通过技术和工艺知识 潜在的污染源被归结于微生物及细胞残骸 ( 例如热原 / 内毒素 ) 以及微粒 ( 玻璃及其他可见和不可见微粒 ) Elements to be considered within such a documentedcontamination control strategy should include (but not be limited to): 文件中需记录的污染控制策略应考虑的要素有 ( 但不限于 ): a. Design of both the plant andprocess. 工厂及工艺的设计 b. Equipment and facilities. 设备和设施 c. Personnel. 人员

5 d. Utilities. 公用系统 e. Raw Materials Control including in-process controls. 原料控制 - 包括过程控制 f. Product containers andclosures. 产品容器及密闭 g. Vendor approval such as keycomponent suppliers, sterilization of components and single use systems, andservices. 供应商的批准 - 例如关键成分的供应商 组分的灭菌及一次性系统和服务 h. For outsourced services, suchas sterilization, sufficient evidence should be provided to the contract giverto ensure the process is operating correctly. 对于外部提供的服务, 例如灭菌, 应将充分的证据提供给合同的委托方, 以确保工艺被正确地操作 i. Process risk assessment. 工艺风险评估 j. Process validation. 工艺验证 k. Preventative maintenance maintaining equipment and premises (planned and unplanned maintenance) to astandard that will not add significant risk of contamination. 预防性维护保养 - 设备及设施的维护保养 ( 计划性及非计划性维护保养 ) 应有一个标准, 使之不会带来重大的污染风险 l. Cleaning and disinfection. 清洁和消毒 m. Monitoring systems - includingan assessment of the feasibility of the introduction of scientifically sound,modern methods that optimize the detection of environmental contamination. 监测系统 - 包括对引入科学合理 现代方法的可行性评估, 该方法用于优化环境污染的检测 n. Prevention Trending,investigations, corrective and preventive actions (CAPA), root causedetermination and the need for more robust investigational tools. 预防 - 趋势化 调查 纠正和预防措施 根本原因的确定以及对更有利的调查工具的需要 o. Continuous improvement based oninformation from the above systems. 基于来自上述系统信息的持续改进 The manufacturer should take all steps andprecautions necessary to assure the sterility of the products manufacturedwithin its facilities. Sole reliance for sterility or other quality aspectsmust not be placed on any terminal process or finished product test. 生产者应采取所有必要的步骤及防范措施以确保在其设施内所生产产品的无菌性 无菌性或其他质量因素不能仅仅依靠任何一个最终工艺步骤或成品检测 Note 1: This guidance does not lay downdetailed methods for determining the microbiological and particulatecleanliness of air, surfaces etc. Reference should be made to other documentssuch as the EN/ISO Standards and Pharmacopoeial monographs for more detailedguidance. 注释 1: 不建议用本指导方法来确定空气 表面等的微生物及微粒洁净度 更具体的指导应参照其他标准, 例如 EN/ISO 标准以及药典中各论的相关要求 Note 2: Where national legislation permits,additional guidance regarding the preparation of unlicensed sterile medicinalproducts normally performed by healthcare establishments for direct supply topatients, reference may be made to the Annex 1: Guidelines on the standardsrequired for the sterile preparation of medicinal products of the PIC/S guideto good practices for the preparation of medicinal products in healthcareestablishments, PE 010. 注释 2: 如国家立法许可, 由医疗机构建立的用于直接供患者使用的非上市的无菌药品的制备其他指导标准可参见 PIC/S 良好的医疗机构药品制备管理规范,PE010 附录 1: 药品无菌制备标准指

6 南.

7 3 Pharmaceutical Quality System (PQS) 制药质量体系 (PQS) 3.1 The manufacture of sterile medicinalproducts is a complex activity that requires additional controls and measuresto ensure the quality of products manufactured. Accordingly, the manufacturer spharmaceutical Quality System (PQS) should encompass and address the specificrequirements of sterile product manufacture and ensure that all activities areeffectively controlled so that all final products are free from microbial andother contamination. In addition to the PQS requirements detailed in chapter 1of the EU GMPs, the PQS for sterile product manufacturers should also ensurethat: 无菌药品的生产是一个复杂的活动, 该活动需要额外的控制和措施以确保所生产的产品质量 通常, 生产者的制药质量体系 (PQS) 应包括或强调无菌药品生产的具体要求以确保所有的活动均得到了有效地控制, 以便使所有的最终产品没有微生物或其他的污染 此外, 在 EU GMP 第一章关于 PQS 的描述中, 无菌产品生产者的 PQS 应能确保 : a. There is an effective risk management system integrated into theproduct life cycle to minimise microbial conta ination m to ensure the safety,quality and efficacy of sterile manufactured product, including assurance ofsterility. 应有一个有效的风险管理系统与产品的生命周期相结合以降低微生物污染, 确保无菌生产的药品的安全 质量及效力, 包括无菌保证 b. The manufacturer has sufficient knowledge and expertise inrelation to the products manufactured and the manufacturing methods employed. 生产者应具有足够的与产品生产及所开发的生产方法相关的知识和经验 c. Root cause analysis of procedural, process or equipment failureis key to ensure that the risk to product is correctly understood and suitablecorrective and preventative actions are implemented. 程序上的 工艺或设备失败的根本原因的分析是保证正确地理解产品风险, 实施恰当的纠正和预防措施的关键 d. Risk assessment is performed to identify, assess, eliminate (whereapplicable) and control contamination risks to prevent contamination, tomonitor and detect contamination, and to establish process requirements andacceptance criteria for all elements of a sterile manufacturing process. Therisk assessment should be documented and should include the rationale fordecisions taken in relation to mitigating risks, discounting of potential risksand residual risk. The risk assessment should be reviewed regularly as part ofon-going quality management, during change control and during the periodicproduct quality review. 实施风险评估是为了识别 评价 排除 ( 如适用 ) 及控制污染风险以防止污染, 监测和检测污染, 并为所有无菌生产工艺要素建立工艺要求和接受标准 风险评估应被记录并包括所采取的用于减轻风险 降低潜在风险和剩余风险的合理决定 风险评估应被作为持续质量管理的一部分在变更控制以及产品周期质量回顾时进行定期审核 e. Processes associated with the finishing and transport of sterileproducts should not compromise the finished sterile product in terms ofcontainer integrity or pose a risk of contamination and ensure that medicinalproducts are stored and maintained in accordance with registered storageconditions. 与无菌产品的结束和运输相关的过程不应对无菌产品的容器密闭性造成危害或形成一个污染风险以确保药品按照其注册的储存条件被储存和维护 f. Persons responsible the quality release of sterile medicinesshould have appropriate access to manufacturing and quality information andpossess adequate knowledge and experience in the manufacture of sterile dosageforms and their critical quality attributes in order to be able to ascertainthat the medicines have been manufactured in accordance with the registeredspecification and are of the required safety, quality and efficacy.

8 负责无菌产品质量放行的人员应能获得足够的生产及质量信息, 并具备足够的无菌剂型生产和关键质量属性的知识和经验以便能够确定药品是按照注册的质量标准被生产出来并符合所要求的安全 质量及效力 3.2 Investigations should be performed intonon-conformities, such as sterility test failures or environmental monitoringexcursions or deviations from established procedures, with a specific focusregarding the potential impact to sterility, to not only the specific batchconcerned but also any other potentially impacted batch. The reasons forincluding or excluding product from the scope of the investigation should beclearly recorded and justified within the investigation. 应对不符合项进行调查, 例如无菌性检验失败或环境监控超标或与已建立的程序存在偏差 调查可通过对无菌性的潜在影响进行具体关注, 不仅涉及到某一具体批次, 还涉及到其他存在潜在影响的批次 对于在调查范围内涵盖或排除产品的原因, 应在调查时被明确地记录并证明 4 Personnel 人员 4.1 The manufacturer should ensure thatthere are sufficient appropriate personnel, suitably qualified and experiencedin the manufacture and testing of sterile medicines and any of the specificmanufacturing technologies used in the site s manufacturing operations, toensure compliance with Good Manufacturing Practice applicable to themanufacture of sterile medicinal products. 生产商应确保有足够的符合条件的人员, 这些人员有对无菌药品生产和检测的资质和经验, 以及在生产现场所使用的任何一种具体生产技术, 以确保无菌药品的生产符合良好药品生产质量管理规范的要求 4.2 Only the minimum number of personnelrequired should be present in cleanrooms. The maximum number of operators incritical areas should be determined based on QRM principles, documented in thecontamination control strategy, and validated during activities such as initialqualification and aseptic process simulations, so as not to compromisesterility assurance. This is particularly important during aseptic processing.inspections and controls should be conducted outside the clean areas as far aspossible. 应规定洁净室内允许进入的最小人员数量 关键区域内允许进入的操作人员的最大数量的确定应基于 QRM 原则, 并记录在污染控制策略中, 然后在生产活动时进行验证, 例如首次确认和无菌工艺模拟, 以确保不会对无菌保证带来危害 这对于无菌工艺过程尤其重要 检查和控制应尽可能的在洁净区域外进行 4.3 All personnel (including thoseperforming cleaning and maintenance) employed in such areas should receiveregular training, qualification (including sampling of the operators bioburden,using methods such as contact plates, at key locations e.g. hands arms andchest) and assessment in disciplines relevant to the correct manufacture ofsterile products. This training should include reference to hygiene, cleanroompractices, contamination control, aseptic techniques, and potential safetyimplications to the patient of a loss of product sterility and in the basicelements of microbiology. 工作在这一区域的所有人员 ( 包括那些从事清洁和维护保养的人员 ) 应经常接受培训, 确认 ( 包括操作人员微生物负荷的取样 ; 使用方法, 例如接触碟 ; 关键位置, 例如手部, 手臂及胸部 ) 以及与无菌药品正确生产相关的纪律的评估 该培训应包括关于卫生, 洁净室实践, 污染控制, 无菌技术以及由于产品无菌性及微生物基本要素的缺失而对患者造成的的潜在安全影响 4.4 The personnel working in a grade A/Bcleanroom should be trained for aseptic gowning and aseptic practices.compliance with aseptic gowning procedures should be assessed and confirmed andthis should be periodically reassessed at least annually and should involveboth visual and microbiological assessment (using additional locations such asarms and chest). Only trained personnel who have passed the gowning assessmentand have participated in a successful aseptic process simulation (APS) test,during which they performed their normal duties, should be authorized

9 to enterany grade A/B area, in which aseptic operations will be conducted, or are beingconducted, whilst unsupervised. The microbial monitoring of personnel in thegrade A/B area should be performed to assess their aseptic behaviour. Thismonitoring should take place immediately after completion of a criticalintervention and upon each exit from the cleanroom. It should be noted thatthere should also be an ongoing continuous monitoring program for personnelincluding some consideration of periodic monitoring under the supervision ofthe quality unit. 在 A/B 级洁净室工作的人员应接受无菌更衣以及无菌实践的培训 应对无菌更衣程序的符合性进行评估和确认, 并且应当至少每年进行周期性再评价, 包括目测及微生物的评估 ( 使用额外的位置, 例如手臂及胸不 ) 只有经过培训并通过更衣的评估, 并且成功地参与了一次按照其日常任务执行的无菌工艺模拟试验 (APS) 的人员方可被授权进入 A/B 级区域, 该区域将要从事无菌操作或正在进行, 即使没有监督 应通过对 A/B 级区域的人员的微生物监测来评估其无菌行为 该监测应在关键干扰结束后以及每次退出洁净室前立即进行 值得注意的是, 应有一个对人员的持续的连续监测计划, 包括考虑在质量部门监督下的一些周期性监测 4.5 There should be systems in place fordisqualification of personnel from entry into cleanrooms, based on aspectsincluding ongoing assessment and/or the identification of an adverse trend fromthe personnel monitoring program. Once disqualified, retraining andrequalification is required before permitting the operator to have any furtherinvolvement in aseptic practices. This should include consideration ofparticipation in a successful Aseptic Process Simulation (APS). 现场应有取消人员进入洁净室资质的体系, 该体系基于来自人员监测计划的负面趋势的持续评估和 / 或的识别 一旦取消资质, 需要在允许该操作人员重新获得任何再次参与无菌实践之前被再次培训并重新获得资质 这应当包括其成功参与一次无菌工艺模拟 (APS) 的考虑 4.6 Manufacturers should establish writtenprocedures outlining the process by which outside staff who have not receivedsuch training (e.g. building or maintenance contractors) need to be broughtinto grade A/B areas. Access by these persons should only be given inexceptional circumstances, evaluated and recorded in accordance with the PQS. 生产者应建立书面程序来规定没有接受过相应培训 ( 例如建筑物或维护保养的合同商 ) 的外部员工需要进入 A/B 级区域的流程 这些人员的进入只能被指定在特定的环境下, 并根据 PQS 进行评估和记录 4.7 High standards of personal hygiene andcleanliness are essential. Personnel involved in the manufacture of sterile preparationsshould be instructed to report any specific health conditions or ailments whichmay cause the shedding of abnormal numbers or types of contaminants andtherefore preclude clean room access; periodic health checks for such conditionsshould be performed. Actions to be taken with regard to personnel who could beintroducing an undue microbiological hazard should be described in proceduresdecided by a designated competent person. 人员卫生和洁净度的高标准是非常重要的 参与无菌制备生产的人员应被指导报告任何可能引起非正常的污染数量或污染类型的具体健康状况或不适, 并禁止进入洁净区 ; 对该种状况的周期性体检应被执行 应在程序中描述由指定负责人所确定的对可能引入一个不合适的微生物危害的人员所采取的措施 4.8 Staff who have been engaged in theprocessing of human or animal tissue materials or of cultures ofmicroorganisms, other than those used in the current manufacturing process, orany activities that may have a negative impact to quality, e.g. microbialcontamination, should not enter sterile product areas unless rigorous, clearlydefined and effective entry procedures have been followed. 从事人体或动物的组织材料加工或微生物培养的员工, 除用于当前生产工艺的, 或任何可能对质量产生负面影响的活动, 例如微生物污染, 不应进入无菌产品区域, 除非按照严格 清晰定义的和有效的进入程序执行 4.9 Wristwatches, make-up and jewellery andother personal items such as mobile phones should not be allowed in cleanareas.

10 手表, 化妆和首饰及其他个人物品, 如手机, 不得被带入洁净区 4.10 Changing and hand washing shouldfollow a written procedure designed to minimize contamination of clean areaclothing or carry-through of contaminants to the clean areas. Garments shouldbe visually checked for cleanliness and integrity prior to entry to the cleanroom. For sterilized garments, particular attention should be taken to ensurethat garments and eye coverings have been sterilized and that their packagingis integral before use. Re usable garments should be replaced based at a setfrequency determined by qualification or if damage is identified. 更衣和洗手应按照书面程序执行, 该程序的设计用于降低洁净区的更衣污染或带入洁净区的污染 进入洁净区前, 应通过目测的方式检查洁净服的洁净度和完整性 对于无菌洁净服, 应特别注意使用前的检查, 以确保洁净服及放护目镜已经过灭菌, 且包装是完整的 可重复使用的洁净服的更换应基于确认或可被识别的破损所确定的一组频率 4.11 The clothing and its quality should beappropriate for the process and the grade of the working area. It should beworn in such a way as to protect the product from contamination. 工服及其质量应适用于工艺及所处工作区域的级别 其穿戴方式应能保护产品不被污染 4.12 The description of clothing requiredfor each grade is given below: 下面给出了每个洁净级别更衣要求的描述 a. Grade D: Hair, beards andmoustaches should be covered. A general protective suit and appropriatelydisinfected shoes or overshoes should be worn. Appropriate measures should betaken to avoid any contamination coming from outside the clean area. 应当将头发 胡须等相关部位遮盖 应当穿合适的工作服和鞋子或鞋套 应当采取适当措施, 以避免带入洁净区外的污染物 b. Grade C: Hair, beards andmoustaches should be covered. A single or two-piece trouser suit gathered atthe wrists and with high neck and appropriately disinfected or sterilized shoesor overshoes should be worn. They should shed virtually no fibres orparticulate matter. C 级洁净区 : 应当将头发 胡须等相关部位遮盖, 应当戴口罩 应当穿手腕处可收紧的连体服或衣裤分开的工作服, 并穿适当的鞋子或鞋套 工作服应当不脱落纤维或微粒 c. Grade A/B: Sterile headgearshould totally enclose hair and facial hair; it should be tucked into the neckof the sterile suit; a sterile face mask and sterile eye coverings should beworn to cover all facial skin and prevent the shedding of droplets and particles.appropriate sterilized, non-powdered rubber or plastic gloves and sterilizedfootwear should be worn. Trouser-legs should be tucked inside the footwear andgarment sleeves into the gloves. The protective clothing should shed virtuallyno fibres or particulate matter and retain particles shed by the body. Garmentsshould be packed and folded in such a way as to allow operators to change intothe garments with contact to the outer surfaces of the garment reduced to aminimum. A/B 级洁净区 : 应当用头罩将所有头发以及胡须等相关部位全部遮盖, 头罩应当塞进衣领内, 应当戴口罩以防散发飞沫, 必要时戴防护目镜 应当戴经灭菌且无颗粒物 ( 如滑石粉 ) 散发的橡胶或塑料手套, 穿经灭菌或消毒的脚套, 裤腿应当塞进脚套内, 袖口应当塞进手套内 工作服应为灭菌的连体工作服, 不脱落纤维或微粒, 并能滞留身体散发的微粒 工服的包装和折叠应便于操作人员在更换时尽可能地接触工服的外表面 Note: This is minimum guidance and higherstandards of clothing may be required dependent on the processes performed inthe specific area. 注意 : 这只是一个最低指导原则, 更高标准的更衣要求可能会取决于所处的具体区域的具体步骤 4.13 Outdoor clothing should not be broughtinto changing rooms leading to grade B and C rooms. It is recommended thatfacility suits, including dedicated socks be worn before entry to change roomsfor grade C and B. Where clothing is reused this should be considered as partof the qualification.

11 个人外衣不得带入通向 B 级或 C 级洁净区的更衣室 建议在进入 C 级和 B 级区的更衣室前应穿戴好包括有专用的袜子在内的厂区工作服 应考虑将工作服的再次使用应作为确认的一部分 4.14 For every worker in a grade A/B area,clean sterilized protective garments (including eye coverings and masks) of anappropriate size should be provided at each work session. Gloves should beregularly disinfected during operations. Garments and gloves should be changedat least for every working session. 每位员工每次进入 A/B 级洁净区, 每班应当更换合适尺寸无菌防护服 ( 包括放护目镜和口罩 ) 手套在操作过程中应经常被消毒 每班应至少更换一次工服及手套 但应当用监测结果证明这种方法的可行性 操作期间应当经常消毒手套, 并在必要时更换口罩和手套 4.15 Clean area clothing should be cleaned,handled and worn in such a way that it does not gather additional contaminantswhich can later be shed. These operations should follow written procedures.separate laundry facilities for such clothing are desirable. Inappropriatetreatment of clothing will damage fibres and may increase the risk of sheddingof particles. After washing and before sterilization, garments should bechecked for integrity. 洁净区所用工作服的清洗, 处理和穿戴方式应当能够保证其不携带有污染物, 该污染物随后可能会脱落 操作应按照书面程序执行 洗衣间最好单独设置 对工服处理不当会损坏纤维物并可能增加颗粒脱落的风险 清洗后和灭菌前, 应对工服的完整性进行检查 4.16 Activities in clean areas, especiallywhen aseptic operations are in progress, should be kept to a minimum andmovement of personnel should be controlled and methodical to avoid excessiveshedding of particles and organisms due to over-vigorous activity. Operatorsperforming aseptic operations should adhere to strict aseptic technique at alltimes. To prevent changes in air currents that introduce lower quality air,movement adjacent to the critical area should be restricted and the obstructionof the path of the unidirectional airflow must be avoided. The ambienttemperature and humidity should be set to prevent shedding due to operatorsbecoming too cold (leading to excessive movement) or too hot. 在洁净区内的活动应尽量减少, 尤其是当无菌操作正在进行时 人员的移动应当是受控的并有方法的, 以避免由于过分的活动而导致的额外的微粒和微生物的脱落 操作人员无论在任何时候进行无菌操作时均应执行严格的无菌技术 为防止因气流的变化而导致的空气质量下降, 应严格限制其流至与之相邻的关键区域, 并防止单向流的路径被阻碍 应设置周围环境的温湿度以防止操作人员因过冷 ( 导致过多的活动 ) 或过热而带来的脱落

12 5 Premises 设施 5.1 The manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. 无菌产品的生产要在洁净区域内进行, 进入这些区域内的人员和 / 或设备 物料, 必须通过气闸室 洁净区必须保持一定的洁净级别, 空气必须通过规定的过滤器 5.2 The various operations of component preparation, product preparation and filling should be carried out with appropriate technical and operational separation measures within the clean area. 各种原料的准备 产品的准备和灌装, 必须使用适当的技术和操作隔离的方式在洁净区进行 5.3 For the manufacture of sterile medicinal products 4 grades of clean room can be distinguished. 对于无菌药品的生产, 应确定以下 4 个级别的洁净室 : Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally, such conditions are provided by a localised air flow protection, such as laminar air flow work stations or isolators. Unidirectional air flow systems should provide a homogeneous air speed in a range of m/s (guidance value), the point at which the air speed measurement is taken should be clearly justified in the protocol. During initial qualification and requalification air speeds may be measured either close to the terminal air filter face or at the working height, Where ever the measurement is taken it is important to note that the key objective is to ensure that air visualization studies should correlate with the airspeed measurement to demonstrate air movement that supports protection of the product and open components with unidirectional air at the working height, where high risk operations and product and components are exposed. The maintenance of unidirectional airflow should be demonstrated and validated across the whole of the grade A area. Entry into the grade A area by operators should be minimized by facility, process and procedural design. A 级 : 用于高风险的生产操作, 如灌装区 压塞区 容器开口区 和进行无菌连接的地方 通常这种情况是带有局部气流保护的, 例如层流工作站或隔离器 单向流系统应提供 m/s( 指导值 ) 的均匀气流速度, 气流速度的测试点应被明确定义在方案中 在首次确认和再确认时, 气流速度可以在靠近终端空气过滤器或工作面高度的位置测试, 不管以何种方式测试, 需要重点注意的是关键目的是确保气流流型测试需要与气流流速测试相关联, 从而证实在高风险操作和产品 原料暴露区域, 气流流动可以工作高度对产品和暴露的原料提供单向流的保护 应证实和验证整个 A 级区域单向流的保持 应通过设施 工艺和程序化设计最大程度减少操作人员进入 A 级区域 Grade B: For aseptic preparation and filling, this is the background environment for the grade A zone. In general, only grade C cleanrooms should interface with the grade B aseptic processing area. Lower grades can be considered where isolator technology is used (refer to clause ). B 级 : 对于无菌制备和灌装,B 级区域是 A 级区域的背景环境 通常情况下, 只有 C 级洁净区才能与 B 级无菌生产区域对接 当使用隔离技术时, 可以考虑低级别 ( 见 ) Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. C 级和 D 级 : 执行无菌产品非关键生产步骤的洁净区 5.4 In clean areas, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms and to permit the repeated application of cleaning agents, and disinfectants, where used.

