《Microbial Data Deviation Investigations in the中英文双版本完整.docx》由会员分享，可在线阅读，更多相关《Microbial Data Deviation Investigations in the中英文双版本完整.docx（68页珍藏版）》请在taowenge.com淘文阁网|工程机械CAD图纸|机械工程制图|CAD装配图下载|SolidWorks_CaTia_CAD_UG_PROE_设计图分享下载上搜索。
1、Technical Report No.88技术报告第88号Microbial Data Deviation Investigations in the Pharmaceutical Industry制药行业的微生物数据偏差调查Table of Contents目 录1.0 Introduction 5 简 介 51.1. Purpose 5目 的 51.2. Scope 6范围 62.0 Glossary of Terms 7术 语 表 72.1. Abbreviations /Acronyms 9缩 写 / 首 字 母 缩 略 词 93.0 Microbiologist Roles and
2、Responsibilities 9微生物学家的角色和职责 93.1. Laboratory Microbiologist Responsibilities 9实验室微生物学家的职责103.2. Microbiologist Role in a ManufacturingInvestigation 10微生物学家在制造调查中的作用 103.3. Microbiology Laboratory ManagementResponsibilities 11微生物实验室管理职责 113.4. Subject Matter Expert Responsibilities 11主题专家的职责 113.5.
3、 Quality Control Unit Responsibilities 12质量控制部门职责 124.0 Phase I: Conducting the MicrobiologyLaboratory Investigation 12第一阶段：进行微生物实验室调查 124.1. Microbial ldentification 17微生物鉴定 174.2. Phase I : Specific Points to Consider 19第一阶段：需要考虑的具体要点 194.2.1. Sterility Testing Investigations 19无菌检测调查 194.2.2. Bac
4、terial Endotoxins Testing Investigations 25细菌内毒素检测调查 254.2.3. Antimicrobial Effectiveness TestingInvestigations 28抗菌有效性测试调查 284.2.4. Mycoplasma Testing Investigations 29支原体检测调查 294.2.5. Biological Indicators Investigations 31生物指标调查 314.2.6. Aseptic Process Simulation Failures (MediaFills) 32无菌过程模拟失败
5、(培养基填充)324.2.7. Environmental Monitoring 33环 境 监 测 334.2.8. Utilities Monitoring 34公用事业监控 344.3. Phase I: Conclusion and Next Steps 36第一阶段：结论和后续步骤 365.0 Phase ll: Manufacturing Investigation 37第二阶段：制造调查 375.1. Root Cause Analysis 39根本原因分析 395.2. Phase Il : SpecificPoints to Consider 45第二阶段：需要考虑的具体要点
6、 465.2.1. Sterility -Positive Investigations 46无菌阳性调查 465.2.2. Determining Sources of Bacterial Endotoxin 48确定细菌内毒素的来源485.2.3. Pharmaceutical Ingredient -RelatedInvestigations 49药物成分相关调查 495.2.4. Evaluation of Confirmed MycoplasmaContamination 51确认支原体污染的评估 515.2.5. Component (Container Closure)Inves
7、tigations 51组件(容器封闭)调查 515.2.6. Environmental Monitoring 53环境监测 535.2.7. Investigation of Confirmed ContaminationDuring AProcess Simulation /Media Fill 56在过程模拟/介质填充过程中确认污染的调查 565.2.8. Utilities Monitoring 57公用事业监控 576.0 Conclusions 61结论 617.0 References 62参考资料 62FIGURESANDTABLES INDEX图表索引Figure 4.0-
8、1 Fishbone Diagram Showing Inputs of Microbial Testing during Root Cause Analysis 13图4.0-1 显示根本原因分析期间微生物检测输入的鱼骨图13Table 4.0-1 Sample Questions for Laboratory Investigations 13表4.0-1 实验室调查示例问题 13Table 4.1-1 General Points to Consider in Microbial Identification 18表4.1-1 微生物鉴定的一般注意事项 18Table 4.2.1-1 D
9、ata of the Sterility Testing Facility Show a Fault 22表4.2.1-1 无菌检测设备数据显示故障 22Table 4.2.1-2 Testing Procedure Used Reveals a Fault 22表4.2.1-2 使用的测试程序显示故障 23Table 4.2.3.1-1 QuestionsConcerningAntimicrobial EffectivenessTesting 29表4.2.3.1-1 抗菌素有效性检测问题 29Table 4.3.4.1-1 Culture- Based Mycoplasma Testing
10、 Considerations 30表4.3.4.1-1 基于培养的支原体检测注意事项 30Table 4.3.4.1-2 Mycoplasma PCR -Based Detection Testing Considerations 31表4.3.4.1-2 基于支原体 PCR 的检测测试注意事项 31Table 4.3.7-1 Environmental Monitoring : Questions Concerning Laboratory and Sampling 33表4.3.7-1 环境监测：有关实验室和采样的问题 33Figure 5.1-1 Fishbone Diagram Ex