13 在洁净区, 所有暴露的表面应光滑 不透水的和不破裂, 以减少粉尘和微生物的脱落和累积, 允许重复使用清洁剂和消毒剂 5.5 To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed to avoid uncleanable recesses. 为减少粉尘的累积并且易于清洁, 不能有清洁不到的角落, 保持最少量的突出物 支架 柜子和设备 门的设计要避免难清洁角落 5.6 Materials liable to generate fibres should not be permitted in clean areas 该区域不得使用易生产纤维的物料 5.7 False ceilings should be designed and sealed to prevent contamination from the space above them. 吊顶应密封, 防止来自夹层的污染 5.8 Sinks and drains should be prohibited in grade A/B areas. In other areas air breaks should be fitted between the machine or sink and the drains. Floor drains in lower grade rooms should be fitted with traps or water seals to prevent back flow and should be regularly cleaned and disinfected. A/B 级区域不得设水池和地漏 其他区域的设备或水槽与排水系统间要设置空气断路 低洁净级别区域的房间的地漏要有水弯或水封防止倒流, 并应定期清洁和消毒 5.9 Airlocks should be designed and used to provide physical separation and to minimize microbial and particulate contamination of the different areas, and should be present for material and personnel moving from different grades, typically airlocks used for personnel movement are separate to those used for material movement. They should be flushed effectively with filtered air. The final stage of the airlock should, in the at-rest state, be the same grade as the area into which it leads. The use of separate changing rooms for entering and leaving clean areas is generally desirable. 应设计和使用气闸以对不同区域提供物理隔离并减少微生物和颗粒污染 物料和人员在穿越不同级别应设置气闸, 通常, 用于人员穿越的气闸应独立于物料传递的 它们应经过过滤空气的有效冲洗 气闸室的最终状态应是, 在静态条件下, 与其进入区域的级别相同 通常进入和离开洁净室分别使用独立更衣室是令人满意 a) Personnel airlocks. A cascade concept should be followed for personnel (e.g. from grade D to grade C to grade B). In general hand washing facilities should be provided only in the first stage of the changing rooms. 人员气闸室, 应遵循瀑布原理 ( 例如从 D 级到 C 级到 B 级 ) 通常洗手设施只能在第一阶段更衣室使用 b) Material airlocks (used for materials and equipment). 物料气闸 ( 用于物料和设备 ) i. Pass through hatches without active filtered air supply should be avoided. If necessary, provisions and procedures should be in place to avoid any risk of contamination (e.g. by the incoming material or by entering air). 应避免使用非空气过滤的传递窗 必要时, 应有规定和规程以避免任何污染的风险 ( 例如传入物料或进入空气的污染 ) ii. ii. For airlocks leading to grade A and B areas, only materials and equipment that have been included as part of the qualification list should be allowed to be transferred into the grade A/B area via the air lock or pass through; the continuity of grade A should be maintained in the aseptic core when the materials have to be transferred from grade B to grade A areas, consideration should be given to listing these items on

14 an authorized list. Any unapproved items that require transfer should be an exception. Appropriate risk evaluation and mitigation strategies should be applied and recorded as per the manufacturer s contamination control strategy and should include a specific sanitisation and monitoring regime approved by quality assurance. 对于进入 A 级和 B 级的气闸室, 只有已经列入作为确认清单部分的物料和设备才可以被允许通过气闸或传递窗传入 A/B 级区域 ; 当物料从 B 级传入 A 级时, 无菌核心区域 A 级应能够连续保持, 应考虑罗列允许传入的清单 任何未被允许的物品在需要传递时, 均被视为异常 应根据生产商的污染控制策略使用适当的风险评估和减轻的措施并进行记录, 风险评估和措施应包括特殊的清洁消毒和监测机制, 并经 QA 批准 iii. The movement of material from clean not classified (CNC) to grade C should be based on QRM principles, with cleaning and disinfection commensurate with the risk. 物料从洁净未定级区域 (CNC) 到 C 级应基于质量风险管理原则, 通过与风险相当的清洁和消毒 5.10 Both airlock doors should not be opened simultaneously. The opening of more than one door at a time should be prevented, for airlocks leading to grade A and B an interlocking system should usually be used; for airlocks leading to grade C and D at least a visual and/or audible warning system should be operated. Where required to maintain zone segregation, a time delay between the closing and opening of interlocked doors should be established. 气闸室的门不能同时打开 应避免在同一时间打开超过一道门, 对于进入 A 级和 B 级的气闸室, 通常应使用互锁系统 ; 对于进入 C 级和 D 级的气闸室, 应至少使用声和 / 或光报警系统 必要时, 为了保持区域隔离, 互锁的门关闭后开启应设置一段延迟时间 5.11 A HEPA or ULPA filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have a pressure differential of Pascals (guidance values). Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate environment to which a product and cleaned components which contact the product are exposed. The recommendations regarding air supplies and pressure differentials may need to be modified where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or bacterial materials or products. Decontamination of facilities, e.g. the clean rooms and HVAC, and the treatment of air leaving a clean area may be necessary for some operations. 在所有运行条件下,HEPA 或 ULPA 过滤空气送风 (A 级送风 ) 应对周围低级别区域保持正向压力和气流 并应能有效冲洗该区域 不同级别相邻房间压差范围 10-15Pa( 指导值 ) 应特别关注对高风险区域的保护, 高风险区域即产品和原料直接暴露的环境 当该区域包含一些物料如致病性 剧毒性 放射性 病毒性或微生物物料或产品时, 送风和压差的建议可能需要调整 对一些操作, 可能需要设施, 如洁净室和 HVAC 的文件记录和排风的处理 5.12 It should be demonstrated that air-flow patterns do not present a contamination risk, e.g. care should be taken to ensure that air flows do not distribute particles from a particle- generating person, operation or machine to a zone of higher product risk. Air flow patterns should be visualised in grade A/B areas to evaluate if airflow is unidirectional. Where unidirectional air flow is not demonstrated, corrective actions, such as design improvements, should be implemented. In the other areas, the need to demonstrate the air flow patterns should be based on a risk assessment. Air flow pattern studies should be performed under dynamic conditions. Video recordings of the airflow patterns are recommended. The outcome of the air visualisation studies should be considered when establishing the facility's environmental monitoring program. 应证实气流组织不存在污染的风险, 例如, 应小心确保气流不会将颗粒从产尘的人员 操作或设备上带入高风险区域 A/B 级区域应拍摄气流流型以评价气流是否单向 当无法证实单向时, 应采取纠正措

15 施, 例如设计方面的改善 在其他区域, 应基于风险评估确定哪些区域需要进行气流流型测试 气流流型测试应在动态条件下进行 建议拍摄视频记录 建立厂房的环境监测程序应考虑气流流型测试的结果 5.13 A warning system should be provided to indicate failure in the air supply and reduction of pressure differentials below set limits. Indicators of pressure differences should be fitted between areas, based on QRM principles. These pressure differences should be recorded regularly or otherwise documented. 应有一个报警系统来识别空气供应故障和压差降低至设定限度以下的情况 应基于风险管理原则在不同区域之间安装压差计 这些压差要定期进行记录或用文件证明 5.14 Consideration should be given to designing facilities that permit observation of activities from outside the clean areas, e.g. through the provision of windows or remote camera access with a complete view of the area and processes to allow observation and supervision without entry. 应考虑设计设施以允许可以在洁净区外观察活动, 例如通过视窗或监控录像提供区域和生产全视图以允许不需进入即可观察和监管 Barrier Technologies 隔离技术 5.15 Isolator or Restricted Access Barrier System (RABS) technologies, and the associated processes, should be designed so as to provide maximum protection of the grade A environment. The transfer of materials into and out of the RABS or isolator is one of the greatest potential sources of contamination and therefore the entry of additional materials following sterilisation should be minimized. Any activities that potentially compromise the sterility assurance of the critical zone should be assessed and controls applied if they cannot be eliminated. 隔离器和 RABS 技术及其相关工艺应设计以对 A 级环境提供最大保护 物料传入和传出 RABS 或隔离器是最大的污染潜在来源, 应减少多余物料的传递 任何可能对关键区域的无菌保证造成破坏的活动均应被评估, 如无法消除, 应采取控制 5.16 The design of the RABS or isolator shall take into account all critical factors associated with these technologies, including the quality of the air inside and the surrounding area, the materials and component transfer, the decontamination, disinfection or sterilization processes and the risk factors associated with the manufacturing operations and materials, and the operations conducted within the critical zone. RABS 或隔离器的设计应考虑与包括内部和外部空气质量 物料和部件传递, 净化, 消毒或灭菌程序技术相关的关键因素, 以及与生产操作和物料 关键区域内操作相关的风险因素 5.17 The critical zone of the RABS or isolator used for aseptic processes should meet grade A with unidirectional air flow. Under certain circumstances turbulent airflow may be justified in a closed isolator when proven to have no negative impact on the product. The design of the RABS and open isolators should ensure a positive airflow from the critical zones to the surrounding areas; negative pressure isolators should only be used when containment of the product is considered essential. 用于无菌生产的 RABS 或隔离器关键区域应符合 A 级, 提供单向流 在特定条件下, 当证实对产品没有不良影响时, 密闭隔离器也可以是湍流 RABS 的设计和开放式隔离器应确保从关键区域到周围区域维持正向气流 ; 负压隔离器仅可以在当产品的限制被认为很必要时 5.18 For RABS, the background environment should meet grade B. For open RABS, or where doors may be very rarely opened during processing, and studies should be performed to demonstrate the absence of air ingress.

16 对于 RABS, 背景环境应符合 B 级 对于开放式 RABS 或生产过程中存在开门情况的, 应进行测试证明没有空气进入 5.19 For open, positive pressure isolators or closed isolators with decontamination by a sporicidal agent, the surrounding area should correspond to a minimum of grade D. The disinfection regime should be included as a key consideration when performing the risk assessment to design the contamination control strategy for an isolator. 对于带杀孢子剂进化的开放式正压隔离器或密闭式隔离器, 周围环境应至少达到 D 级 当进行风险评估确定污染控制策略时, 应包括对消毒机制的考虑 5.20 For isolators, the required background environment can vary depending on the design of the isolator, its application and the methods used to achieve bio-decontamination. The decision as to the supporting background environment should be documented in a risk assessment where additional risks are identified, such as for negative pressure isolators. Where items are introduced to the isolator after disinfection then a higher grade of background should be considered. 对于隔离器, 所需的背景环境取决于该隔离器的设计, 使用, 以及用以实现生物净化的方法 当识别了额外的风险, 对于背景环境的决定应记录于风险评估中, 例如对于负压隔离器 当物品是在消毒后传入隔离器的, 则需要考虑更高级别的背景 5.21 Glove systems, as well as other parts of an isolator, are constructed of various materials that can be prone to puncture and leakage. The materials used shall be demonstrated to have good mechanical and chemical resistance. Integrity testing of the barrier systems and leak testing of the isolator and the glove system should be performed using visual, mechanical and physical methods. They should be performed at defined periods, at a minimum of the beginning and end of each batch, and following any intervention that may affect the integrity of the unit. 手套系统, 以及隔离器的其他部件, 由不同材料组成, 容易刺穿和泄漏 所用的材料应被证实拥有良好的机械和化学稳定性 应进行屏障系统的完整性测试以及隔离器和手套系统的泄漏测试, 使用目测的 机械的和物理的方法 应定期进行, 测试频率至少应是每批的开始和结束, 以及在任何可能影响该系统完整性的干预之后 5.22 Decontamination processes of an isolator or RABS should be validated and controlled in accordance with defined parameters. Evidence should also be available to demonstrate that the agent does not affect any process performed in the isolator or RABS, such as having an adverse impact on product or sterility testing. 隔离器或 RABS 的净化程序应被验证并控制以符合规定参数 应有证据证实试剂不会影响在隔离器或 RABS 里面的任何操作, 例如不会对产品或无菌检查造成不良影响 Clean room and clean air device qualification 洁净室和洁净空气设备确认 5.23 Clean rooms and clean air devices (clean areas) for the manufacture of products should be qualified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risks of particulate or microbial contamination of the product or materials being handled. 无菌产品生产的洁净室和洁净空气设备 ( 洁净区 ) 应根据所需求的环境特性进行确认 每个生产操作都需要一个适当的操作状态下的环境洁净度以减少被处理产品或物料颗粒或微生物污染的风险 Note: Classification is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean area device by measuring the airborne particle concentration. The classification is part of the qualification of a clean area.

17 注释 : 分级是一种评估空气洁净度水平的方法, 通过监测空气悬浮粒子符合洁净室或洁净区设备的标

18 准 分级是洁净区确认的一部分 5.24 Clean rooms and clean air devices should be qualified in accordance with Annex 15 of EU GMP. Reference for the classification of the clean rooms and clean air devices can be found in the ISO series of standards. 洁净室和洁净空气设备应根据 EU GMP 附录 15 进行确认 洁净室和洁净空气设备的分级参考 ISO14644 系列标准 5.25 For classification, the airborne particles equal to or greater than 0.5 µm should be measured. This measurement should be performed both at rest and in operation. The maximum permitted airborne particle concentration for each grade is given in table 1. 对于分级, 应监测大于等于 0.5µm 空气悬浮粒子 静态和动态条件下都要进行测试 各级别的最大允许悬浮粒子浓度检表 1: Table 1: Maximum permitted airborne particle concentration during classification 表 1: 分级时的最大允许悬浮粒子浓度 Grade 级别 Maximum permitted number of particles equal to or greater than 0.5 µm 大于等于 0 5µm 悬浮粒子最大允许数量 At rest 静态 equal to or greater than 0.5 µm per m3 0.5µm 粒子 /m3 In operation 动态 equal to or greater than 0.5 µm per m3 0.5µm 粒子 /m3 A /5 B /7 C /8 D Not defined(a) 未定义 8 ISO classification in operation/at rest ISO 分级静态 / 动态 (a) For grade D, no in operation limits are defined; the company should establish in operation limits based on a risk assessment and on historical data, where applicable. 对于 D 级, 没有定义动态的标准 ; 必要时, 企业应基于风险评估和历史数据建立动态标准 5.26 For initial classification the minimum number of sampling locations can be found in ISO14644 Part 1. 对于首次确认, 采样点的数量见 ISP However, a higher number of samples and sample volume is typically required for the aseptic processing room and the immediately adjacent environment (grade A/B) to include consideration of all critical processing locations such as point of fill stopper bowls. With the exception of the aseptic processing room, the sampling locations should be distributed evenly throughout the area of the clean room. For later stages of qualification and classification, such as performance qualification, locations should be based on a documented risk assessment and knowledge of the process and operations to be performed in the area 但是, 对于无菌生产房间和与直接相邻的环境 (A/B 级 ), 则通常需要更多的采样点数量和采样体积, 考虑所有关键生产位置, 如分装加塞区 除了无菌生产房间之外, 采样点位置应该均匀分布覆盖整个房间 在确认和分级的后续阶段, 例如性能确认, 应基于书面的风险评估和该房间所进行的工艺 操作的知识确定采样点位置

19 a) The in operation and at rest states should be defined for each clean room or suite of clean rooms. 应定义每个或每套洁净室的动态和静态状态 b) The definition of at rest is the room complete with all HVAC systems, utilities functioning and with manufacturing equipment installed as specified but without personnel in the facility and the manufacturing equipment is static. 静态 是指房间 HVAC 系统 公用设施具备其功能, 生产设备已经按要求安装但是没有操作人员在场并且生产设备不运行 c) The in operation state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working. 动态 是指在规定运行条件下和有规定数量的人员在场操作 d) In operation classification, qualification and requalification may be performed during normal operations, simulated operations or during aseptic process simulations (where worst case simulation is required). 动态的分级 确认和再确认可以在正常操作 模拟操作条件下或在无菌工艺模拟期间进行 ( 需要考察最差条件 ) e) The particle limits given in Table 1 above for the at rest state should be achieved after a clean up period on completion of operations. The "clean up" period should be determined during the initial classification of the rooms. 在操作完成后通过一段自净时间应达到表 1 给出的静态条件粒子限度, 房间的首次分级应确定自净时间 f) In order to meet in operation conditions these areas should be designed to reach certain specified air-cleanliness levels in the at rest occupancy state. 为了符合动态条件, 这些区域应被设计以达到规定的静态空气洁净水平 5.27 The microbial load of the clean rooms should be determined as part of the clean room qualification. The recommended maximum limits for microbial contamination during qualification for each grade are given in table 2. 应确定洁净室的微生物负荷作为洁净室确认的一部分, 各级别推荐的微生物污染最大限度见表 2. Table 2: Recommended limits for microbial contamination in operation 表 2: 推荐的动态条件下微生物污染限度 Grade 级别 air sample cfu/m3 浮游菌 settle plates (diameter contact plates 90 mm) cfu/4 hours (a) (diameter 55 mm) 沉降菌 ( 直径 90mm) A(b) B C D cfu/plate 接触皿 ( 直径 55mm) (a) Individual settle plates may be exposed for less than 4 hours. Where settle plates are exposed for less than 4 hours the limits in the table should still be used, no recalculation is necessary. Settle plates should be exposed for the duration of critical operations and changed as required after 4 hours.

20 单个沉降碟可以放置少于 4 小时 这种情况下, 仍然使用表中的限度, 不需要换算 应在关键操作期间放置沉降碟, 必要时, 超过 4 小时需要更换 (b) It should be noted that for grade A the expected result should be 0 cfu recovered; any recovery of 1 cfu or greater should result in an investigation. 需要注意的是, 对于 A 级, 期望的结果应是 0cfu; 任何大于或等于 1cfu 的结果均应调查 Note: For qualification of personnel, the limits given for contact plates and glove prints in table 6 should be applied. 注释 : 对于人员的确认, 应使用表 6 中给出的接触碟和衣服限度标准 5.28 Clean room qualification (including classification) should be clearly differentiated from operational process environmental monitoring. 洁净室确认 ( 包括分级 ) 应与日常工艺环境监测区分开来 5.29 Clean rooms should be requalified periodically and after changes to equipment, facility or processes based on the principles of QRM. For grade A and B zones, the maximum time interval for requalification is 6 months. For grades C and D, the maximum time interval for requalification is 12 months. 洁净室应定期再确认, 并在设备 设施 工艺变更后基于风险管理原则进行再确认 对于 A 级和 B 级, 再确认的最大间隔是 6 个月, 对于 C D 级, 再确认的最大间隔是 12 个月 5.30 Other characteristics, such as temperature and relative humidity, depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard. 其他特性, 例如温度和相对湿度, 应基于产品和所进行的操作的特点 这些参数不应影响既定的洁净标准 Disinfection 消毒 5.31 The disinfection of clean areas is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme (for disinfection to be effective, cleaning to remove surface contamination must be performed first)., More than one type of disinfecting agent should be employed, and should include the periodic use of a sporicidal agent. Disinfectants should be shown to be effective for the duration of their in use shelf-life taking into consideration appropriate contact time and the manner in and surfaces on which they are utilized. Monitoring should be undertaken regularly in order to show the effectiveness of the disinfection program and to detect the development of resistant and/or spore forming strains. Cleaning programs should be effective in the removal of disinfectant residues. 洁净室的消毒是非常重要的 应根据书面规程全面清洁和消毒 ( 为了使消毒有效, 应先进行清洁以清除表面的污染 ) 应使用至少一种消毒剂, 包括定期使用杀孢子剂 应证实消毒剂在其使用期限内有效, 考虑适当的接触时间 使用方式及其接触的表面 应定期进行监测以证实消毒程序的有效性并发现耐药菌株或芽孢生长 清洁程序应有效清除消毒残留 5.32 Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for defined periods. Disinfectants and detergents used in grade A and B areas should be sterile prior to use. 应监测消毒剂和清洗剂的微生物污染 ; 稀释应在预先清洗的容器中进行并只能在规定期限内存放 用于 A 级和 B 级的消毒剂和清洗剂在使用前应是无菌的 5.33 Disinfectants should be shown to be effective when used on the specific facilities, equipment

21 and processes that they are used in. 应证实消毒剂对其使用的具体设施 设备和工艺有效 5.34 Fumigation or vapour disinfection of clean areas such as Vapour Hydrogen Peroxide (VHP) may be useful for reducing microbiological contamination in inaccessible places. 洁净区的熏蒸或汽化消毒, 如汽化过氧化氢 (VHP) 可以有效降低难以达到的角落的微生物污染 6 Equipment 设备 6.1 A written, detailed description of the equipment design should be produced (including diagrams as appropriate) and kept up to date. It should describe the product and other critical gas and fluid pathways and controls in place. 应有详细描述设备设计 ( 包括适当的图纸 ) 的书面文件, 并保持持续更新 应描述产品及关键气体 液体的路径, 及其控制 6.2 Equipment monitoring requirements should be determined during qualification. Process alarm events should be reviewed and approved and evaluated for trends. 应在设备确认期间确定设备监测要求 应对工艺报警事件进行审核批准并趋势分析 6.3 As far as practicable equipment, fittings and services should be designed and installed so that operations, maintenance, and repairs can be carried out outside the clean area, if maintenance has to be performed in the clean area then precautions such as additional disinfection and additional environmental monitoring should be considered. If sterilization is required, it should be carried out, wherever possible, after complete reassembly. 设备 配件及服务器的设计或安装应尽可能确保其操作 维护及维修可在洁净区外进行 如果不得不在洁净区内进行维护, 则应该考虑相应的措施如额外的消毒和环境监测 如需灭菌, 尽可能在完成重新组装后再进行 6.4 When equipment maintenance has been carried out within the clean area, the area should be cleaned, disinfected and/or sterilized where appropriate, before processing recommences if the required standards of cleanliness and/or asepsis have not been maintained during the work. 若在洁净区内进行设备保养, 并且保养过程中无法维持洁净区的洁净和 / 或无菌要求, 则在重新生产 前, 应对该区域进行清洁消毒和 / 或灭菌 ( 如适用 ) 6.5 The cleaning process should be validated so that it can be demonstrated that it: 清洁工艺应经过验证, 应证明如下方面 : a) Can remove any residues that would otherwise create a barrier between the sterilizing agent and the equipment surfaces. 能去除任何在灭菌试剂和设备表面间形成屏障的残留物 b) Prevents chemical and particulate contamination of the product during the process and prior to disinfection. 防止产品在生产过程中和消毒前受化学和微粒污染 6.6 All critical surfaces that come into direct contact with sterile materials should be sterile. 所有与无菌物料直接接触的关键表面均应无菌 6.7 All equipment such as sterilizers, air handling and filtration systems, water treatment, generation, storage and distribution systems should be subject to qualificion, monitoring and planned maintenance; their return to use should be approved.

22 所有设备如灭菌柜 空调系统 水系统 ( 处理 制备 存储及分配 ) 都应进行确认, 监控以及计划性维修 恢复使用需经过批准 6.8 A conveyor belt should not pass through a partition between a grade A or B area and a processing area of lower air cleanliness, unless the belt itself is continually sterilized (e.g. in a sterilizing tunnel). 传送带不得从 A/B 级洁净区跨越到低级别生产区, 除非传送带不断灭菌 ( 例如在灭菌隧道内 ) 6.9 Particle counters should be qualified (including sampling tubing). Portable particle counters with a short length of sample tubing should be used for qualification purposes. Isokinetic sample heads shall be used in unidirectional airflow systems. 粒子计数器 ( 包括采样管 ) 需经过确认 应当用较短采样管的手持式粒子计数器来进行确认 在单向气流系统内应使用等动力采样头 6.10 Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an assessment of the potential impact to the sterility of the product should be performed and recorded. 对产品无菌性能有重大影响的设备进行非计划性维修时, 应对给产品无菌性带来的潜在影响进行评估并记录 7 Utilities 公用系统 7.1 The nature and amount of controls associated with utilities should be commensurate with the risk associated with the utility determined via risk assessment. 应通过风险评估确定与公用系统风险相对应的控制措施的程度和数量 7.2 In general higher risk utilities are those that: 一般而言, 高风险的公用系统主要包括如下 : a) Directly contact product e.g. compressed gases. 与药品直接接触的, 如压缩空气 b) Contact materials that ultimately will become part of the product. 与物料接触并最终成为药品的一部分的 c) Control contamination of surfaces that contact the product. 用以控制药品接触表面污染的 d) Or otherwise directly impact the product. 或者直接影响药品的 7.3 Utilities should be installed, operated and maintained in a manner to ensure the utility functions as expected. 应该以适当方法对公用系统进行安装 运行及维护以保证其功能符合预期 7.4 Results for critical parameters of the high risk utility should be subject to regular trend nalysis to ensure that system capabilities remain appropriate. 应对高风险公用系统关键参数结果进行定期的趋势分析, 以保证系统性能保持良好 7.5 Current drawings should be available that identify critical system attributes such as: pipeline flow, pipeline slopes, pipeline diameter and length, tanks, valves, filters, drains and sampling points.

23 应具备现行版图纸并能识别关键系统属性, 如管道流向 管道倾斜度 管道直接和长度 储罐 阀门 过滤器 排放口 取样点 7.6 Pipes and ducts and other utilities should be installed so that they do not create ecesses, unsealed openings and surfaces which are difficult to clean. 所有管道或其他公用系统应当正确安装以防止凹槽 缺口或难于清洁的表面 Water systems 水系统 7.7 Water treatment plants and distribution systems should be designed, constructed and maintained to minimize the risk of microbial contamination and proliferation so as to ensure a reliable source of water of an appropriate quality. Water produced should comply with the current monograph of the relevant Pharmacopeia. 水处理车间及分配系统应经过设计 建造和维护以降低微生物污染及扩散的风险, 从而保证一个合格 水质的可靠来源 所制备的水应符合现行版药典标准 7.8 Water for injections (WFI) should be produced from purified water, stored and distributed in a manner which prevents microbial growth, for example by constant circulation at a temperature above 70 C. Where the WFI is produced by methods other than distillation further techniques post as Reverse osmosis (RO) membrane should be considered such ultra-filtration. nanofiltration, and 注射用水应从纯化水制备而来, 并应以适当方法进行存储和分配以防止微生物生长, 如 70 上不断循环 当采用非蒸馏法制备注射用水, 则应在 RO 膜采取进一步控制, 如纳米过滤, 超滤 7.9 Water systems should be validated to maintain the appropriate levels of physical, hemical and microbial control, taking seasonal variation into account. 水系统应经过验证以证明其物理化学微生物控制处于适当的水平, 并考虑季节变化 7.10 Water flow should remain turbulent through the pipes to prevent microbial adhesion. 管道内流水应保持湍流以防止细菌黏附 7.11 The water system should be configured to prevent the proliferation of microorganisms, e.g. sloping of piping to provide complete drainage and the avoidance of dead legs. Where filters are included in the system, special attention should be taken with regards to the monitoring and maintenance of these filters. 水系统应设计以防止微生物扩散, 例如管道倾斜保证排水充分, 防止死角 对于水系统的过滤器, 应特别关注其监测及维护 7.12 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters he filters should be sterilized, and the integrity of the filter tested before and after use. 当注射用水储罐安装有疏水性细菌截留过滤器时, 应对过滤器进行灭菌, 并在使用前后进行完整性测试 7.13 To prevent the formation of biofilms, sterilization or disinfection or regeneration of water systems should be carried out according to a predetermined schedule and also when microbial counts exceed action and alert limits. Disinfection of a water system with chemicals should be followed by a validated rinsing procedure. Water should be analyzed after disinfection/regeneration; results should be approved before the start of use of the water system. 为防止生物膜的形成, 应根据既定计划或当微生物计数超过行动限和警告限时, 对水系统进行灭菌或 消毒或重新制备 对水系统的化学消毒应按照经过验证的冲洗程序 应对消毒 / 重新制备后的水进行 检测分析, 其结果经过批准后方可重新开始用水

24 7.14 A suitable sampling schedule should be in place to ensure that representative water amples are obtained for analysis on a regular basis. 应具备适当的取样计划以保证可定期取得代表性的水样用于检测 7.15 Regular ongoing chemical and microbial monitoring of water systems should be performed with alert limits based on the qualification that will identify an adverse trend in the performance of the systems. Sampling should include all outlets and user points at a specified interval. A sample from the worst case sample point, e.g. the end of the distribution loop return, should be included each time the water is used for manufacturing and manufacturing processes. A breach of an alert limit should trigger review and follow-up, which might include investigation and corrective action. Any breach of an action limit should lead to a root cause investigation and risk assessment. 应对水系统进行化学微生物的持续监测, 警戒限应确保能够识别系统性能的不良趋势 取样应在一定时间间隔内覆盖所有出水口及使用点 针对最差点的水样, 例如分配管道末端回水点, 每次生产均应进行取样 超出警戒限应进行审查和跟踪, 其中可能包括调查和纠正措施 超出行动限应进行根本原因调查及风险评估 7.16 WFI systems should include continuous monitoring systems such as Total Organic arbon (TOC) and conductivity. 注射用水系统应具备连续监测系统如 TOC 和电导率 Steam used for sterilization 灭菌用蒸汽 7.17 Purified water, with a low level of endotoxin, should be used as the minimum quality eed water for the pure steam generator. 纯蒸汽发生器源水至少应当是具有较低内毒素水平的纯化水 7.18 Steam used for sterilization processes should be of suitable quality and should not contain additives at a level which could cause contamination of product or equipment. The quality of steam used for sterilization of porous loads and for Steam-In-Place (SIP) should be assessed periodically against validated parameters. These parameters should include consideration of the following examples: non-condensable gases, dryness value (dryness fraction), superheat and steam condensate quality. 灭菌用蒸汽应具有合适的质量, 不能含有在一定程度上可导致产品或设备污染的添加剂 对于多孔装 载灭菌和 SIP 的蒸汽质量应对验证参数进行定期评估 这些参数包括考虑以下几种 : 不凝性气体 干 度 过热和冷凝水质量 Compressed gases and vacuum systems 压缩气体及真空系统 7.19 Compressed gases that come in direct contact with the product/container primary surfaces should be of appropriate chemical, particulate and microbiological purity, free from oil with the correct dew point specification and, where applicable, comply with appropriate pharmacopoeial monographs. Compressed gases must be filtered through a sterilizing filter (with a nominal pore size of a maximum of 0.22µm) at the point of use. Where used for aseptic manufacturing, confirmation of the integrity of the final sterilization gas filter should be considered as part of the batch release process 与产品 / 容器内表面直接接触的压缩气体应有具备合适的化学, 微粒和微生物纯度, 在相应露点标准下应无油, 在适当情况下, 应符合相应的药典各论 压缩气体在使用时须通过除菌过滤器过滤 ( 最大孔径为 0.22µm) 如使用于无菌工艺中, 终端除菌气体过滤器完整性的确认应作为批放行审核的一部分

25 7.20 There should be prevention of backflow when any vacuum or pressure system is shut off. 当真空或压力系统关闭时应有防止倒流的措施 Cooling systems 冷却系统 7.21 Major items of equipment associated with hydraulic and cooling systems should, where possible, be located outside the filling room. Where they are located inside the filling room there should be appropriate controls to contain any spillage and/or cross contamination associated with the hydraulics of cooling system fluids. 与液压和冷却系统相关设备的主要部件应尽可能安装在分装间外部 当其安装在分装间内部时, 应当有适当的措施以控制冷却系统冷凝液相关的泄漏和 / 或污染 7.22 Any leaks from the cooling system must be detectable (i.e. an indication system for leakage). In addition, there must be adequate cooling flow within the system. 冷却系统的所有泄漏应当是可检测的 ( 如有泄漏指示系统 ) 另外, 系统内应当有足够的冷却流 7.23 The cooling circuit should be subject to leak testing both periodically and following any maintenance. 冷却循环系统应定期进行泄漏检测, 并跟踪维护 7.24 There should be periodic cleaning/disinfection of both the vacuum system and cooling systems. 真空系统和冷却系统应进行定期清洁和消毒

26 8 Production and Specific Technologies 产品和特定技术 Terminally sterilized products 最终灭菌产品 8.1 Preparation of components and most products should be done in at least a grade D environment in order to give a low risk of microbial, pyrogen and particulate contamination, so that the product is suitable for filtration and sterilization. Where the product is at a high or unusual risk of microbial contamination, (for example, because the product actively supports microbial growth and/or must be held for a long periods before sterilisation and/or is not processed mainly in closed vessels), then preparation should be carried out in a grade C environment. 原料和大多数产品的准备在不低于 D 级的环境下进行, 以尽可能降低微生物 热原和微粒污染的风险, 使产品对适用于过滤和最终灭菌 产品本身具有高的或特殊的微生物染污风险的 ( 例如产品容易长菌 配制后需要等待较长时间方可灭菌或不在密闭系统中配制 ), 应在 C 级环境下进行制备 8.2 Filling of products for terminal sterilization should be carried out in at least a grade C environment. 最终灭菌产品的灌装应该在至少 C 级环境下进行 8.3 Where the product is at an unusual risk of contamination from the environment because, for example, the filling operation is slow, the containers are wide necked or are necessarily exposed for more than a few seconds before closing, or the product is held for extended periods prior to terminal sterilization, then the product should be filled in a grade A zone with at least a grade C background. Preparation and filling of ointments, creams, suspensions and emulsions should generally be carried out in a grade C terminal sterilization. environment before 当产品存在特殊的环境污染风险, 如, 灌装操作慢, 广口容器或是容器需要暴露数秒方可进行密封, 或是产品需要在最终灭菌前需要存放较长时间, 则产品灌装至少需要 C 级背景下的 A 级环境进行 在最终灭菌前, 软膏, 霜剂, 混悬液和乳剂的配制和灌装通常应在 C 级环境下进行 Processing of the bulk solution should include a filtration step to reduce bioburden levels and particulates prior to filling into the final product containers. 灌装到最终产品容器之前, 溶液的处理应包含过滤步骤以降低生物负载水平和微粒 Examples of operations to be carried out in the various grades are given in table 3. 最终灭菌产品不同级别环境生产操作举例见表 3 Table 3: Examples of operations and grades they should be performed in for terminally sterilized products

27 表 3 : 最终灭菌产品生产操作及其对应洁净级别示例 A C D Filling of products, when unusually at risk. 高污染风险产品的灌装 Preparation of solutions, when unusually at risk. Filling of products. 高污染风险产品溶液的配制, 产品的灌装 ; Preparation of solutions and components for subsequent filling. 灌装前产品溶液和组分的准备 Aseptic preparation 无菌工艺 8.3 Aseptic processing is the handling of sterile product, containers and/or devices in a controlled environment, in which the air supply, materials and personnel are regulated to prevent microbial contamination. Additional requirements apply to Restricted Access Barrier Systems (RABS) and isolators (refer clauses ). 无菌处理是指无菌产品 容器和 / 或设备在受控环境中进行处理, 该环境对送风 物料和人员进行管理以防止微生物污染 其它要求适用于 RABS 系统和无菌隔离系统 ( 参照条款 ) 8.4 The aseptic process should be clearly defined. The risks associated with the aseptic process, and any associated requirements, should be identified, assessed and appropriately controlled. The site s contamination control strategy should clearly define the acceptance criteria for these controls, requirements for monitoring and the review of their effectiveness. Methods and procedures to control these risks should justified. be described and implemented. Residual risks should be 无菌工艺应有明确定义 与无菌工艺相关的风险, 以及其他相关要求, 都应被确定 评估和适当地控制 工厂的污染控制策略应明确规定这些控制的可接受标准和监测要求, 并回顾其有效性 应描述并执行控制这些风险的方法和程序 遗留风险应被论证 8.5 Precautions to minimise microbiological, pyrogen and particulate contamination should be taken, as per the site s contamination control strategy, during the preparation of the aseptic environment, during all processing stages, including the stages before and after filter sterilization, and until the product is sealed in its final container. Materials liable to generate fibres should not be permitted in clean areas. 在无菌环境准备过程 生产操作过程包括无菌过滤前后, 直到产品被密封入最终容器的整个过程中, 应根据工厂污染控制策略采取预防措施最大程度降低微生物 热原和微粒的污染 易产生纤维的物料不得进入洁净区 8.6 Where possible, the use of equipment such as RABS, isolators or closed systems, should be considered in order to reduce the need for interventions into the grade A environment and minimize the risk of contamination. Automation of processes should also be considered to emove the risk of contamination by interventions (e.g. dry heat tunnel, automated lyophilizer loading, SIP).

28 应尽可能考虑使用如 RABS 隔离器或密闭系统等设备以减少对 A 级环境的干扰, 将污染风险降到最低 ; 也应考虑自动化工艺以排除干扰导致污染的风险 ( 例如 : 灭菌燧道 自动装载冻干机 SIP) 8.7 Examples of operations to be carried out in the various environmental grades are given in the table 4. 无菌工艺不同级别环境生产操作举例见表 3 Table 4: Examples of operations and which grades they should be performed in 表 4 : 无菌工艺生产操作及其对应洁净级别示例 A Critical processing zone. 关键生产区域 ; Aseptic assembly of filling equipment. 灌装设备的无菌组装 ; Aseptic connections (should be sterilized by steam-in-place whenever feasible). 无菌连接 ( 应尽可能使用流通蒸汽灭菌 ); Aseptic compounding and mixing. 无菌配制和混合 ; Replenishment of sterile product, containers and closures. 生产过程中添加无菌产品 容器和密封部件 Removal and cooling of items from heat sterilizers. 热力灭菌器中物品的转移和冷却 Staging and conveying of sterile primary packaging components. 无菌内包材的分装和转运 ; Aseptic filling, sealing, transfer of open or partially stoppered vials, including interventions. 开口或半压塞瓶子的无菌灌装 密封 转移, 包括干扰过程 ; B Loading and unloading of a lyophilizer 冻干机的装载和卸载 Direct support zone for the critical processing (grade A) zone. 关键生产区域的背景区域 ; Transport and preparation of packaged equipment, components and ancillary items for introduction into the grade A zone.

29 待传入 A 级的设备包裹 原料和辅助物品的转运和准备 ; Removal of sealed product from the grade A zone. 已密封产品从 A 级区域传出 ; C D Preparation of solutions to be filtered. 待过滤溶液的配制 Cleaning of equipment. 设备清洗 Handling of components, equipment and accessories after washing. 清洗后组件 设备和配件的处理 Assembly of cleaned equipment to be sterilized. 已清洗的待灭菌设备的组装 Note: If Isolators are used then a risk assessment should determine the necessary background environment grade; at least a minimum of grade D should be used. Refer clauses 备注 : 如果使用隔离器, 应通过风险评估确定必要的背景环境等级 ; 至少应为 D 级 参考 节 8.8 Where the product is not subsequently sterile filtered, the preparation of equipment, components and ancillary items and products should be done in a grade A environment with a grade B background. 如果产品不再进行除菌过滤, 设备 部件和辅助用品的准备和产品的制备均应在 B 级背景下的 A 级环境中进行 8.9 Preparation and filling of sterile products such as ointments, creams, suspensions and emulsions should be performed in a grade A environment, with a grade B background, when the product and components are sterilized. exposed and the product is not subsequently filtered or 在产品和组分暴露并不再进行过滤或灭菌的情况下, 无菌产品 ( 如软膏, 乳膏, 混悬剂和乳剂 ) 的制备和充填应在 B 级背景下的 A 级环境中进行 8.10 Unless subsequently sterilized by steam-in-place or conducted with validated intrinsic sterile connection devices, aseptic connections should be performed in a grade A environment with a grade B background (or in an isolator with a suitable background), in a way that minimizes the potential contamination from the immediate environment, e.g. from operators or boundaries with lower grades. Aseptic connections, including those performed to replace equipment, should be appropriately assessed and their effectiveness verified process simulation tests. (For requirements regarding intrinsic devices (refer clause 8.115). as acceptable by sterile connection 除非后续采取流通蒸汽灭菌或在经验证的内部无菌的连接装置内进行, 无菌连接应在 B 级背景下的 A 级环境中 ( 或在适当背景下的隔离器中 ) 进行, 以将相邻环境污染的风险降到最低 ( 例如来自操作人

30 员或相邻低级别区域边界的污染 ) 应适当评估无菌连接 ( 包括更换设备操作 ), 并通过工艺模拟试验确认其有效性 ( 对于内部无菌连接设备的要求请参见条款 8.115) 8.11 The transfer of partially closed containers to a lyophilizer, should be done under grade A conditions (e.g. HEPA filtered positive pressure) at all times and, where possible, without operator intervention. Portable transfer systems (e.g. transfer carts, portable Laminar Flow Work Stations, etc.) should ensure that the integrity of transfer system is maintained and the process of transfer should minimize the risk of contamination. 将半压塞容器转移至冻干机应始终在 A 级条件下 ( 例如经 HEPA 过滤的正压环境 ), 并且尽可能减少人员干预 移动式转运系统 ( 如转运车 移动式层流工作台等 ) 应确保转运系统的完整性, 应减少转移过程污染的风险 8.12 Aseptic manipulations (including non-intrinsic aseptic connections) should be minimized using engineering solutions such as the use of preassembled and sterilized equipment. Whenever feasible, product contact piping and equipment should be pre-assembled, then cleaned and sterilized in place. The final sterile filtration should be carried 849 out as close as possible to the filling point and downstream of aseptic connections wherever possible 应从工程的角度考虑尽可能减少无菌操作 ( 包括非内部无菌连接 ) 的解决方案 ( 例如使用预先组装和灭菌的设备 ) 如可行, 直接接触产品的管道和设备应先进行组装, 再进行清洗和灭菌 终端除菌过滤尽可能靠近灌装点并在无菌连接下游处 8.13 The duration for each aspect of the aseptic manufacturing process should be limited to a defined and validated maximum, including: 无菌生产过程的各个环节的持续时间应限定在规定最大限度内, 并经过验证, 包括 : a) Time between equipment, component, and container cleaning, drying and sterilization. 设备 部件和容器的清洁 干燥和灭菌之间的时间 b) Holding time for sterilized equipment, components, and containers prior to and during filling/assembly. 在灌装 / 组装之前和期间, 已灭菌设备 组件和容器的保存时间 c) The time between the start of the preparation of a solution and its sterilization or filtration through a micro-organism-retaining filter. There should be a set maximum permissible time for each product that takes into account its composition and the prescribed method of storage. 溶液配制开始与其灭菌或除菌过滤之间的时间 每种产品的最长允许保存时间应根据其成分和规定的贮存方法确定 c) Aseptic assembly. 装机时间 d) Holding sterile product prior to filling.

31 无菌产品灌装前的保存时间 e) Filling. 灌装时长 f) Maximum exposure time of sterilized containers and closures in the critical processing zone (including filling) prior to closure. 密封前已灭菌容器和封闭部件在关键操作区 ( 包括灌装区 ) 的最长暴露时间 Finishing of sterile products 无菌产品最终处理 8.14 Partially stoppered vials or prefilled syringes should be maintained under grade A conditions (e.g. use of isolator technology, grade A with B background, with physical segregation from operators) or grade A LAF carts (with suitable grade B background environment and physical segregation from operators) at all times until the stopper is fully inserted. 半压塞的瓶子或预充 式注射器在塞子完全插入之前应始终保持在 A 级条件下 ( 如使用隔离技术 B 级背景下的 A 级, 及操 作人员的物理隔离 ) 或具有 A 级环境的 LAF 推车 ( 在 B 级背景下, 并将操作员物理隔离 ) 8.15 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Form-Fill-Seal Small Volume Parenteral (SVP) & Large Volume Parenteral (LVP) bags, glass or plastic ampoules, should be subject to 100% integrity testing. Samples of other containers should be checked for integrity utilising validated 887 methods and in accordance with QRM, the frequency of testing should be based on the 888 knowledge and experience of the container and closure systems being used. A statistically 889 valid sampling plan should be utilized. It should be noted that visual inspection alone is integrity test method. 890 not considered as an acceptable 应使用经验证的适当的方法密封容器 熔封容器, 例如塑 - 灌 - 封小容量注射剂 (SVP) 和大容量注射剂 (LVP) 的袋 玻璃或塑料安瓿瓶, 应进行 100% 的完整性测试 其他容器样品的完整性测试应选择经验证的方法并符合 QRM 要求, 测试的频率应根据所使用的容器和封闭系统的知识和经验来确定 应该使用统计有效的抽样计划 应该注意仅仅使用目视检查进行完整性测试是不被接受的 8.16 Containers sealed under vacuum should be tested for maintenance of vacuum after an appropriate, pre-determined period and during shelf life. 密封在真空条件下的容器应在既定时间后和货架期内测试其真空度的维持水平 8.17 The container closure integrity validation should take into consideration any transportation or shipping requirements. 容器密封完整性验证应考虑运输的要求 8.18 As the equipment used to crimp vial caps can generate large quantities of non- viable particulates, the equipment should be located at a physically separate station equipped with adequate air extraction. 由于轧盖设备会产生大量的非活性粒子, 此类设备应安装在物理隔离的位置并配置适当的抽风装置

32 8.19 Vial capping can be undertaken as an aseptic process using sterilized caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by grade A conditions up to the point of leaving the aseptic processing area, and there after stoppered vials should be protected with a grade A air supply until the cap has been crimped. Where capping is a manual process it must be performed in grade A conditions with a grade B background. 瓶子的轧盖可以使用无菌铝盖进行无菌操作, 也可以在无菌核心区域外进行洁净操作 在采用后一种方法时, 瓶子在离开无菌操作区前应处于 A 级环境下 然后已加塞的瓶子在完成轧盖前应处于 A 级送风保护下 如果是手动轧盖, 则必须在 B 级背景下的 A 级环境进行 8.20 In the case where capping is conducted as a clean process with grade A air supply protection, vials with missing or displaced stoppers should be rejected prior to capping. Appropriately validated, automated methods for stopper height detection should be in place. Microbial ingress studies (or alternative methods) should be utilized to determine the 913 acceptable stopper height displacement. 在 A 级送风保护下进行轧盖操作的, 在轧盖之前, 应无塞或翘塞的样品剔除 应采用经过适当验证的胶塞高度自动检测方法 应使用微生物侵入试验 ( 或替代方法 ) 来确定可接受的塞子翘起高度 8.21 Where human intervention is required at the capping station, appropriate technology should be used to prevent direct contact with the vials and to minimize microbial contamination. 轧盖过程需要人工干预时, 应采取适当的措施防止直接接触玻璃瓶, 最大限度减少微生物污染 8.22 RABS and isolators may be beneficial in assuring the required conditions and minimising direct human interventions into the capping operation. RABS 和隔离器有助于实现所要求的条件并减少人员直接干预轧盖操作 8.23 All filled containers of extraneous contamination or for parenteral products should be inspected individually for other defects. QRM principles should be used determination of defect classification and criticality. Factors to consider include, but are not limited, to the potential impact to the patient of the defect and the route of administration. Different defect types should be categorized and batch performance analyzed. Batches with unusual levels of defects, when compared to routine defect levels for the process, should lead to investigation consideration of partial or the whole rejection of the batch concerned. A defect library should be generated and maintained which captures all known defects. The defect library can be used as a training tool for production and quality assurance personnel. Critical defects should not be identified during any subsequent sampling of acceptable containers as it indicates a failure of the original inspection process. 所有已灌装的注射用产品都应分别检查外部污染或其他缺陷 应根据 QRM 原则确定缺陷分类和严重性 考虑的因素包括但不限于缺陷对患者潜在影响以及给药途径 应对不同缺陷类型进行分类并对批产品性能进行分析 与日常工艺缺陷水平相比, 出现异常的批次应进行调查, 并考虑部分或全部报废 and

33 应建立和维护包括所有已知缺陷的缺陷库, 该库可以作为生产和质量保证人员的培训工具 已检查合

34 格的产品, 任何取样过程中都不得检出关键缺陷, 因为这表明最开始的检查过程是失败的 8.24 When inspection is done manually, it should be done under suitable and controlled conditions of illumination and background. Inspection rates should be appropriately validated. Operators performing the inspection should undergo robust visual inspection qualification (whilst wearing corrective lenses, if these are normally worn) at least annually. The qualification should be undertaken using appropriate sample sets and taking into consideration worst case scenarios (e.g. inspection time, line speed (where the product is transferred to the operator by a conveyor system), component size or fatigue at the end of shift) and should include consideration of eyesight checks. and frequent breaks of appropriate duration from inspection should be taken. Operator distractions should be removed 如果使用人工灯检, 应在受控的合适的照度和背景条件下进行 检查速度应经过适当验证 灯检人员应至少每年接受一次灯检确认 ( 戴眼镜的, 应配备矫正镜片 ) 使用合适的一系列样品进行确认, 并考虑最差情况 ( 例如检查时间 传送速度 ( 产品通过传送系统输送给操作人员 ) 部件尺寸或班次结束时的疲劳度 ) 且应该包含视力检查 应避免检查人员分心, 并应在合适的检查时间后给予休息 8.25 Where automated methods of inspection are used, the process should be validated to 945 detect known defects with sensitivity equal to or better than manual inspection methods and 946 the performance of the equipment checked prior to start up and at regular intervals. 使用自动灯检方法前应验证该方法对已知缺项的灵敏度等于或优于人工灯检方法 启用前应检查设备的性能并定期进行 8.26 Results of the inspection should be recorded and defect types and levels trended. Reject rates for the various defect types should also be trended. Investigations should be performed as appropriate to address adverse trends or discovery of new defect types. Impact to product market should be assessed as part of this investigation. on the 应记录灯检结果, 缺陷类型和等级应进行趋势分析 各类缺陷的不合格品率也应进行趋势分析 当发现不良趋势或发现新的缺陷类型, 应酌情进行调查 对已上市产品的影响也应作为调查的一部分进行评估 Sterilization 消毒 8.27 Where possible, finished product should be terminally sterilized using a validated and controlled sterilization process as this provides a greater assurance of sterility than a validated and controlled sterilizing filtration process and/or aseptic processing. Where it is not possible for a product to undergo a sterilisation, consideration should be given to using terminal bioburden reduction steps, such as heat treatments (pasteurization), combined with aseptic processing to give improved sterility assurance. 最终产品应尽可能采用经过验证和受控的灭菌工艺进行最终灭菌, 它能提供比经过验证和受控的除菌过滤和 / 或无菌工艺更高的无菌保证 产品不能经受灭菌时, 应考虑使用如热处理 ( 巴氏消毒 ) 等降低终端生物负载的步骤, 并结合无菌工艺以提高无菌性保证

35 8.28 The selection, design and location of the equipment and cycle/programme used for sterilization should be decided using QRM principles. Critical parameters should be defined, monitored and recorded. controlled, 应根据 QRM 原则确定设备和灭菌循环 / 程序的选择 设计和位置 应定义关键参数 并进行控制 监测和记录 8.29 There should be mechanisms in place to detect a cycle that does not conform to the validated parameters. Any failed or atypical sterilization cycles must be formally investigated. 应采取适当的方法监测不符合已验证参数的循环 任何失败或异常的灭菌周期均必须进行正式的调查 8.30 All sterilization processes adopted sterilization method Pharmacopoeia, or when it should be validated. Particular attention should be given when the is not described in the current edition of the is used for a product which is not a simple aqueous solution. Where possible, heat sterilization is the method of choice. Regardless, the sterilization process must be in accordance with the registered marketing and manufacturing specifications. 所有灭菌工艺都应该被验证 尤其注意采用的灭菌方法没被当前版本的药典描述, 或者被灭菌产品不是简单的水溶液的情况 如有可能, 应尽量选择热力灭菌 灭菌工艺必须符合注册的上市和生产标准 8.31 Before any sterilization process is adopted, its suitability for the product and equipment and its efficacy in achieving the desired sterilizing conditions in all parts of each type of load to be processed should be demonstrated by physical measurements and by biological indicators where appropriate. 采用任何灭菌工艺前, 应视情况采用物理测量手段和生物指示剂来证明灭菌工艺适用于被灭菌的产品和设备, 并证明该灭菌工艺在每种装载模式下的所有部位均能有效的达到预期的灭菌效果 8.32 The validity of the process should be verified at scheduled intervals, with a minimum of at least annually. Revalidation of the sterilization process should be conducted whenever significant modifications have been made to the product, product packaging, sterilization load configuration, sterilizing equipment or sterilization process parameters. 应按照预定的周期对工艺有效性进行确认, 至少进行一次 当对产品 产品包装 灭菌装载方式 灭菌设备和灭菌工艺参数的重大变更, 应对灭菌工艺进行再验证 8.33 For effective sterilization, the whole of the material and equipment must be subjected to the required treatment and the process should be designed to ensure that this is achieved. 为进行有效灭菌, 所有物料和设备均必须进行必要的处理, 且生产工艺的设计要能确保其是可以实现 8.34 Routine operating parameters should be established and adhered to for all sterilization processes, e.g. physical parameters and loading patterns, etc. 所有灭菌工艺均应建立日常操作参数, 并应遵循这些参数进行灭菌, 如物理参数和装载方式等 8.35 Suitable biological indicators (BIs) placed at appropriate locations may be considered as an

36 additional method for monitoring the sterilization. BIs should be stored and used according to the

37 manufacturer s instructions. Prior to use of a new batch/lot of BIs, the quality of the batch/lot should be verified by confirming the viable spore count and identity. Where BIs are used to validate and/or monitor a sterilization process (e.g. for Ethylene Oxide), positive controls should be tested for each sterilization cycle, with strict precautions in place to avoid transferring microbial contamination from BIs, including preventing positive control BIs from contaminating BIs exposed to the sterilization cycle. If biological indicators are used, strict precautions should be taken to avoid transferring microbial contamination to the manufacturing or other testing processes. 在适当位置放置合适的生物指示剂 (BI) 可作为监测灭菌过程的附加手段 BI 应按生产商说明进行保存和使用 在启用一批新的 BI 前, 应鉴别并确认其活芽孢数量以确认该批 BI 的质量 当用 BI 来验证和 / 或监测某种灭菌工艺 ( 如, 环氧乙烷 ) 时, 每个灭菌周期均进行阳性对照检查 应建立严格的预防措施以避免 BI 之间的微生物污染, 包括防止阳性对照污染已暴露于灭菌程序的 BI 如使用生物指示剂, 应建立严格的预防措施来避免将微生物污染转移至生产或其他检查过程 8.36 There should be a clear means of differentiating products, equipment and components, which have not been sterilized from those which have. Each basket, tray or other carrier of products, items of equipment or components should be clearly labelled with the material name, its batch number and an indication of whether or not it has been sterilized. Indicators such as autoclave tape, or irradiation indicators may be used, where appropriate, to indicate whether or not a batch (or sub-batch) has passed through a sterilization process. However, these indicators show only that the sterilization process has occurred; they do not necessarily indicate product sterility or achievement of the required sterility assurance level. 应明确区分已灭菌和未灭菌产品 设备和部件的方法 每个筐 托盘或其他产品的载具 设备或组件应清楚标识有物料名称 批号并指示是否已灭菌 应视情况使用热压灭菌指示胶带或辐射指示卡来指示某批 ( 或亚批 ) 物料是否已进行了灭菌 不过, 这些指示剂只能显示是否进行了灭菌操作, 它们不一定能代表产品处于无菌状态或达到了要求的无菌保障水平 8.37 Sterilization records should be available for each sterilization run. They should be reviewed and approved as part of the batch release procedure. 每次灭菌操作都要有灭菌记录 这些记录的审核和批准应作为批放行的一部分 8.38 Where possible, materials, equipment and components should be sterilized by validated methods appropriate to the specific material. Suitable protection after sterilization should be provided to prevent recontamination. If items sterilized in house are not used immediately after sterilization, these should be stored, using appropriately sealed packaging, in at least a grade B environment, a maximum hold period should also be established. Components that have been packaged with multiple sterile packaging layers need not be stored in grade B (where justified) if the integrity and configuration (e.g. multiple sterile coverings that can be removed at each transfer from lower to higher grade) of the sterile pack allows the items to be readily disinfected during transfer into the grade A zone. Where protection is achieved by containment in sealed packaging this process should be undertaken prior to sterilisation. 如可能, 各物料 设备和组件的灭菌应采用适用于其特定材料并经验证的方法 灭菌后应采取适当的保护措施以防止再次污染 如果公司内部对灭菌后物品不是立即使用, 应将其适当密封包装, 并保存于至少 B 级环境, 应建立最长保存时间 当某组件用多层无菌袋包装时, 如果无菌袋包装的完整性和

38 结构能够使其在传入 A 级区时易于消毒 ( 如, 多层无菌呼吸袋, 且每转移到更高级别环境时可脱去一层 ), 则其不需要保存在 B 级环境 ( 需要论证 ) 当用密封袋包装来实现保护时, 应在灭菌前就实施 8.39 Transfer of materials, equipment, and components into an aseptic processing area should be via a unidirectional process (e.g. through a double-door autoclave, a depyrogenation oven, effective transfer disinfection, or, for gaseous or liquid materials, a bacteria-retentive filter). 物料 设备和组件转移入无菌生产区域, 应通过单向的过程 ( 如, 采用双扉灭菌器, 去热原烘箱, 有效的转移消毒, 或, 对于气态或液态物料, 采用细菌截留过滤器 ) 8.40 Where materials, equipment, components and ancillary items are sterilized in sealed packaging and then transferred into the grade A/B area, this should be done using appropriate, validated methods (for example, airlocks or pass through hatches) with accompanying disinfection of the exterior of the sealed packaging. These methods should be demonstrated to be effective in not posing an unacceptable risk of contamination of the grade A/B area and, likewise, the disinfection procedure should be demonstrated to be effective in reducing any contamination on the packaging to acceptable levels for entry of the item into the grade A/B area. Packaging may be multi-layered to allow removal of a single layer at each interface to a higher grade. 当将物料 设备 部件和辅助物品装于密封包装内灭菌后转移至 A/B 级区时, 应采用适当的, 经验证的方法 ( 如气闸或传递窗 ) 并对密封包装的外表面进行消毒 应证明这些方法能有效防止对 A/B 级区的环境造成的不可接受的污染 同样, 应证明消毒方法能将包装上的任何污染有效降低至进入 A/B 级区的可接受水平 包装可为多层形式, 以便每进入一个更高级别的洁净区都可脱去一层包装 8.41 Where materials, equipment, components and ancillary items are sterilized in sealed packaging or containers, the integrity of the sterile protective barrier should be qualified for the maximum hold time, and the process should include inspection of each sterile item prior to its use to ensure that the sterile protective measures have remained integral. 当将物料 设备 组件和辅助物品置于密封包装或容器内灭菌时, 应确认无菌保护屏障完整性的最长保持时间 每件无菌物品在使用前应进行检查, 以确认无菌保护措施仍然保持完整 8.42 For materials, equipment, components and ancillary items that are necessary for aseptic processing but cannot be sterilized, an effective and validated disinfection and transfer process should be in place. These items once disinfected should be protected to prevent recontamination. These items, and others representing potential routes of contamination, should be included in the environmental monitoring program. 对于必须用于无菌工艺但不能进行灭菌的物料 设备 组件和辅助物品, 应建立有效并经验证的消毒和传递程序 这些物品一旦消毒完成, 应保护以防止再污染 这些物品以及其他存在潜在污染途径的物品, 应纳入环境监测程序中 8.43 When a depyrogenation process is used for any components or product contact equipment, validation studies should be performed to demonstrate that the process will result in a minimum 3 log reduction in endotoxin. There is no additional requirement to demonstrate sterilization in these cases. 当对任何组件或产品接触设备进行除热原处理时, 应进行验证研究证明该工艺至少能降低 3 个对数值

39 的内毒素 在此情况下, 无需额外证明灭菌效果 Sterilization by heat 热力灭菌 8.44 Moist heat sterilization utilises clean steam, typically at lower temperatures and shorter duration than dry heat processes, in order to sterilize a product or article. Moist heat sterilization is primarily effected by latent heat of condensation and the quality of steam is therefore important to provide consistent results. The reduced level of moisture in dry heat sterilization process reduces heat penetration which is primarily effected by conduction. Dry heat processes may be utilized to sterilize or control bioburden of thermally stable materials and articles. Dry heat sterilization is of particular use in the removal of thermally robust contaminants such as pyrogens and is often utilized in the preparation of aseptic filling components. Moist heat sterilization processes may be utilized to sterilize or control bioburden (for non-sterile applications) of thermally stable materials, articles or products and is the preferred method of sterilization, where possible. 湿热灭菌采用纯蒸汽对产品或物品进行灭菌, 与干热灭菌工艺相比, 其灭菌温度更低且灭菌时间更短 湿热灭菌主要是通过冷凝释放潜热实现灭菌, 因此蒸汽质量对于获得一致的灭菌结果而言是非常重要的 干热灭菌工艺因湿度较低导致热穿透性低, 因此热穿透主要是通过热传导来实现的 干热灭菌可用于热稳定物料和器具的灭菌或生物负载控制 干热灭菌尤其适用于去除耐热污染物如热原, 常用于无菌分装部件的准备 湿热灭菌可用于热稳定材料 器具和产品的灭菌或生物负载控制 ( 非无菌用途 ), 是首选的灭菌方法 8.45 In those cases where parametric release has been authorized, a robust system should be applied to the product lifecycle validation and the routine monitoring of the manufacturing process. This system should be periodically reviewed. 在允许进行参数放行的情况下, 应采用稳健的系统来进行产品生命周期验证以及生产工艺的日常监控 该系统应定期审核 8.46 Each heat sterilization cycle should be recorded on a time/temperature chart with a sufficiently large scale or by other appropriate equipment with suitable accuracy and precision. Monitoring and recording systems should be independent of the controlling system. 每个热力灭菌循环都应记录在一个具有足够大比例的时间 / 温度图表上或其他适当的有合适的准确度和精度的设备上 监测和记录系统应独立于控制系统 8.47 The position of the temperature probes used for controlling and/or recording should have been determined during the validation (which should include heat distribution and penetration studies), and, where applicable, also checked against a second independent temperature probe located at the same position. 用于控制和 / 或记录的温度探头的位置应在验证过程中确定 ( 验证应该包括热分布和热穿透试验 ), 如适用, 应在同一位置用第二个独立的温度探头进行核对 8.48 Chemical or biological indicators may also be used, but should not take the place of physical measurements.

40 可以使用化学或生物指示剂, 但不的代替物理测试 8.49 Sufficient time must be allowed for the whole of the load to reach the required temperature before measurement of the sterilizing time-period is commenced. This time must be determined for each type of load to be processed. 在监测灭菌周期时长前, 必须允许足够的升温时间使得整个装载达到所要求的温度 应确定每种装载方式的升温时间 8.50 After the high temperature phase of a heat sterilization cycle, precautions should be taken against contamination of a sterilized load during cooling. Any cooling fluid or gas in contact with the product should be sterilized unless it can be shown that any leaking container would not be approved for use. 在热力灭菌程序的高温阶段结束之后, 应采取预防措施防止灭菌后装载物在冷却过程中被污染 任何与产品接触的冷却液或气体必须灭菌, 除非能证明不会使用存在任何泄漏容器 Moist heat sterilization 湿热灭菌 8.51 Time, temperature and pressure should be used to monitor the process. Each item sterilized should be inspected for damage, seal and packaging material integrity and moisture on removal from the autoclave. Seal and packaging integrity should also be inspected immediately prior to use. Any items found not to be fit for purpose should be removed from the manufacturing area and an investigation performed. 应监测灭菌过程的时间 温度和压力 每个灭菌后的物品均需检查其破损 密封和包装物料完整性以及水分 在临使用前也需检查密封和包装物料完整性 发现任何不合预期的物品都应该将其移出生产区, 并进行调查 8.52 System and cycle faults should be registered and recorded by the control and monitoring system and appropriate actions taken prior to release of the process. 应使用控制和监测系统来登记并记录系统和运行故障 并在工艺放行前采取适当措施 8.53 For sterilizers fitted with a drain at the bottom of the chamber, it may also be necessary to record the temperature at this position throughout the sterilization period. For Steam-In- Place (SIP) systems, it may also be necessary to record the temperature at condensate drain locations throughout the sterilization period. 对于在腔室底部安装有排水口的灭菌柜, 需在整个灭菌期间记录该点的温度 对于在线灭菌系统, 也需要整个灭菌期间记录冷凝水排水点的温度 8.54 Validation should include a consideration of equilibration time, exposure time, correlation of pressure and temperature and maximum temperature range during exposure for porous cycles and temperature, time and Fo for fluid cycles. These critical parameters should be subject to defined limits (including appropriate tolerances) and be confirmed as part of sterilization validation and routine cycle acceptance criteria. Revalidation should be performed annually.

41 验证时, 针对多孔装载需考虑平衡时间 曝热时间 压力与温度的关系 曝热期间的最大温度范围, 针对液体装载需考虑温度 时间和 F0 值 应确定这些关键参数的限度 ( 包括适当的容差 ), 并作为验证及日常操作的可接受标准的一部分 应每年进行再验证 8.55 There should be frequent leak tests on the system to be sterilized when a vacuum phase is part of the cycle or the system is returned, post-sterilization, to a pressure equivalent to or lower than the environment surrounding the sterilized system. The frequency of testing should be based on the principles of QRM. 当灭菌周期的某个部分为真空阶段, 或者系统在灭菌后恢复到或者低于周围环境压力时, 应该经常对其进行泄漏测试 测试频率应基于风险管理原则 8.56 When the sterilization process includes air purging (e.g. porous autoclave loads, lyophilizer chambers) there should be adequate assurance of air removal prior to and during sterilization. Loads to be sterilized should be designed to support effective air removal and be free draining to prevent the build-up of condensate. 当灭菌过程包含空气置换时 ( 如多孔装载灭菌柜 冻干腔室 ), 需要充分保证灭菌前及灭菌期间的排气 灭菌装载的设置应能确保有效排气, 并利于排水以防止凝结水积聚 8.57 The items to be sterilized, other than products in sealed containers, should be dry, wrapped in a material which allows removal of air and penetration of steam but which prevents recontamination after sterilization. All load items should be dry upon removal from the sterilizer. Load dryness should be confirmed as a part of sterilization process acceptance. 除装于密封容器内的产品以外, 其他待灭菌物品应干燥, 并包裹于一种可去除空气和可穿透蒸汽的材料中以防止灭菌后再污染 所有装载物从灭菌柜移出时均应是干燥的 装载物干度应作为灭菌程序标准的一部分来确认 8.58 Distortion and damage of flexible containers, such as containers produced by Blow-Fill- Seal and Form-Fill-Seal technology that are terminally sterilized, should be prevented by setting correct counter pressure and loading patterns. 应通过设定正确的内压和装载方式来防止对弹性容器 ( 如通过吹 - 灌 - 封或成型 - 灌 - 封技术生产并最终灭菌的容器 ) 的变形和破损 8.59 Care should be taken to ensure that materials or equipment are not contaminated after the sterilization exposure phase of the cycle due to the introduction of non-sterile air into the chamber during subsequent phases; typically only sterile filtered air would be introduced into the chamber during these phases. 应小心保证防止物料或设备在灭菌后的暴露阶段由于后续程序非无菌空气进入腔室所造成的污染, 通常在这些阶段应当只有无菌过滤的空气才能进入腔室 Where Sterilization in place (SIP) systems are used, (for example, for fixed pipework, vessels and lyophilizer chambers), the system should be appropriately designed and validated to assure all parts of the system are subjected to the required treatment. The system should be monitored for temperature, pressure and time at appropriate critical locations during routine use, this is to ensure

42 all areas are effectively and reproducibly sterilized; these critical locations should be demonstrated as being representative, and correlated with, the slowest to heat locations during initial and routine validation. Once a system has been sterilized by SIP it should remain integral prior to use, the maximum duration of the hold time should be qualified 当使用在线灭菌系统时,( 如固定的管道 容器和冻干室,) 该系统应恰当设计并验证以保证系统的所有部件受到必要处理 在日常使用中该对系统的恰当的关键位置监测温度 压力及时间, 以保证灭菌的有效性和可重复性 这些关键位置应该被证明是具有代表性的 并且与首次及常规验证过程中升温最慢的位置相关 一旦系统已经通过 SIP 进行了灭菌, 应该在使用之前保持系统的完整, 最大保持时间应通过确认 Dry heat sterilization 干热灭菌 8.61 The combination of time and temperature to which product, components and equipment are exposed should produce an adequate and reproducible level of lethality and/or pyrogen (endotoxin) inactivation/removal when operated routinely within the established tolerances. 在既定允许范围内进行日常操作时, 产品 部件和设备暴露的时间和温度的组合应能产生充分且可重复的杀灭率和 / 或去热原 ( 内毒素 ) 水平 8.62 Dry heat sterilization or depyrogenation tunnels are typically employed to prepare components for aseptic filling operations but may be used for other processes. Tunnels should be configured to ensure that airflow patterns protect the integrity and performance of the sterilizing zone, by maintaining a stable pressure differential and airflow pattern through the tunnel from the higher grade area to the lower grade area. All air supplied to the tunnel should pass through a HEPA filter; periodic tests should be performed to demonstrate filter integrity. Any tunnel parts that come into contact with sterilized components should be appropriately sterilized or disinfected. Critical process parameters that should be considered during validation and/or routine processing should include, but may not be limited to: 干热灭菌或除热原隧道通常用于准备无菌灌装操作所需的部件, 但也可用于其他工艺 应确保隧道的气流组织以保护灭菌区域的完整性和性能, 通过维持隧道内高级别至低级别区域的稳定压差及气流流型来实现 所有提进入隧道的空气均应通过 HEPA 过滤器 ; 应该定期进行测试来证明过滤器的完整性 任何与无菌后组件接触的隧道部件都应该经过适当灭菌或消毒 验证和 / 或日常操作过程中需考虑的关键参数包括但不限于 : a) Belt speed or dwell time within sterilising zone. 网带速度或灭菌区停留时间 b) Temperature Minimum and maximum temperatures. 温度 - 最小和最大温度 c) Heat penetration of material/article. 物料 / 部件的热穿透 Heat distribution/uniformity.

43 d) 热分布 / 均匀性 Airflows correlated with the heat distribution and penetration studies. e) 气流 - 与热分布和热穿透测试相关 8.63 When using endotoxin spiked containers these need to be carefully managed with a full reconciliation performed. Endotoxin quantification and recovery efficiency should also be demonstrated. 当使用已加入内毒素的容器时, 需要小心管理并 100% 平衡 并且需证实内毒素数量及回收率 8.64 Dry heat ovens are typically employed to sterilize or depyrogenate primary packaging components, finished materials or APIs but may be used for other processes. They should be maintained at a positive pressure to lower grade areas. All air entering the oven should pass through a HEPA filter. Critical process parameters that should be considered in validation qualification and/or routine processing should include, but may not be limited to: 干热灭菌柜通常用于成品或 API 内包材部件的灭菌或去热原, 但可用于其他工艺 应该对较低级别保持正压 所有进入灭菌柜的空气需经过 HEPA 过滤器 验证过程和 / 或日常操作过程中需考虑的关键参数包括但不限于 : Temperature. a) 温度 Exposure period/time. b) 曝热周期 / 时间 Chamber pressure. c) 腔室压力 Heat penetration of material/article (slow to heat spots and different loads). d) 物料 / 部件的热穿透 ( 冷点和不同装载 ) Heat distribution/uniformity. e) 热分布 / 均匀性 8.65 For dry heat sterilization of starting materials and intermediates the same principles should be applied. Consideration should be given to factors affecting heat penetration such as the container type, size and packing matrix. 对于起始材料和中间体的干热灭菌, 应该采用同样的原则 应考虑影响热穿透的因素, 如容器类型 尺寸和包装基质 Sterilization by radiation 辐照灭菌

44 8.66 Guidance regarding ionising radiation sterilization can be found within Annex 12 of the EU GMP. 关于电离辐射灭菌的指南参见 EUGMP 附录 Radiation sterilization is used mainly for the sterilization of heat sensitive materials and products. Many medicinal products and some packaging materials are radiation- sensitive, so this method is permissible only when the absence of deleterious effects on the product has been confirmed. Ultraviolet irradiation is not normally an acceptable method of sterilization. 辐射灭菌主要用于热敏感材料和产品的灭菌 许多医药产品和包装材料是辐射敏感的, 所以只有在确认对产品没有不良影响的情况下才允许这种方法 紫外线照射通常不是一种可接受的灭菌方法 8.68 Validation procedures should ensure that the effects of variations in density of the packages are considered. 验证程序应确保考虑到不同包材的密度影响 Sterilization with ethylene oxide 环氧乙烷灭菌 8.69 This method should only be used when no other method is practicable. During process validation it should be shown that there is no damaging effect on the product conditions and time allowed for degassing to reduce any residual ethylene reaction products to defined acceptable limits for the type of product or material. and that the oxide (EO) gas and 仅在其他方法不适用情况下采用此法 在工艺验证中应证实对产品无破坏性影响, 以及可减少残留环氧乙烷气体和反应产物至规定的产品或物料接受限度的排气条件和时间 8.70 Direct contact between gas and microbial cells is essential; precautions should be taken to avoid the presence of organisms likely to be enclosed in material such as crystals or dried protein. The nature and quantity of packaging materials can significantly affect the process. 气体和微生物细胞之间的直接接触是至关重要的 应当注意避免包裹在诸如晶体或干的蛋白质内的生物体 包装材料的性质和数量严重影响此工艺的效果 8.71 Before exposure to the gas, materials should be brought into equilibrium with the humidity and temperature required by the process. The time required for this should be balanced against the opposing need to minimize the time before sterilization. 在暴露气体前, 物料应达到工艺所要求的温度和湿度的平衡 应平衡该时间与待灭菌时间的之间的矛盾 8.72 Each sterilization cycle should be monitored with suitable biological indicators, using the appropriate number of test pieces distributed throughout the load unless parametric release has been authorized by the National Competent Authority. 每个灭菌周期都应使用适当的生物指示剂进行监测, 将适当数量的生物指示剂分布于装载中, 除非获得国家主管当局批准进行参数放行

45 8.73 Critical process variables that should be considered as part of sterilization process validation and routine monitoring include, but are not limited to: EO gas concentration, relative humidity, temperature and EO gas pressure and exposure time. 灭菌工艺验证和日常监测应考虑的关键工艺变量包括但不限于 :EO 气体浓度, 相对湿度 温度和 EO 气体压力和曝露时间 8.74 After sterilization, the load should be aerated to allow EO gas and/or its reaction products to desorb from the packaged product to predetermined levels. Aeration can occur within a sterilizer chamber and/or in a separate aeration chamber or aeration room. The aeration phase should be validated as part of the overall EO sterilization process validation. 在灭菌后, 应对装载物通气, 以使 EO 气体和 / 或其反应物从包装产品中释放并达到设定水平 通气可以在灭菌柜内或在单独的通气柜或通气室内 通气阶段应该作为整个 EO 灭菌工艺的一部分进行验证 Filtration of medicinal products which cannot be sterilized in their final container 非最终灭菌药品的过滤 8.75 If a liquid product cannot be terminally sterilized by a microbiocidal process, it should be sterilized by filtration through a sterile, sterilizing grade filter (with nominal pore size of 0.22 micron (or less) or with at least equivalent micro-organism retaining properties), and subsequently aseptically filled into a previously sterilized container, the selection of the filter used should ensure that it is compatible with the product, see Suitable bioburden reduction and/or sterilizing grade filters may be used at multiple points during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the primary sterilizing grade filter. Due to the potential additional risks of a sterilizing filtration process as compared to other sterilization processes, a second filtration through a sterile, sterilising grade filter (positioned as per clause 8.15), immediately prior to filling, is advisable 如果某液态产品无法通过灭菌工艺进行最终灭菌, 应经过无菌的除菌级过滤器 ( 孔径至少是 0.22 微米或至少具有等效截留性能 ) 进行除菌过滤, 随后通过无菌分装至已灭菌容器内, 应选择与产品相容的过滤器, 见 节 可在生产过程多个位置使用降低微生物负荷和 / 或无菌级的过滤器, 以保证液体在经过前端过滤器前具有一个较低和受控的微生物水平 与其他灭菌工艺相比, 除菌过滤工艺存在额外的潜在风险, 建议在灌装前使用另一个无菌的除菌级别过滤器 ( 见 8.15 节 ) 进行二级过滤 8.79 The selection of components for the filtration system (including air, gas and vent filters) and their interconnection and arrangement within the filtration system, including pre-filters, should be based on the critical quality attributes of the products, documented and justified. The filtration system should not generate fibres, unacceptable levels of impurities or otherwise alter the quality and efficacy of the product. Similarly, the filter characteristics should not be adversely affected by the product to be filtered. Adsorption of product components and extraction/leaching of filter components should be evaluated (see Single- Use-Systems, Clauses ). 过滤系统 ( 包括空气 气体或空调过滤器 ) 部件的选择, 及其在过滤系统中的相互连接和排列, 包括预过滤, 应基于产品质量属性, 并记录和论证 过滤系统不能产生纤维 或不可接受的杂质 或影响产品质量或药效 同样的, 过滤器特性不应受待过滤产品影响 应对产品吸附 过滤器组分的浸出 / 析出进行评估 ( 见一次性使用系统 节 )

46 8.80 The filtration system should be designed to: 过滤系统应被设计为 : Allow operation within validated process parameters. a) 允许在经过验证的工艺参数中进行操作 Maintain the sterility of the filtrate. b) 维持滤液的无菌性 Minimise the number of aseptic connections required between the sterilizing filter and the final filling of the product. c) 最大程度降低除菌级过滤器与产品最终灌装的之间的无菌连接的次数 Allow cleaning procedures to be conducted as necessary. d) 允许在必要时进行清洁操作 Allow sterilization procedures, including SIP, to be conducted as necessary. The sterilization procedures should be validated to ensure achievement of a target sterilization assurance level (SAL) of 10-6 or better (e.g. 10-7). e) 允许在必要时进行包括 SIP 在内的灭菌程序 灭菌程序应经验证以达到 10-6 的无菌保障水平 (SAL) 目标或更佳 ( 如 10-7) Permit in-place integrity testing, preferably as a closed system, prior to filtration as necessary. In-place integrity testing methods should be selected to avoid any adverse impact on the quality of the product. f) 必要时, 允许在过滤前进行在线完整性测试, 最好是一个封闭的系统 应选择合适的在线完整性测试方法以避免对产品质量造成负面影响 8.81 Liquid-sterilizing filtration should be validated during initial process validation. Validation can be grouped by different strengths or variations of a product, but should be done under worst-case conditions. The rational for grouping fluids should be justified and documented. 在首次工艺验证时应对液体灭菌过滤器进行验证 验证可按不同规格或不同产品组合进行, 但应在最差条件进行 应论证和记录分组的合理性 8.82 Wherever possible, the product to be filtered should be used for bacterial retention testing. Where the product to be filtered is not suitable for use in bacterial retention testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the bacterial retention test should be justified. 应尽可能使用待过滤产品进行微生物截留测试 当待过滤产品不适用于微生物截留测试时, 应评估适当的代替产品用于该测试 微生物截留测试所用的挑战菌也应经过评估 8.83 Filtration parameters that should be considered in validation and routine processing should

47 include but are not limited to: 验证和日常操作过程中应考虑的过滤参数应包括但不限于 : a) If the system is flushed or integrity tested in-situ with a fluid other than the product, then flushing with the product should be part of the process. 如果用产品外的其他液体对系统进行冲洗或进行完整性测试, 则之后应使用产品进行冲洗 b) The wetting fluid used for filter integrity testing based on filter manufacturer s recommendation or the fluid to be filtered. For the latter, the appropriate integrity test value specification should be established. 用于过滤器完整性测试的润湿液应基于生产商的建议或待过滤液体 对后者, 应建立适当的完整性测试标准 c) Filtration process conditions including: 过滤工艺条件包括 : i. Fluid prefiltration holding time and effect on bioburden. 待过滤液体的保存时间和对生物负载的影响 ii. Filter conditioning, with fluid if necessary. 如有必要, 用液体对过滤器进行润湿 iii. Maximum filtration time/total time filter is in contact with fluid. 最长过滤时间 / 过滤器接触液体的总时间 iv. Flow rate. 流速 v. Filtration volume. 过滤量 vi. Temperature. 温度 vii. The time taken to filter a known volume of bulk solution and the pressure difference to be used across the filter. Any significant differences from those validated to those observed during routine manufacturing should be noted and investigated. Results of these checks should be included in the batch record. 过滤已知量原液所用时间和过滤时过滤器两端的压差 应关注并调查任何在日常生产中观察到的数值与验证过的数值之间的明显差异 这些检查结果应包含在批记录中 8.84 The integrity of the sterilized filter assembly should be verified by testing before use, in case of damage and loss of integrity caused by processing, and should be verified by on line testing

48 immediately after use by an appropriate method such as a bubble point, diffusive flow, water intrusion or pressure hold test. It is recognised that for small batch sizes, this may not be possible; in these cases an alternative approach may be taken as long as a formal risk assessment has been performed and compliance is achieved. There should be written integrity test methods, including acceptance criteria, and failure investigation procedures and justified conditions under which the filter integrity test can be repeated. Results of the integrity tests (including failed and repeated tests) should be included in the batch record. 应在使用前对灭菌后的过滤器的完整性进行测试, 如果因操作而造成完整性遭到破坏或降低, 则应在其使用后立即通过适当的方法进行在线完整性确认, 例如起泡点法 扩散流法 水侵入法 或压力保持试验 批量较小时不宜采用这种方式 在这种情况下, 应进行正式的风险评估并确保合规, 可采用其他方法代替 应有书面的完整性测试方法, 包括可接受标准和失败调查程序以及复测的条件 完整性测试的结果 ( 包括失败的和复测的结果 ) 应被包含在批记录中 8.85 The integrity of critical sterile gas and air vent filters in the filter assembly should be verified by testing after use. The integrity of non-critical air or gas vent filters should be confirmed and recorded at appropriate intervals. 关键的无菌气体和空气呼吸过滤器的完整性应在使用后测试确认 非关键空气或气体呼吸过滤器的完整性应以适当的间隔进行确认并记录 8.86 For gas filtration, the avoidance of unintended moistening or wetting of the filter or filter equipment is important. This can be achieved by the use of hydrophobic filters. 对于气体过滤, 应避免对滤器或过滤设备的意外润湿 这可以通过使用疏水性过滤器实现 8.87 Where serial filtration (one filtration is followed by a subsequent filtration) is a process requirement the filter train is considered to be a sterilizing unit and all sterilizing-grade filters within it should satisfactorily pass integrity testing both before use, in case of damage during processing, and after use. 当工艺要求进行串联过滤 ( 一次过滤后再次进行过滤 ) 时, 它们应被视为一个除菌单元, 且其中所有除菌级过滤器在使用前以及使用后均应成功地通过完整性测试, 以防止过滤器在使用过程中损坏 8.88 Where a redundant sterilizing filter is used, the additional filter does not require post- integrity testing unless the primary sterilizing filter fails, in which case the redundant filter must then satisfactorily pass post-use integrity testing. Bioburden samples should be taken prior to the first filter and the sterilizing filter, systems for taking samples should be designed so as not to introduce contamination. 当使用了冗余除菌过滤器时, 附加的过滤器不必进行使用后的完整性测试, 除非主除菌过滤器不合格 在此情况下, 冗余过滤器必须成功通过使用后的完整性测试 应在第一个过滤器以及除菌过滤器前分别取样测试生物负荷, 取样系统的设计不得引入污染 8.89 Liquid sterilizing filters should be discarded after the processing of a single lot. The same filter should not be used for more than one working day unless such use has been validated. 液体除菌过滤器在处理完一批产品后应废弃 同一个过滤器使用不能超过一个工作日, 除非经过验证

49 Form-Fill-Seal 成型 - 灌装 - 密封 8.90 Form-Fill-Seal (FFS) units include blow moulding from thermoplastic granulate and thermoforming from thermoplastic film typically known as Blow-Fill-Seal (BFS) and Vertical-Form-Fill-Seal (VFFS) respectively. VFFS process is an automated filling process, typically for terminally sterilized processes, that may utilize a single or dual web system which constructs the primary container out of a flat roll of thermoplastic film while simultaneously filling the formed bags with product and sealing the filled bags in a continuous process. All such containers are considered to be sealed by fusion and, as such, fall under the requirement to perform 100% integrity testing. 成型 - 灌装 - 密封 FFS 单元包括吹塑成型和热压成型, 通常分别被称为吹 - 灌 - 封 (BFS) 和垂直 - 成型 - 灌装 - 密封 VFFS VFFS 工艺是一种自动化的灌装工艺, 通常用于最终灭菌工艺 该工艺可用单网或双网系统将成卷的热塑性薄膜制成内包装材料, 并同时对成型的软袋产品进行灌装, 然后对灌装好的软袋进行密封 该工艺是一个连续的工艺过程 所有这些容器均被视为熔封型容器, 并因此需要进行 100% 的完整性检查 8.91 Process parameters relating to seal integrity should be validated and appropriately controlled. Critical parameters include, but are not limited to: seal strength, seal uniformity, sealing temperatures, pressures, sealing times and dwell time for filling. Seal strength and uniformity should be monitored routinely. 与密封完整性有关的工艺参数应进行验证并进行适当的控制 这些关键参数包括, 但不限于 : 密封强度 密封均匀度 密封温度 压力 密封时间 密封后待灌装时间 密封强度和均匀度应进行日常监控 8.92 Samples of filled containers should be tested for general performance e.g. ease-of- opening, and seal uniformity. Sample size and frequency should be based on the principles of QRM. 应对灌装后容器取样进行一般性能的检查, 如易开启性和密封均匀度 取样量和频率应基于 QRM 原则制定 Blow-Fill-Seal technology 吹 - 灌 - 封技术 8.93 Blow-Fill-Seal (BFS) units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine, see glossary for full definition. 吹灌封 (BFS) 单元是特制的设备, 可连续操作, 通过全自动一体化设备进行热塑成型 分装然后密封, 详细定义见术语部分 8.94 Risk management principles should be used to justify the machine s design and operational controls. These controls should be in alignment with the site s contamination control strategy. Aspects to be considered should include (but are not limited to): 应使用风险管理原则论证设备设计和运行控制 这些控制应与工厂的污染控制策略相联系 考虑的方面包括 ( 但不限于 ) 如下 :

50 a) Determination of the critical zone that should be protected from contamination, and its control. 关 键区域 的确定及其控制, 应避免污染 b) Environmental control and monitoring, both of the BFS machine and the background in which it is placed. 应对吹灌封设备及其所处的背景进行环境控制和环境监测 c) Integrity testing of the BFS product pathways. 吹灌封产品路径的完整性测试 d) Duration of the batch or filling campaign. 批生产或灌装的时长 e) Control of polymer starting material. 高分子起始物料的控制 f) Cleaning-in-place and sterilization-in-place of equipment, and air and product pathways. 设备 气体和产品通道的在线清洁和在线灭菌 8.95 Shuttle and Rotary-type equipment used for aseptic production which is fitted with an effective grade A air shower should be installed in at least a grade C environment, provided that grade A/B clothing is used. 当装有 A 级风淋的往复式和旋转式吹灌封设备用于无菌生产时, 应至少安装在戴 A/B 级工作服 C 级的环境中, 并穿 8.96 For Shuttle type equipment, the environment should comply with the viable and non- viable limits at rest and the viable limit only when in operation. The shuttle zone should meet grade A viable limits. 对于往复式设备, 其环境应符合静态条件下的微生物和悬浮粒子标准, 动态条件下, 仅微生物限度应达到标准 穿梭区域应符合 A 级微生物限度要求 8.97 For Rotary-type equipment the environment should comply with the viable and non- viable limits at rest. It is not normally possible to perform environmental monitoring within the parison during operation" Monitoring of the background environment should be performed in accordance with risk management principles 对于旋转式设备, 其环境应符合静态条件下的微生物和悬浮粒子标准 动态条件下通常无法对吹气成型部位进行环境监测 背景环境的监测应根据风险管理原则进行 8.98 The environmental control and monitoring program should take into consideration the complex gas flow paths generated by the BFS process and the effect of the high heat outputs of the process.

51 环境控制及监测程序应同时考虑 BFS 操作产生气流的复杂性及高温工艺的影响 8.99 In addition, for Shuttle-type designs, the area between parison cutting and mould sealing should be covered by a flow of HEPA filtered or sterile air of appropriate quality to provide grade A at the critical zone. 另外, 对于往复式设计的设备, 吹气成型切割和模具密封区域应覆盖 HEPA 过滤的空气或合适质量的无菌空气, 以为关键区域提供 A 级环境 Blow-Fill-Seal equipment used for the production of products which are terminally sterilized should be installed in at least a grade D environment 对于最终灭菌产品生产所用的 BFS 设备应至少安装在 D 级环境 External particle and microbial contamination of the polymer should be prevented by appropriate design, control, and maintenance of the polymer storage and distribution systems. 应通过对高分子聚合物存放和分发系统进行恰当的设计 控制和维护以防止其外部异物及微生物污染 Interventions requiring cessation of filling and/or blowing and sealing and, where required, re-sterilization of the filling machine should be clearly defined and well described in the aseptic filling procedure, and included in the aseptic process simulation (refer clause 9.36). 应在无菌分装规程中明确定义并描述需要停止分装和 / 或吹气密封的干扰, 必要时, 对分装设备重新灭菌, 并包含在无菌工艺模拟中 ( 参见 9.36 节 ) Process validation should take into consideration critical operating parameters and variables of the equipment that impact on the quality of the product, e.g. filling speed, extrusion temperature, filling times. 工艺验证中应考虑影响产品质量的关键操作参数和设备变量, 如分装速度 挤压温度 灌装次数 Samples of filled containers should be tested for general performance e.g. ease-of- opening and wall thickness; sample size and frequency should be based on the principles of QRM. 应对灌装后的容器取样测试其性能, 如易打开性 壁厚 应根据风险管理确定取样数量及频次 Lyophilization 冻干法 Lyophilization is a critical process step and all activities that can affect the sterility of the product or material need to be regarded as extensions of the aseptic processing of that sterilized product or material. The lyophilization equipment and its processes should be designed so as to ensure product or material sterility is maintained during lyophilization by preventing microbiological and particulate contamination between the filling operation and completion of lyophilization process. All control measures in place should be determined by the site s contamination control strategy.

52 冷冻干燥是一个非常关键的操作步骤, 所有影响产品或物料无菌性的活动均应认为是对已灭菌产品或物料的无菌操作 冻干设备及其工艺均应当设计以保证产品或物料的无菌性, 防止在灌装和冻干程序完成期间的微生物或微粒污染 The lyophilizer should be sterilized before each load. The lyophilizer should be protected from contamination after sterilization. 每一次装载前冻干机均需经过灭菌 并在灭菌后防止污染 Where there is a closing system for partially closed containers, the surfaces of any equipment protruding into the chamber to effect sealing should also be sterilized. 对用于半密封容器的密闭式系统, 任何通过伸入箱体来影响密封的设备表面也应进行灭菌 Lyophilization trays should be checked to ensure that they are not misshapen and damaged. 冻干托盘应检查以确保无变形或损坏 The maximum permitted leakage of air into the lyophilizer should be specified. 应规定冻干机的最大允许空气泄漏 The integrity of the system should be monitored periodically along with consideration of the leak rate test. 应定期监测系统完整性并考虑泄漏率测试 With regard to loading and unloading the lyophilizer: 关于冻干机的装载和卸载 : a) The loading pattern within the lyophilizer should be specified and documented. 应规定并记录冻干机的装载方式 b) Transport to the lyophilizer and loading of filled product, or other equipment into the lyophilizer should take place under a grade A environment. 产品或其他设备的转运至冻干机及装载过程, 应在 A 级环境下 c) Airflow patterns should not be adversely affected by transport devices and venting of the loading zone. Unsealed containers should be maintained under grade A environment. 气流流型应不受运输装置和装载区排气的影响 未密封的容器应保持在 A 级环境下 d) Where seating of the stoppers is not completed prior to opening the lyophilizer chamber, product removed from the lyophilizer should remain under a grade A environment during subsequent handling. 在冻干机打开前, 产品处于不完全加塞状态的, 产品移出冻干机进行下一步操作的过程中应维持在 A 级环境下

53 e) Utensils used during transfer to, loading and unloading of, the lyophilizer (such as trays, bags, placing devices, tweezers, etc.) should be subjected to a validated sterilization process. 转运 装载和卸载过程中用到的工具 ( 例如托盘 袋子 定位装置 镊子等 ) 应经过已验证的灭菌工艺灭菌 Closed systems 密封系统 Closed systems can be both single use systems (SUS) (i.e. disposable) and fixed systems (such as vessels with fixed pipework). Guidance in this section is equally applicable to both systems. 密封系统可以是一次性使用系统 (SUS)( 用完即丢 ) 和固定系统 ( 如有固定管理的容器 ) 本章节的指导意见同时适用于两个系统 The use of closed systems can reduce the risk of both microbial and chemical contamination due to interventions. 使用隔离系统可减少干扰产生的微生物和化学污染的风险 It is critical to ensure the sterility of product contact surfaces of closed systems used for aseptic processing. The design and selection of any closed system used for aseptic processing must ensure maintenance of sterility. Tubing/pipework that is not assembled prior to sterilization should be designed to be connected aseptically, e.g. by intrinsic aseptic connectors or fusion systems. 保证无菌工艺所用隔离系统的产品接触面的无菌性是非常关键的 无菌工艺所用的任何隔离系统的设计及选择必须确保无菌性维持 未在灭菌前组装的管道应设计为无菌连接, 如通过无菌连接器或熔接系统 Appropriate systems should be in place to assure the integrity of those components used. The manner in which this is conducted should be determined based on QRM principles. Appropriate system integrity tests should be considered when there is a risk of compromising product sterility. 应有适当的系统以确保这些组件的完整性 应根据 QRM 原则确定所使用的方式 当有破坏产品无菌性的风险时, 应考虑适当的系统完整性测试 The background in which closed systems are located will vary. If there is a high risk that the system will not remain integral during processing it should be located in a grade A environment. If the system can be shown to remain integral at every usage then lower grades, including grade D, can be considered. 隔离系统所处的背景条件可能会有所不同 如果系统在生产过程中无法保持完整性的风险高, 它应当处于 A 级环境 如果能证明在各使用环境均能保持其完整性, 则可以考虑较低级别, 包括 D 级 Single use systems

54 一次性使用系统 Single use systems (SUS) are those technologies used in manufacture of sterile medicinal products which are designed to replace reusable equipment. SUS are typically defined systems made up of components such as bags, filters, tubing, connectors, storage bottles and sensors. 一次性使用系统 (SUS) 是指在无菌药品生产中运用到的设计以代替重复使用性设备的技术 SUS 通常定义为由相关部件如袋子 过滤器 管道 连接器 储瓶及传感器组成的系统 There are some specific risks associated with SUS which include, but are not limited to: SUS 有一定风险, 包括但不限于 : a) Interaction between the product and product contact surface (adsorption, leachable and extractables). 产品与产品接触表面的相互作用 ( 吸附 浸出物和溶出物 ) b) More fragile than fixed reusable systems. 与固定的重复使用系统相比更脆弱 c) Increase in number and complexity of manual operations and connections made. 人工操作和连接的数量和复杂性增加 d) Design of the assembly. 组装的设计 e) Performance of the pre-use integrity testing for sterilizing grade filters. (Refer to clause 8.84.) 无菌级过滤器使用前完整性测试的执行 ( 参见 8.84 节 ) f) Integrity testing. 完整性测试 g) Pin-hole and leakage. 针孔和泄漏 h) The potential for compromising the system at the point of opening the outer packaging. 打开外包装时对系统的潜在影响 i) Assessment of suppliers of disposable systems (including sterilization of these disposable systems. 一次性系统供应商的评估 ( 包括这些一次性系统的灭菌 ) j) Risk of particulate contamination. 微粒污染的风险

55 8.119 The compatibility of materials used for product contact surfaces with the products should be ensured under the process conditions by evaluating e.g. adsorption and reactivity to the product 应评价工艺条件下产品接触面的材料和产品的相容性, 如产品吸附 产品反应 Extractable profile data obtained from the supplier of the components of SUS may be useful to ensure that extractables and leachables from the SUS do not alter the quality of the product. A risk assessment should be conducted for each component to evaluate the applicability of the extractable profile data. For components considered to be at high risk to leachables, including those taking up leachables extensively or those stored for longer periods, an assessment of leachable profile studies, including safety concerns, and should be taken into consideration, as necessary. If applying simulated processing conditions these should accurately reflect the actual processing conditions and be based on a scientific rationale. 从 SUS 组件供应商处获得的可提取物数据可用来证明其浸出和析出物对产品质量无影响 应进行风险评估以评价每一个组件的这些可提取物数据的适用性 对于认为是析出物高风险的组件, 包括产生大量析出物或长期存放的组件, 必要时, 应对其析出物试验数据进行评估, 包括安全性方面的考虑 如果模拟工艺条件, 应能准确反映实际工艺条件并基于一个科学的原理 SUS should be designed so as to maintain integrity during the intended operational conditions and duration, especially the structural integrity of the single use components under extreme process and transport conditions such as during freeze and thaw processes. This should include verification that intrinsic aseptic connections (both heat and mechanical) remain integral under these conditions. SUS 的设计应能在预期操作条件和持续时间内下保持完整性, 特别是在极端工艺和运输条件下的一次性组件的结构完整性, 例如冷冻和解冻过程 这应包括确认在这些条件下保持其固有无菌连接 ( 包括热连接和机械连接 ) 完整性的确认 Acceptance procedures should be established and implemented for SUS corresponding to the risks or criticality of the products and its processes. On receipt, a visual inspection of outer packaging (e.g. appearance of exterior carton, product pouches), label printing, and attached documents (e.g. Certificate of Analysis, radiation certificate) should be carried out. Prior to use, each piece of SUS should be checked to ensure that they have been manufactured and delivered in accordance with the approved specification. 应建立并实施与产品及其工艺的关键性或风险相关的验收程序 验收时, 应检查其外包装 ( 例如外箱 产品保护袋的外观 ) 标签打印和随货文件 ( 例如检验报告单 (COA) 辐照证书 ) 使用前应检查每个 SUS 以确保他们的生产和运输符合已批准的质量标准 Critical manual handling operation of SUS, such as assembling and connecting, should be subject to appropriate controls and verified during the aseptic process simulation test. SUS 的关键人工处理操作, 如装配和连接, 应该采取适当的控制措施, 并应在无菌工艺模拟试验中验证 9 Viable and non-viable environment & process monitoring 9 活性和非活性环境 & 工艺监测 General 概述

56 9.1 The site s environmental and process monitoring program forms part of the overall contamination control strategy designed to minimise the risk of microbial and particulate contamination. 车间的环境和工艺监测计划是整个用于降低微生物及粒子污染的污染控制策略的一部分 9.2 This program is typically comprised of the following elements: 这个监测计划通常由以下要素组成 : a) Environmental monitoring non viable. 环境监测 非活性 b) Environmental monitoring viable. 环境监测 活性 c) Aseptic process simulation (aseptically manufactured product only). 无菌工艺模拟 ( 仅适用于无菌生产产品 ) 9.3 These key elements provide information with regards to the process and facility capabilities with respect to the maintenance of sterility assurance. The information from these systems should be used for routine batch release and for periodic assessment during process review or investigations. 这些关键要素提供了关于维持无菌保障设施能力和工艺能力的信息 这些系统的信息应该用于日常批放行以及工艺回顾或调查期间的周期性评估 Environmental monitoring 环境监测 9.4 In order to establish a robust environmental monitoring program, i.e. locations, frequency of monitoring and incubation conditions (e.g. time, temperature(s) and aerobic and or anaerobic), appropriate risk assessments should be conducted based on detailed knowledge of the process inputs, the facility, equipment, specific processes, operations involved and knowledge of the typical microbial flora found, consideration of other aspects such as air visualization studies should also be included. These risk assessments should be re-evaluated at defined intervals in order to confirm the effectiveness of the site s environmental monitoring program, and they should be considered in the overall context of the trend analysis and the contamination control strategy for the site. 为了制定一份稳健的环境监测计划, 例如, 布点 监测频率和培养条件 ( 如时间 温度 需氧和 / 或厌氧 ), 应该基于相关的工艺输入 设施 设备 特定工艺 操作的详细知识以及所发现的典型微生物种群进行适当的风险评估, 其他方面的考虑如烟雾试验研究也应包括在内 这些风险评估应该在规定时间后进行再评价, 以确认环境监测计划的有效性, 应将其考虑到趋势分析以及污染控制策略中 9.5 Routine monitoring for clean rooms, clean air devices and personnel should be performed in operation throughout all critical stages, including equipment set up. The locations, frequency, volume and duration of monitoring should be determined based on the risk assessment and the results obtained during the qualification. 洁净室 净化空气设备和人员的日常监测应在动态条件下进行, 并覆盖所有关键阶段, 包括设备装配 监测的位置 频率 监测量以及持续时间应基于风险评估和确认期间获得的结果来确定 9.6 Monitoring should also be performed outside of operations within the area, e.g. pre disinfection, post disinfection, prior to start of manufacturing and after a shutdown period etc., in order to detect potential incidents of contamination which may affect the controls within the areas. The number of samples and frequency of monitoring should be considered in the context of the risk assessments and contamination control strategy.

57 除了日常操作之外, 其他时间如, 消毒前 消毒后 开始生产前以及停产期结束后等也应该监测以发现可能影响相关区域环境控制的潜在污染事件 监测的数量和频率应在风险评估和污染控制策略予以考虑 9.7 For grade A monitoring, it is important that sampling should be performed at locations posing the highest risk of contamination to the sterile equipment surfaces, container-closures and product in order to evaluate maintenance of aseptic conditions during critical operations. 对于 A 级的监测, 重要的是应该在无菌设备表面 容器密封件和产品的最高污染风险位置进行取样, 以评估关键操作期间无菌条件的保持 9.8 Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. Alert levels should be established based on results of Performance Qualification (PQ) tests or trend data and should be subject to periodic review. 应该对粒子和微生物监测的结果制定适当的警戒限和行动限 警戒限应该基于性能确认 (PQ) 试验的结果或趋势数据来制定, 并进行定期回顾 9.9 The alert limits for grade B, C and D should be set based on the area performance, with the aim to have limits lower than those specified as action limits, in order to minimise risks associated and identify potential changes that may be detrimental to the process. 为了让警戒限低于规定的行动限,B C D 级警戒限的制定应该基于该区域的性能, 从而减少相关风险, 又能识别到可能对工艺有害的潜在变化 9.10 If action limits are exceeded operating procedures should prescribe a root-cause investigation followed by corrective and preventive action. If alert limits are exceeded,operating procedures should prescribe scrutiny and follow-up, which might include investigation and corrective action. 如果超出行动限, 操作规程应该规定在纠正预防措施之后进行根本原因调查 如果超出警戒限, 操作规程应该规定进行监控和跟进, 包括调查和纠正措施 9.11 Surfaces and personnel should be monitored after critical operations. Results from monitoring should be considered when reviewing batch documentation for finished product release. 应在关键操作之后对表面和人员进行监测 审核批放行的文件时应考虑这些监测结果 Non-viable monitoring 非活性粒子监测 9.12 Non-viable particle monitoring systems should be established to obtain data for assessing potential contamination risks and to maintain the environment for sterile operations in the qualified state. 应建立非活性粒子监测系统, 以获得评估潜在污染风险的数据, 及维持无菌操作环境处于已确认状态 9.13 The recommended limits for airborne particle concentration in monitoring for each grade are given in Table 5. 各级别悬浮粒子推荐的监测浓度限度见表 5

58 Table 5: Recommended limits for airborne particle concentration for the monitoring of non-viable contamination 非活性悬浮粒子污染监测浓度的推荐限度 Grade 级别 Recommended maximum limits for particles 0.5 μm/m μm/m 3 粒子的建议最大限度 in operation at rest 动态静态 Recommended maximum limits for particles 5 μm/m 3 5 μm/m 3 粒子的建议最小限度 in operation at rest 动态静态 A B C D Set a limit based on the risk assessment 基于风险评估制定限度 Set a limit based on the risk assessment 基于风险评估制定限度 Note 1: The particle limits given in the table for the at rest state should be achieved after a short clean up period defined during qualification in an unmanned state after the completion of operations (see 5.26e). 备注 1: 表格中给出的静态下的粒子限度应该在完成操作之后的无人状态条件下, 经过一个已确认的短暂的自净时间后达到,( 见条款 5.26e) Note 2: With regards to the monitoring of 5.0 μm, the limit of 20 is selected due to the limitations of monitoring equipment. It should be noted that alert limits should also be set based on historical and qualification data, such that frequent sustained recoveries below the action li an m it should also trigger investigation. 备注 2: 对于 5.0μm 粒子的监测, 选择 20 的限度是由于监测设备的限制 应该注意的是警戒限应该也要基于历史和确认数据来制定, 如此, 当频繁持续超警戒时, 即使低于行动限也应该发起调查 9.14 For grade A zones, particle monitoring should be undertaken for the full duration of critical processing, including equipment assembly. 对于 A 级区, 粒子监测应该在关键操作的全过程进行, 包括设备装配 9.15 The grade A zone should be monitored continuously and with a suitable sample size (at least 28 litres (a cubic foot) per minute) so that all interventions, transient events and any system deterioration would be captured and alarms triggered if alert limits are exceeded. A 级区应该持续监测并选取合适的取样量 ( 至少 28 升 / 分钟 (1 立方尺 / 分钟 )), 以便所有干扰 瞬变事件以及系统恶化都能被捕捉到, 如果超出警戒限, 则触发警报 9.16 It is recommended that a similar system be used for grade B zones although the sample frequency may be decreased. The design of the monitoring system should be based on risk assessment and be commensurate with the risk of the process to the product sterility assurance. The grade B zone should be monitored at such a frequency and with suitable sample sizes that the programme captures any change in levels of contamination and system deterioration. If alert limits are exceeded, alarms should be triggered.

59 建议对 B 级使用类似的系统, 但是取样频率可以减少 监测系统的设计应该基于风险评估, 并与产品无菌保障工艺的风险相匹配 B 级区应该在相称的频率及合适的取样量下进行监测, 以便捕捉各个程度的污染和系统恶化的所有变化 如果超出警戒限, 则应触发警报 9.17 The monitoring of grade C and D areas in operation should be performed in accordance with the principles of QRM to provide sufficient data to allow effective trend analysis. The requirements and alert/action limits will depend on the nature of the operations carried out. C 级和 D 级区的动态监测应该根据质量风险管理 (QRM) 的原则来进行, 以提供充分的数据来进行有效的趋势分析 监测要求和警戒 / 行动限将取决于所进行操作的性质 9.18 The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example those involving live organisms or radiopharmaceuticals that may give rise to biological or chemical hazards. 监测系统的选择应该考虑生产 操作所用物料带来的任何风险, 比如这些涉及可能引起生物或化学危害的活性生物体或放射性药物 9.19 In the case where contaminants present due to the processes involved would damage the particle counter or present a hazard, e.g. live organisms and radiological hazards, the frequency and strategy employed should be such as to assure the environment classification both prior to and post exposure to the risk. Additionally, monitoring should be performed during simulated operations. Such operations should be performed at appropriately defined intervals. The approach should be defined in the contamination control strategy. 在由于相关工艺存在的污染物将损坏粒子计数器或者有危害的情况下, 例如, 活性生物体和放射学危害, 所制定的监测频率和策略应该能确认暴露该风险前后的环境级别 另外应在模拟操作期间进行监测 这种模拟操作应该在规定的合适周期间隔内进行 该方法应在污染控制策略中明确 9.20 Where powdery products are manufactured, monitoring of particles may have to take into consideration an alternative monitoring scheme and frequency, e.g. monitoring for particle levels prior to and after the manufacturing process step. 如果生产粉状类产品, 粒子监测可能不得不考虑替代的监测方案和频率, 如, 生产工序步骤前后的颗粒浓度监测 9.21 The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal qualification of clean rooms and clean air devices. 出于监测目的的自动化系统其取样量将通常是所用系统的取样率 取样量不必和洁净室 净化空气设备正式确认中所用的量一样 9.22 Although monitoring of 5.0 μm particles are not required for room qualification and classification purposes, it is required for routine monitoring purposes as they are an important diagnostic tool for early detection of machine, equipment and HVAC failure. 尽管在房间确认和分级中不要求 5.0 μm 粒子的监测, 但要求日常监测, 因为及早发现机器 设备和 HVAC 故障的重要诊断工具 9.23 The occasional indication of macro particle counts, especially 5.0 μm, may be considered false counts due to electronic noise, stray light, coincidence, etc. However,consecutive or regular counting of low levels may be indicative of a possible contamination event and should be investigated. Such events may indicate early failure of the room air supply filtration (HVAC) system, filling equipment failure, or may also be diagnostic of poor practices during machine set-up and routine operation.

60 大颗粒, 尤其是 5.0 μm 的粒子计数的偶尔出现, 可认为是由于电子噪声 杂散光 巧合等造成的技术错误 但是, 持续或有规律的低水平计数可能暗示污染事件, 并应进行调查 这些事件可能暗示房间空气过滤系统 (HVAC) 早期故障 灌装设备故障, 或者可能是设备组装和日常操作中发现的不良操作 9.24 Monitoring conditions such as frequency, sampling volume or duration, alert and action limits and corrective action including investigation should be established in each manufacturing area based on risk assessment. 对于每一个生产区域, 其监测条件, 如频率 取样量或取样时间 警戒限和行动限, 以及包括调查在内的纠正预防措施应该基于风险评估制定 Viable monitoring 活性监测 9.25 Where aseptic operations are performed, microbiological monitoring should be frequent using a combination of methods such as settle plates, volumetric air, glove print and surface sampling (e.g. swabs and contact plates). 进行无菌操作, 应频繁进行微生物监测, 使用如沉降碟 气体容积测定 五指手套 表面取样 ( 如擦拭和接触碟 ) 等组合的方法 9.26 Monitoring should include sampling of personnel at periodic intervals during the process. Particular consideration should be given to monitoring personnel following involvement in critical interventions and on exit from the grade A/B processing area. 在生产过程中, 监测应该包括定期的人员取样 应该特别关注参与了关键干扰以及从 A B 级操作区域退出的人员的监测 9.27 Continuous monitoring in grade A and B areas should be undertaken for the full duration of critical processing, including equipment (aseptic set up) assembly and filling operations(i.e., an understanding of function and interactions of each clean area). The monitoring should be performed in such a way that all interventions, transient events and any system deterioration would be captured and any risk caused by interventions of the monitoring operations is avoided. A B 级区域的关键工艺的整个过程中应进行连续监测, 包括设备 ( 无菌装配 ) 组装和分装操作 ( 即, 每个洁净区功能及相互作用的理解 ) 监测应该以这样一种方式进行, 即捕捉所有干扰 瞬变事件及所有系统恶化事件, 并避免任何由监测操作干扰导致的风险 9.28 Rapid microbial monitoring methods may be adopted after validation as long as they are demonstrated to be at least equivalent to the established methodology. 快速微生物监测方法可在验证后使用, 只要能证明它们至少等效于已有的方法 9.29 Sampling methods should not pose a risk of contamination to the manufacturing operations. 取样方法不应给生产操作带来污染的风险 9.30 Additional microbiological monitoring should also be performed outside production operations, e.g. after validation of systems, cleaning and disinfection. 除了生产操作之外, 应进行额外的微生物监测, 如系统验证 清洁 消毒之后 9.31 Recommended action limits for microbial contamination are shown in Table 6 推荐的微生物污染行动限见表 6.

61 Table 6: Recommended maximum limits for microbial contamination 表 6: 微生物污染建议最大限度 Contact plates Settle plates (diam. Air sample (diam. 90 mm) cfu/4 cfu/m3 hours (a) 55mm), cfu/ 空气取 plate 沉降碟 ( 直径 90mm) 样 cfu/m3 (a) 接触碟 ( 直径 cfu/4 小时 55mm)cfu/ 碟 A (b) B C D Grade 级别 Glove print 5 fingers on both hands cfu/ glove 双手五指手套 cfu/ 每只手套 (a) Individual settle plates may be exposed for less than 4 hours. Where settle plates are exposed for less than 4 hours the limits in the table should still be used. Settle plates should be exposed for the duration of critical operations and changed as required after 4 hours. (a) 单个沉降碟可暴露小于 4 小时 如果沉降碟暴露时间小于 4 小时, 那么表中的限度仍然适用 应在关键操作全程放置沉降碟,4 小时后根据需要进行更换 (b) It should be noted that for grade A the expected result should be 0 cfu recovered; any recovery of 1 cfu or greater should result in an investigation. 值得注意的是, 对于 A 级, 期望的结果是 0CFU; 若出现 1 个菌落, 则需要调查 9.32 Monitoring procedures should define the approach to trending. Trends can include but are not limited to: 监测规程应该定义趋势分析的方法 趋势应该包括但不仅限于 : a) Increasing numbers of action or alert limit breaches. 超出行动限或警戒限的数量的增加 b) Consecutive breaches or alert limits. 连续超警戒限 c) Regular but isolated breaches of limits that may have a common cause, for example single excursions that always follow planned preventative maintenance. 多个单值超限有规律出现可能由于相同原因, 比如总是在计划性预防性维护后出现单值超限 d) Changes in flora type and numbers. 种群类别和数量的变化 9.33 If microorganisms are detected in a grade A or B zone, they should be identified to species level and the impact of such microorganisms on product quality (for each batch implicated) and state of control should be evaluated. Consideration may also be given to the identification of grade C and D contaminants and the requirements should be defined in the contamination control strategy. 如果在 A 或 B 级区监测到微生物, 应该鉴别到种, 应该评估这些微生物对产品质量 ( 涉及到的每一批 ) 的影响和控制状态 也应考虑 C D 级污染菌的鉴别, 并且应该在污染控制策略中规定该要求 Aseptic process simulation (APS)1 无菌工艺模拟 (APS) Periodic verification of the effectiveness of the controls in place for aseptic processing should include a process simulation test using a sterile nutrient media and/or placebo. Selection of an appropriate nutrient media should be made based on the ability of the media to imitate product characteristics at all processing

62 stages. Where processing stages may indirectly impact the viability

63 of any introduced microbial contamination, (e.g. sterile aseptically produced semi-solids, powders, solid materials, microspheres, liposomes and other formulations where product is cooled or heated or lyophilized, etc.), alternative surrogate procedures that represent the operations as closely as possible can be developed and justified. Where surrogate materials, such as buffers, are used in parts of the process simulation, the surrogate material should not inhibit the growth of any potential contamination. 对无菌工艺的控制有效性的定期确认, 应该包括一个使用无菌营养培养基和 / 或安慰剂的工艺模拟试验 根据培养基在所有工艺阶段模仿产品特性的能力, 应选择适当的培养基 当工艺阶段可能会间接影响被引入的微生物的生长时 ( 如无菌生产的无菌半固体 粉末 固体 微球 脂质体等产品和其它冷却的或加热的或冻干的剂型 ), 可以开发尽可能紧密代表操作的替代程序, 并进行论证 如在工艺模拟的某些地方使用替代物质, 如缓冲液, 其不应抑制任何潜在微生物污染的生长 For further details on the validation of aseptic processing, please refer to the PIC/S Recommendation on the Validation of Aseptic Processing (PI 007) For PICS version only 关于无菌工艺验证的更多细节, 详见 PIC/S 无菌工艺验证的建议 (PI 007) 9.35 The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and include all the critical manufacturing steps. Specifically: 工艺模拟试验应该尽可能接近的模拟日常无菌生产工艺, 并包括所有关键生产步骤 具体有 : a) Process simulation tests should assess all aseptic operations performed subsequent to the sterilisation of materials utilised in the process. 工艺模拟试验应该评估工艺中使用的物料在灭菌之后进行的所有无菌操作 b) For non-filterable formulations any additional aseptic steps should be assessed. 对于不能过滤的剂型, 任何额外的无菌步骤都应进行评估 c) Aseptic manufacturing performed in a strict anaerobic environment should be evaluated with an anaerobic media in addition to aerobic evaluation. 在严格厌氧的环境下进行的无菌生产, 除了有氧评估外, 还应使用厌氧培养基进行评估 d) Processes requiring the addition of sterile powders should employ an acceptable surrogate material in containers identical to those utilised in the process being evaluated. 需要添加无菌粉末的工艺应使用可接受的替代物料, 使用与被评估工艺相同的容器 e) Processes involving blending, milling and subdivision of a sterile powder require similar attention. 涉及无菌粉末混合 粉碎及细分的工艺需要类似的关注 f) The process simulation test for lyophilized products should include the entire aseptic processing chain, including filling, transport, loading, chamber dwell, unloading and sealing. The process simulation should duplicate the lyophilization process, with the exception of freezing and sublimation, including partial vacuum and cycle duration and parameters as appropriate for the media. Boiling over or actual freezing of the solution should be avoided. 冻干产品的工艺模拟试验应该包括整个无菌工艺链, 包括分装 转运 上料 存放 卸料和密封 工艺模拟应该包括冻干工艺, 除了冷冻和升华以外, 包括对介质保持部分真空和持续循环及适当的参数 应该避免过度煮沸或溶液冻结 9.36 The process simulation testing should take into account various aseptic manipulations and interventions known to occur during normal production as well as worst-case situations, including: 工艺模拟试验应考虑在正常生产过程中发生的各种无菌处理作和固有干扰, 以及最差情况, 包括 : a) Inherent interventions at the maximum accepted frequency per number of filled units. 每一定数量充填单元最大可接受的固有干扰频次

64 b) Corrective interventions in representative number and with the highest degree of intrusion acceptable. 一定代表数量的纠正性干扰, 以及可接受的最高介入程度 9.37 There should be an approved list of allowed interventions, both inherent and corrective,which may occur during production and in the APS. The procedures listing the types of inherent and corrective interventions, and how to perform them, should be updated, as necessary, to ensure consistency with the actual manufacturing activities. 应有一份经过批准的允许干扰的清单, 包括在无菌工艺模拟及生产期间可能出现的固有的干扰和纠正性干扰 规程应列出固有干扰和纠正性干扰的类型, 以及如何执行这些干扰, 应根据需要进行更新以保证与实际生产活动保持一致 9.38 In developing the process simulation test plan, risk management principles should be used and consideration should be given to the following: 应使用风险管理原则制定工艺模拟试验计划, 并考虑以下 : a) Identification of worst case conditions covering the relevant variables and their microbiological impact on the process. The outcome of the assessment should justify the variables selected. 确定最差情况, 包括相关变量及其对工艺的微生物影响 评估的结果所选择的变量提供证明 b) Determining the representative sizes of container/closure combinations to be used for validation. Bracketing or a matrix approach can be considered for initial validation of the same container/closure configuration. 确定用于验证的容器 / 密封件组合的代表性尺寸 对于相同容器 / 密封组件的首次验证可考虑括号法或矩阵法 c) The volume filled per container, which should be sufficient to ensure that the media contacts all equipment and component surfaces that may directly contaminate the sterile product. 每个容器分装的容积, 该容积应该要充分保证培养基能与可能直接污染无菌产品的所有设备 部件表面接触 d) Maximum permitted holding times for sterile product and associated sterile components exposed during the aseptic process. 无菌工艺期间无菌产品和相关无菌组件最长允许保存时间 e) Ensuring that any contamination is detectable. 保证能监测到任何污染度 f) The requirement for substitution of any inert gas used in the routine aseptic manufacturing process by air, unless anaerobic simulation is intended. 在日常无菌生产工艺中使用的任何惰性气体应使用空气进行替代, 除非计划进行厌氧模拟 g) The duration of the process simulation filling run to ensure it is conducted over the maximum permitted filling time. If this is not possible, then the run should be of sufficient duration to challenge the process, the operators that perform interventions, and the capability of the processing environment to provide appropriate conditions for the manufacture of a sterile product. 应考虑工艺模拟分装过程的持续时间, 以确保覆盖最大允许分装时间 如果不可能进行, 应该有足够长的持续时间, 以挑战工艺 进行干扰的操作者以及工艺环境提供合适的无菌产品生产条件的能力

65 h) Simulating normal aseptic manufacturing interruptions where the process is idle. In these cases, environmental monitoring should be conducted to ensure that grade A conditions have been maintained. 在工艺空转时模拟正常无菌生产中断 在这种情况下, 应该进行环境监测以确保 A 级条件的维持 i) The special requirements and considerations for manually intensive operations. 人工密集型操作的特殊要求和考虑 j) Where campaign manufacturing occurs, such as in the use of barrier technologies or manufacture of sterile active substances, consideration should be given to designing and performing the process simulation so that it simulates the risks associated with both the beginning and the end of the campaign and demonstrating that the campaign duration does not pose any risk. If end of production campaign APS are used, then it should be demonstrated that any residual product does not negatively impact the recovery of any potential microbiological contamination. 如果出现生产活动, 比如使用隔离技术或生产无菌活性物质, 应该考虑设计和进行工艺模拟, 这样即可模拟活动开始和结束时相关的风险, 并证明该活动的持续没有造成任何风险 如果对活动的结束步骤进行了模拟, 那么应该证明残留产品对潜在微生物污染的回收没有负面影响 k) Where barrier technologies (RABS, isolators, BFS, etc.) are used in the routine aseptic manufacturing process, the relative risk and unique aspects of these technologies should be taken into consideration when assessing the design of aseptic process simulation tests. 如果日常无菌生产工艺中使用了屏障技术 (RABS 隔离器 BFS 等 ), 那么评估无菌工艺模拟试验的设计时, 应该考虑这些技术相关的风险和独特方面 9.39 For sterile active substances, batch sizes should be large enough to represent routine operation, simulate intervention operation at the worst case, and cover potential contact surfaces. In addition, all the simulated materials (surrogates of growth medium) should be subjected to microbiological evaluation. The recovery rate from simulation materials should be sufficient to satisfy the evaluation of the process being simulated and should not compromise the recovery of micro-organisms. 对于无菌活性物质, 批量应该足够大, 以代表日常运行 最差情况下模拟干扰操作, 以及覆盖可能的接触面 另外, 应该对所有模拟物料 ( 生长介质的替代物 ) 进行微生物评估 模拟物料的回收率应该充分满足被模拟工艺的评估, 且不应影响微生物的回收 9.40 Process simulation tests should be performed as initial validation, generally with three consecutive satisfactory simulation tests per shift, and after any significant modification to the HVAC system, equipment, major facility shut down, process and number of shifts, etc. Normally process simulation tests (periodic revalidation) should be repeated twice a year (approximately every six months) for each aseptic process and filling line, and at least annually for each operator. Consideration should be given to performing an APS after the last batch prior to shut down, before long periods of inactivity or before decommissioning or relocation of a line. 首次验证应进行工艺模拟试验, 通常每班进行三个连续合格的模拟试验, 并在 HVAC 系统 设备 主要设施停用 工艺以及班次等有任何重大变更之后进行再验证 通常, 对于每个无菌工艺和生产线, 应每年进行两次 ( 大约每六个月一次 ) 工艺模拟试验 ( 周期性再验证 ), 并且每个操作人员应每年参加一次 在长期停产前, 或生产线退役或迁移前应该考虑在最后一批产品之后进行无菌工艺模拟 (APS) 9.41 Where manual filling occurs, each product, container closure, equipment train and operator should be revalidated approximately every 6 months. The APS batch size should mimic that used in the routine aseptic manufacturing process. An aseptic process or filling should be subject to a repeat of the initial validation when: 如果有人工分装的情况, 每个品种 容器密封 设备连线和操作人员应该约每六个月进行一次再验证 APS 批量应该模拟日常无菌生产工艺中的批量 下列情况应进行首验证 :

66 a) Revalidation of the unique process has failed and corrective actions have been taken. 工艺失败并采取了纠正措施进行再验证 b) The specific aseptic process has not been in operation for an extended period of time. 无菌工艺长期停运 A change to the process, equipment, personnel, procedures or environment that has potential to affect the aseptic process or the addition of new product containers or container-closure combinations. 工艺 设备 人员 规程或环境发生变化可能影响无菌工艺, 或者增加新的产品容器或容器 - 密封件组合 9.42 The number of units processed (filled) for process simulation tests should be sufficient to effectively simulate all activities that are representative of the aseptic manufacturing process; justification for the number of units to be filled should be clearly captured in the PQS. For small batches, e.g. those under 5,000 units filled, the number of containers for media fills should at least equal the size of the production batch. 工艺模拟试验分装的样品数量应充分有效地模拟能够代表无菌生产过程的所有活动 ; 在 PQS 中应清晰确定分装样品数量的理由 对于小批量, 例如, 那些 <5000 个单位的批次, 模拟分装的容器数量应至少和生产批次批量相等 9.43 The target should be zero growth and any contaminated unit should result in an investigation (refer to clause 9.47) to determine the root cause (if possible) and to identify appropriate CAPA. Following implementation of CAPA, a repeat APS will be required to validate the effectiveness of the CAPA. The number of APS to be repeated should be determined using QRM principles taking into consideration the number and type of CAPA and the level of contamination found in the failed APS. Typically 3 successful consecutive repeat APS would be expected; any differences to this expectation should be clearly justified prior to repeat performance. 目标应该是零生长, 任何样品污染应进行调查 ( 参见条款 9.47) 以确定根本原因 ( 如可能 ), 制定合适的 CAPA CAPA 执行后, 要求重新进行无菌工艺模拟 (APS), 以验证 CAPA 的有效性 重复 APS 的次数应该使用质量风险管理 (QRM) 原则来确定, 并考虑 CAPA 的数量和类型, 以及在失败 APS 中发现的污染程度 通常需要连续进行 3 次成功 APS, 任何不同于此要求的做法在执行前都需要清晰论证 9.44 Filled APS units should be agitated, swirled or inverted before incubation to ensure contact of the media with all interior surfaces in the container. Cosmetic defects, non-destructive weight checks and all other units should be identified and incubated with the other units. Units discarded during the process simulation and not incubated should be comparable to units discarded during a routine fill. APS 分装的样品在培养前应进行震荡 旋转或倒置, 以确保培养基和容器内表面的接触 应标记外观缺陷 非破坏性重量检查及所有其他样品, 并与其他样品一起培养 工艺模拟期间剔除的样品和未培养的样品应该和日常分装中剔除的产品进行对比 9.45 Filled APS units should be incubated in a clear container to ensure visual detection of microbial growth. Microorganisms isolated from contaminated units should be identified to at least the genus, and to the species level when practical, to assist in the determination of the likely source of the contaminant. The selection of the incubation duration and temperature should be justified and appropriate for the process being simulated and the selected growth medium. 经分装的 APS 样品应在透明的容器中培养, 确保目视检查微生物的生长 从被污染容器中分离出来的微生物应该至少鉴别到属, 可行的话鉴别到种, 以帮助确定污染物可能的来源 培养持续时间和温度的选择应该合理, 并且适用于所模拟工艺及所选择的培养基

67 9.46 All products that have been manufactured on a line subsequent to the process simulation should be quarantined until a successful resolution of the process simulation has occurred. 工艺模拟完成之后, 生产线上生产的产品都应该隔离, 直到工艺模拟被判定为成功 9.47 In the case of a failed process simulation there should be a prompt review of all appropriate records relating to aseptic production since the last successful process simulation. The outcome of the review should include a risk assessment of the non-sterility for batches manufactured since the last successful process simulation, and the justification for the disposition of batches of product affected. Subsequent to a failed APS, in addition to a full investigation, production should resume only upon further successful APS unless adequately justified. The number of repeat successful APS prior to resuming production should also be justified. 如果出现失败的工艺模拟, 应立即回顾自上一次成功工艺模拟以来, 所有无菌生产的相关的记录 回顾的结果应该包括自上次成功的工艺模拟以来生产的批次出现染菌的风险评估, 并论证如何处理受影响的产品批次 APS 失败之后, 除了一份全面的调查之外, 只有在后续成功的 APS 基础上才能重新开始生产, 除非有充分理由 生产恢复之前,APS 的成功重复次数也应进行论证 9.48 Where results indicate that an operator may have failed qualification, actions to restrict entry of the operator to the aseptic processing areas should be taken. 如果结果显示某个操作人员确认失败, 那么应该采取措施限制该操作人员进入无菌操作区域 9.49 All process simulation runs should be fully documented and include a reconciliation of units processed and changes in the custody of the APS batch. All interventions performed during the process simulations should be recorded, including the start and end of each intervention. 所有工艺模拟运行都应完整记录, 包括被处理样品的物料平衡以及 APS 批次的转运 应记录工艺模拟期间进行的所有干扰, 包括每个干扰的开始和结束 10 Quality Control (QC) 质量控制 10.1 Microbiological contamination of starting materials should be minimal. Specifications should include requirements for microbiological quality when the need for this has been indicated by monitoring and/orby the contamination control strategy. 起始物料的微生物污染应该尽可能降低 当监测或者污染控制策略有需要时, 产品的质量标准应该包含微生物质量控制 10.2 The bioburden assay should be performed on each batch for both aseptically filled product and terminally sterilized products and the results considered as part of the final batch review. There should be working limits on contamination immediately before sterilization, which are related to the efficiency of the method to be used. 无菌工艺分装的产品和最终灭菌产品的每个批次的都要进行生物负荷检测, 测试结果将作为最终产品批审核的一部分 应该设定待灭菌品的限度, 该限度与所用灭菌方法的效力有关 10.3 Where overkill sterilization parameters are set for terminally sterilized products, bioburden should be monitored at suitable scheduled intervals. 当过度杀灭法的参数设定用于最终灭菌产品时, 生物负荷检查需要在合适的预定间隔内进行监控 10.4 For parametric release systems, the bioburden assay should be performed on each batch and considered as an in-process test. Where appropriate, the level of endotoxins should be monitored. 对于参数放行系统, 每批产品都应该进行生物负荷检查并作为一项中控测试 在适当情况下, 内毒素的水平也要监测

68 10.5 The sterility test applied to the finished product should only be regarded as the last in a series of control measures by which sterility is assured. The test should be validated for the product(s) concerned. 成品的无菌检验应当只作为确保无菌的一系列控制措施中的最后一个 与产品有关的检验方法应当经过验证 10.6 The sterility test should be performed under aseptic conditions, which are at least consistent with the standard of clean room required for the aseptic manufacture of pharmaceutical products. 无菌检验应该在无菌的环境下进行, 至少要与药品无菌生产的洁净厂房标准一致 10.7 Samples taken for sterility testing should be representative of the whole of the batch, but should in particular include samples taken from parts of the batch considered to be most at risk of contamination, for example: 用于无菌检测的样品应能代表整个批次, 尤其应包含该批次中污染风险最高的部分, 比如 : a) Products which have been filled aseptically, samples should include containers filled at the beginning and end of the batch and after any significant intervention. 无菌灌装的产品, 取样应当包括容器灌装的开始和结束以及中间任何重大干扰之后 b) Products which have been heat sterilized in their final containers, consideration should be given to taking samples from the potentially coolest part of the load. 对在最终容器中进行加热灭菌的产品, 应该考虑从装载的潜在最冷处取样 c) Each sterilized load should be considered as different batches and require a separate sterility test. 每一种灭菌的装载 ( 方式 ) 都应被视为不同批次, 都需要一个单独的灭菌结果测试 d) Products that have been lyophilized in different lyophilization loads.. 以不同的装载方式进行冻干的产品 Note: Where sterilization or lyophilization leads to separate sterility tests, consideration of performing separate testing for other finished product tests should also be given. 备注 : 如果无菌或者冻干过程需要分开进行无菌检测, 那么也要考虑其他成品测试也分开进行检测 10.8 Any process (e.g. VHP) used to decontaminate sterility samples prior to testing should not negatively impact the sensitivity of the test method. 任何在检验前去除样品污染的过程 ( 例如 :VHP) 都不应检验方法的灵敏度产生负面影响 10.9 Media used for environmental monitoring and APS should be tested for its growth promotion capability, in accordance with a formal written program. 用于环境监测和培养基模拟灌装的培养基, 应根据一个正式的书面程序, 对其促生长能力进行测试 Environmental monitoring data generated in grade A and B areas should be reviewed as part of product batch release. A written plan should be available that describes the actions to be taken when data from environmental monitoring are found out of trend or out of specification. 洁净区 A 级 B 级的环境监控数据应作为产品批放行审核的一部分 应有书面程序描述当环境监控数据不符合趋势或者超出标准时所应采取的措施 The use of rapid microbial methods can also be considered. These methods should be

69 validated for the product(s) or processes concerned and be approved in testing the registered product specification. 也可以考虑微生物快速检测的方法 这些方法应当经过验证可用于该产品或相关工艺, 且已经在注册产品检验标准中得到批准 11 Glossary 术语 Air lock - A small room with interlocked doors, constructed to maintain air pressure control between adjoining rooms (generally with different air cleanliness standards). The intent of an aseptic processing airlock is to preclude ingress of particulate matter and microorganism contamination from a lesser controlled area. 气闸 ( 气锁 ): 带有互锁门的小房间, 用于维持相邻房间 ( 通常具有不同的空气洁净度标准 ) 之间的空气压力控制 无菌处理气闸的目的是防止微粒物质和微生物污染物从较低控制级别区域引入 Alert Level - An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow- up to address the potential problem. Alert levels are always lower than action levels and are established based on historical and qualification trend data and periodically reviewed. 警戒限 : 一个既定的微生物或空气中悬浮粒子的水平, 对正常操作条件下的潜在漂移可以提前预警, 并触发适当的调查和跟踪, 以解决潜在的问题 警报限总是低于行动限, 应根据历史和确认的趋势数据建立并定期回顾 Action Level - An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation. 行动限 : 一个既定的微生物或空气中悬浮粒子的水平, 如果超过该水平, 应采取适当的调查以及基于调查的纠正措施 Aseptic Manufacturing Area - The classified part of a facility that includes the aseptic processing room and ancillary cleanrooms. aseptic processing facility. For purposes of this document, this term is synonymous with 无菌生产区 : 指某一级别的设施, 包括无菌生产房间和辅助洁净室 就本文件而言, 该术语与 无菌生产设施 同义 Aseptic Processing Facility - A building, or segregated segment of it, containing cleanrooms in which air supply, materials, and equipment are regulated to control contamination. microbial and particle 无菌生产设施 - 指包含有洁净室的建筑物或者该建筑物隔离出的一部分, 包含有受控的送风 物料和设备, 以控制微生物和微粒污染的洁净室 Aseptic Processing Room - A room in which one or more aseptic activities or processes are performed. 无菌生产房间 : 进行一项或多项无菌操作或工艺的房间

70 Asepsis - A state of control attained by using an aseptic work area and performing activities in a manner that precludes microbiological contamination of the exposed sterile product. 无菌 : 通过使用无菌工作区域, 并且暴露的无菌产品以避免微生物污染的方式进行活动 Bacterial retention testing This test is performed to validate that a filter can remove bacteria from a gas or solution. The test is usually performed using a standard organism, such as Brevundimonas diminuta at a minimum concentration of 107 Colony Forming Units/ml. 细菌截留试验 : 进行该项测试是为了验证过滤器可以从气体或溶液中去除细菌 通常使用标准微生物, 如缺陷假单胞杆菌 Brevundimonas diminuta, 浓度最低在 10 7 cfu/ 毫升进行测试 Bioburden - The total number of microorganisms associated with a specific item prior to sterilization. 生物负载 : 灭菌前与特定物品有关的微生物总数 Barrier - A physical partition that affords aseptic processing area (grade A) protection by partially separating it from the surrounding area such as RABS or isolators. 屏障 : 通过将其与周围区域分开 ( 如用 RABS 或隔离器 ), 来提供无菌生产区域 ( 等级 A) 保护的物理分区 Biological Indicator (BI) - A population of microorganisms inoculated onto a suitable medium (e.g. solution, container or closure) and placed within appropriate sterilizer load locations to determine the sterilization cycle efficacy of a physical or chemical process. The challenge microorganism is selected based upon its resistance to the given process. Incoming lot D-value and microbiological count define the quality of the BI. 生物指示 (BI): 将一群微生物接种到合适的培养基 ( 例如溶液 容器或封闭装置 ) 上并置于合适的灭菌器装载位置以确定物理或化学过程的灭菌循环效果 挑战微生物是基于其对给定工艺的抗性来选择的 来料批次的 D 值和微生物数量决定了 BI 的质量 Blow-Fill-Seal - Blow-Fill-Seal (BFS) technology is a pharmaceutical filling process in which containers are formed from a thermoplastic granulate, filled with product, and then sealed in a continuous, integrated, automatic operation. The two most common types of BFS machines are the Shuttling machine (with Parison cut) and the Rotary machine (Closed Parison) types. The equipment design, operation, and therefore controls for these differ. For Shuttling systems the processes of container extrusion and filling occur at two separate locations within the machine. The extrusion of the container parison occurs adjacent to the filling zone, the extruded plastic is collected from underneath the extruder head, is cut and formed and automatically transferred (usually by horizontal shuttling) to the filling and sealing zone. For Rotary design machines the filling needles are enclosed within the extruded parison and therefore there is limited exposure of the container to the external environment. inner surfaces of the 吹塑 灌装 密封 : 吹塑 灌装 密封 (BFS) 技术是一种药品灌装工艺, 其中容器由热塑性颗粒形成, 灌装产品, 然后以连续的 一体化的 自动的操作进行密封 两种最常见的 BFS 机器是穿梭机 ( 带坯体切割 ) 和旋转机 ( 封闭型 ) 类型 这些设备的设计 操作和控制有所不同 对于梭动系统, 容器挤出和灌装的过程发生在机器内的两个分离的位置 容器型坯的挤出发生在灌装区域附近, 挤出的塑料从挤出机头部下方收集, 被切割和成型并自动转移 ( 通常通过水平穿梭 ) 到灌装和密封区域 对于旋转式设计

71 机器, 灌装针被封闭在挤出型坯内, 因此容器的内表面对外部环境的暴露是受限的

72 Clean Area - An area with defined particle and microbiological cleanliness standards. 洁净区 : 具有明确的颗粒和微生物洁净度标准的区域 Cleanroom - A room designed, maintained, and controlled to prevent particle and microbiological contamination of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness classification. 洁净室 : 经设计 维护和控制以防止药物产品的颗粒和微生物污染的房间 这种房间被指定并可重复地满足适当的空气清洁度分级 Clean Non Classified (CNC) area - An area that does not meet any of the formal pre-determined grades of cleanliness included in the Annex, i.e. grades A to D, but where a manufacturer defined level of microbial control is still required. The area should be subject to a formal cleaning/disinfection regime and formal environmental monitoring program to achieve the defined level of control. The level, type and frequency of both the cleaning program and the environmental monitoring program (including contamination limits) should be based on a formal risk assessment (captured within the wider contamination control strategy) and should be commensurate with the specific risks to the processes and product performed manufactured within each CNC area. 洁净非分级 (CNC) 区域 : 一个不符合本附录中规定的任何一个预定的洁净等级 ( 即 A 级至 D 级 ) 的区域, 但是仍然需要生产商定义微生物控制水平 该区域应进行正式的清洁 / 消毒以及正式的环境监测计划, 以达到规定的控制水平 清洁计划和环境监测计划 ( 包括污染限值 ) 的水平 类型和频率应基于正式的风险评估 ( 在更广泛的污染控制策略中获得 ), 并且应与在每个 CNC 区域进行的工艺和产品的特定风险相称 It is possible that different CNC areas within the same facility may have different approaches to control and monitoring, based on differing risks to processes and products. 基于对工艺和产品的不同风险, 同一设施内的不同 CNC 领域可能有不同的控制和监控方法 Clean Zone - See Clean Area. 洁净区 : 请参阅洁净区域 Closed system A system in which the sterile product is not exposed to the surrounding environment. 隔离系统 : 无菌产品不暴露于周围环境的系统 Colony Forming Unit (cfu) - A microbiological term that describes the formation of a single macroscopic colony after the introduction of one or more microorganisms to microbiological growth media. One colony forming unit is expressed as 1 cfu. 菌落形成单位 (cfu): 微生物学术语, 指将一种或者多种微生物接种到微生物生长培养基后形成的单一的肉眼可见菌落 一个菌落形成单位表示为 1 cfu Commissioning Activities to verify that equipment and systems are specification 调试 : 确认设备和系统是否按标准安装的活动 installed according to

73 Component - Any ingredient intended for use in the manufacture of a drug product, including those that may not appear in the final drug product. 组分 : 意图用于生产药品的任何成分, 包括那些可能不会出现在最终药品中的成分 Critical Area - An area designed to maintain sterility of sterile materials. Sterilized product, containers, closures, and equipment may be exposed in critical areas such as the grade A area or a closed system. 关键区域 : 旨在保持无菌物料无菌的区域 灭菌后的产品 容器 封闭系统和设备可能在关键区域暴露, 例如 A 级区域或一个密封的系统 Critical surfaces - Surfaces that may come into contact with, or directly affect, a sterilized product or its containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation, and sterility is maintained throughout processing. 关键表面 : 可能于已灭菌产品或其容器或封闭系统接触或产生直接影响的表面 关键表面在生产操作开始之前达到无菌并在生产过程中保持无菌状态 Critical zone See critical area 关键区 : 见关键区域 D value - The time (in minutes) of exposure at a given temperature that causes a one-log or 90 per cent reduction in the population of a specific microorganism. D 值 : 给定温度下导致特定微生物种群数量减少 1 个对数或 90% 所需的时间 ( 以分钟计 ) Deadleg length of pipe that is not part of the circuit that is greater than 3 internal pipe diameters 死角 : 管道支路管道长度大于 3 倍管道内径 Decontamination - A process that eliminates viable bioburden via use of chemical agents. 去除污染 : 通过使用化学试剂消除存活的生物负载的过程 Depyrogenation - A process used to destroy or remove pyrogens (e.g. endotoxin). 去热原 : 用于破坏或去除热原 ( 例如内毒素 ) 的过程 Disinfection The process by which surface bioburden is reduced to a safe level or eliminated. Some disinfection agents are effective only against vegetative microbes, additional capability to effectively kill bacterial and fungal spores. while others possess 消毒 : 表面生物负载降低到安全水平或消除的过程 一些消毒剂只对微生物营养体有效, 而另一些消毒剂还可以有效杀灭细菌和真菌孢子 Dynamic - Conditions relating to clean area classification under normal production operations. 动态 : 在正常生产操作下与洁净区分级有关的条件 Endotoxin - A pyrogenic product (e.g. lipopolysaccharide) present in the bacterial cell wall. Endotoxin can lead to reactions in patients receiving injections ranging from fever to death.

74 内毒素 : 存在于细菌细胞壁中的致热产物 ( 例如脂多糖 ) 内毒素可导致患者发生反应发烧甚至死亡 Extractables - Chemical entities that migrate from the surface of the process equipment contacting with model solvents under appropriate testing conditions (e.g. kind of solvent, temperature) that exceed worst case process conditions. 可迁移物 : 在超出工艺 最差条件 ( 如溶剂种类 温度等 ) 的适当测试条件下, 从与模拟溶剂接触的工艺设备表面迁移的化学物质 Form Fill seal Similar to Blow fill Seal, this involves the formation of a large tube formed from a flexible packaging material, in the filling machine, the tube is then filled to form large volume bags. 成型 - 灌 - 封 : 类似于吹 - 灌 - 封, 包括从弹性的包装材料形成的大型管, 在灌装机中, 管被灌装并且形成大容量包装 Gowning Qualification - A program that establishes, both initially and on a periodic basis, the capability of an individual to don the complete sterile gown in an aseptic manner. 更衣确认 : 需要首次和定期执行以确定个人通过无菌方式完整穿戴无菌服能力的程序 Grade A air Air which is passed through a filter qualified as capable of producing grade A non-viable quality air, but where there is no requirement to continuously perform non-viable monitoring or meet grade A viable monitoring limits. A 级送风 : 经过过滤器的空气, 该过滤器经确认能够产生符合 A 级非活性粒子质量的空气, 但不要求进行非活性粒子连续监测或满足 A 级微生物标准 HEPA filter - High efficiency particulate air filter with minimum 0.3 μm particle retaining efficiency of percent. HEPA 过滤器 : 高效微粒空气过滤器, 最小 0.3 微米的微粒截留率达 99.97% HVAC - Heating, ventilation, and air conditioning. HVAC: 暖通空调 Intervention - An aseptic manipulation or activity that occurs at the critical area. 干扰 : 在关键区域发生的无菌操作或活动 Intrinsic sterile connection device - A device that removes the risk of contamination during the connection process; these can be mechanical or fusion devices. 固有无菌连接装置 : 在连接过程中消除污染风险的装置 ; 这些可以是机械或融合装置 Isokinetic sampling head A sampling head designed to disturb the air as little as possible so that the same particles go into the nozzle as would have passed the area of the nozzle had it not been there. 等动力采样头 : 设计以尽可能少地干扰气流, 使得采样时如同它没有在那一样的采样头 Isolator - A decontaminated unit supplied with grade A (ISO 5) or higher air quality that provides

75 uncompromised, continuous isolation of its interior from the external environment (e.g., surrounding cleanroom air and personnel). There are two major types of isolators: 隔离器 : 使用 A 级 (ISO 5) 或更高空气质量的净化设备, 可以为其内部提供与外部环境 ( 例如周围洁净空气和人员 ) 无间断的持续隔离 有两种主要类型的隔离器 : Closed isolator systems exclude external contamination from the isolator s interior by accomplishing material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the surrounding environment. Closed systems remain sealed throughout operations. 封闭式隔离系统通过无菌连接到辅助设备完成物料转移, 而不是使用周围环境的开口, 从而隔绝了隔离器内部的外来污染 封闭的系统在整个操作中保持密封 Open isolator systems are designed to allow for the continuous or semi-continuous ingress and/or egress of materials during operations through one or more openings.openings are engineered (e.g., using continuous overpressure) to exclude the entry of external contamination into the isolator. 开放式隔离系统被设计成在操作期间允许通过一个或多个开口连续或半连续传入和 / 或穿出物料 其开口被设计为可以排除外部污染物进入隔离器 ( 例如, 使用连续超压 ) Laminar flow - An airflow moving in a single direction and in parallel layers at constant velocity from the beginning to the end of a straight line vector. 层流 : 从直线矢量的始端到末端, 在平行面上以恒定速度沿单一方向流动的气流 Leachables - Chemical entities that migrate into medicinal products from the product contact surface of the process equipment under actual product and process conditions. 浸出物 : 在实际产品和工艺条件下, 从工艺设备的产品接触表面迁移到药品中的化学物质 Lyophilization- A physical-chemical drying process designed to remove solvents from both aqueous and nonaqueous systems, primarily to achieve product or material stability. Lyophilization is synonymous to the term freeze-drying. 冻干法 : 一个旨在从水性和非水性系统中去除溶剂的物理化学干燥过程, 主要是为了实现产品或物料的稳定性 冻干与术语冷冻干燥是同义的 Manual Filling Where the product is transferred into the final container by systems where operator intervention is required to complete the filling of each container e.g. pipetting liquids. 手动灌装 : 在将产品转移到最终容器中, 需要操作人员干预 ( 例如, 吸取液体 ) 以完成每个容器的灌装 Operator - Any individual participating in the aseptic processing operation, including line set- up, filler, maintenance, or other personnel associated with aseptic line activities. 操作人员 : 参与无菌处理操作的任何个人, 包括生产线装配 灌装 维护以及与无菌生产线相关的其他人员 Overkill sterilization process - A process that is sufficient to provide at least a 12 log reduction of microorganisms having a minimum D value of 1 minute. 过度杀灭工艺 : 足以提供具有最小 D 值为 1 分钟的微生物降低至少 12 个对数的工艺

76 Pass through hatch refer to airlock. 传递窗 : 参考气闸 Pyrogen - A substance that induces a febrile reaction in a patient. 热原 : 引起患者发热反应的物质 Qualification - Establishing documented evidence that provides a high degree of assurance that equipment or facilities will perform to the required specification detailed in specification and the design qualification. the user requirement 确认 : 建立书面证据, 以提供确保设备或设施按照用户需求规范和设计确认中详细规定的要求进行操作的高度保证 Restricted Access Barrier System (RABS) - A restricted access barrier system (RABS) provides an enclosed, but not closed, environment meeting defined cleanroom conditions using a rigid-wall enclosure and air overspill to separate its interior from the surrounding environment. 受限进入屏障系统 (RABS): 限制进入屏障系统 (RABS) 提供了一个封闭但非密闭的环境, 满足洁净室的条件, 使用刚性墙体和空气溢流将其内部与周围环境分开 Active RABS: integral HEPA-filtered air supply 主动 RABS: 整体式 HEPA 过滤送风 Passive RABS: air supply by ceiling mounted HEPA-filters. 被动 RABS: 天花板式 HEPA 过滤器的送风 Open RABS. Where there are vents in the barrier that allow air to move from the grade A to the grade B area. 开放式 RABS:RABS 上有缝隙, 允许空气从 A 级流到 B 级区域 Sterile Product - For purposes of this guidance, sterile product refers to one or more of the elements exposed to aseptic conditions and ultimately making up the sterile finished drug product. These elements include the containers, closures, and components of the finished drug product. 无菌产品 : 就本指南而言, 无菌产品是指一种或多种要素暴露于无菌条件下, 并最终构成无菌成品药品 这些要素包括容器 封闭装置和成品药品的成分 Sterilizing grade filter - A filter that, when appropriately validated, will remove a defined microbial challenge from a fluid stream, producing a sterile effluent. 除菌级过滤器 : 经过适当验证的过滤器, 将从流体流中去除特定的微生物挑战, 下游为无菌 Single Use Systems (SUS) - Systems in which some product contact components are used only once (i.e. single use components) to replace reusable equipment such as stainless steel transfer lines or bulk containers. SUS covered in this document are those that are used in manufacturing processes of sterile medicinal products (e.g. sterile API, sterile bio bulk, sterile finish dosage), and are typically made up of components such as bags, filters, tubing, connectors, storage bottles and sensors. 一次性使用系统 (SUS): 某些产品接触部件只使用一次 ( 即单次使用部件 ) 来替换可重复使用设备 ( 如

77 不锈钢输送管线或散装容器 ) 的系统 本文件中所涵盖的 SUS 是用于无菌医药产品 ( 例如无菌 API 无菌生物散装 无菌制剂 ) 生产工艺中的 SUS, 并且通常由诸如袋 过滤器 管道 连接器 存储瓶和传感器组成 Terminal sterilization - The application of a lethal sterilizing agent to finished product within a sealed container to achieve a predetermined sterility assurance level (SAL) of 10 ⁶ or better (i.e. the theoretical probability of there being a single viable microorganism present on or in a sterilized unit is equal to or less than 1 x 10-6 (one in a million)). 最终灭菌 : 在密封容器内对成品施加致死灭菌剂, 以达到预定的无菌保证水平 (SAL),10-6 或更好 ( 即, 在密封容器中的灭菌单位中或内存在单个存活微生物的理论概率等于或小于 ( 百万分之一 ) ULPA filter - Ultra-low penetration air filter with minimum 0.3 μm particle retaining efficiency of per cent. ULPA 过滤器 : 超低穿透率空气过滤器, 最小 0.3 微米的微粒截留率达 % Unidirectional flow - An airflow moving in a single direction, in a robust and uniform manner, and at sufficient speed, to reproducibly sweep particles away from the critical processing or testing area. 单向流 : 以一种稳定而匀速的方式, 以足够的速度向一个方向移动的气流, 可重复地将颗粒从关键的加工或检验区域中清除出去 Validation - Establishing documented evidence that provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes. 验证 : 建立书面证据, 以提供确保特定的工艺能够持续生产符合其预定标准和质量属性的产品高度的保证 Worst case - A set of conditions encompassing upper and lower processing limits and circumstances, including those within standard operating procedures, that pose the greatest chance of process or product failure (when compared to ideal conditions). Such conditions do not necessarily induce product or process failure. 最差情况 : 一系列包括最大和最小工艺条件和状况, 包括在标准操作规程范围内, 但是导致工艺或产品失败的机会最大 ( 与理想条件相比 ) 这样的条件不一定会导致产品或工艺失败