11、amining Microbial Contamination of a Drug Product 39图5.1-1 检查药品微生物污染的鱼骨图 39Table 5.1-1 Factors to Consider in Root Cause Analysis 39表5.1-1 根本原因分析中要考虑的因素 39Table 5.1-2 Root Cause Evaluation and Follow -Up 44表5.1-2 根本原因评估和跟进 44Table 5.1-3 CAPA Determination 45表5.1-3 CAPA 确 定 45Table 5.2.1-1 Questions
12、for Investigating Manufacturing / Process Sources Associated with a ConfirmedSterility Batch Failure 46表5.2.1-1 调查与已确认的无菌批故障相关的生产/工艺来源问题 46Table 5.2.2-1 Endotoxin -Related Investigation Considerations 48表5.2.2-1 内毒素相关调查注意事项 48Table 5.2.3-1 Additional considerations for raw material investigations 50
13、表5.2.3-1 原材料调查的其他注意事项 50Table 5.2.6-1 Potential Sources of Contamination 54表5.2.6-1 潜 在 污 染 源 54Table 5.2.6.2-1 Examples of Corrective Actions 55表5.2.6.2-1 纠正措施示例 55Table 5.2.7-1 Possible Origin of Representative Microorganisms 57表5.2.7-1 代表性微生物的可能来源 571.0 Introduction简介Microbial data deviations are
14、 microbial test results that fall outside the product specification or acceptance cri- terion established in a drug application,drug master file,official compendia,good manufacturing practice reg- ulations,or internally by the manufacturer.This includes,but is not limited to,results generated during
15、 enviro- nmental and water monitoring as well as pharmaceutical ingredient,inprocess,and finished product testing. The validity of the test results is supported by a documented laboratory and manufacturing investigation,wh- ere applicable.微生物数据偏差是微生物测试结果超出药物申请、药物主文件、官方药典、良好制造实践法规或制造商内部建立的 产品规格或验收标准。
16、这包括但不限于在环境和水监测以及药物成分、过程中和成品测试期间产生的结果。测试结 果的有效性由记录在案的实验室和制造调查(如适用)支持。The information presented in this technical report was compiled by a team of experts representing both indu- stry microbiologists and regulators and reflects current industry best practices.The membership of personnel from the U.S.F
17、ood and Drug Administration (FDA)on the taskforce does not imply Agency endorsement.F- eedback from industry and regulatory professionals was evaluated and incorporated into the technical report to ensure that the suggested methods,terminology,and practices for conducting microbial data deviation in
18、v- estigations reflect sound science and current technological approaches.This technical report is not intended to establish any mandatory or implied standards.Published references supporting the recommendations pre- sented are cited in the text and listed in Section 7.0 References.本技术报告中提供的信息由代表行业微
19、生物学家和监管机构的专家团队编制，反映了当前行业的最佳实践。美国食 品和药物管理局(FDA)人员在工作组中的成员身份并不意味着该机构的认可。对来自行业和监管专业人士的反馈进行 评估并将其纳入技术报告，以确保进行微生物数据偏差调查的建议方法、术语和实践反映合理的科学和当前的技术 方法。本技术报告无意建立任何强制性或隐含的标准。支持所提出建议的已发表参考文献在正文中引用，并在第7 . 0 节参考文献中列出。Definitions for the terms used throughout this report are provided in the Glossary.When available
20、,the sameHarmonization (ICH)guidelines.To avoid ambiguity,the task force members believe that use and definitionsor similar technical definitions have been used as thoseincluded in the FDA or International Conference onof these terms should also be consistent and standardized when incorporated into
21、company-specific standardoperating procedures,validation protocols,and regulatory submissions.术语表中提供了本报告中使用的术语的定义。如果可用，已使用与FDA 或国际协调会议(ICH)指南中包含的技术定义 相同或相似的技术定义。为避免歧义，工作组成员认为，这些术语的使用和定义在纳入公司特定的标准操作程序、 验证协议和监管提交时也应保持一致和标准化。1.1.Purpose目 的The FDA issued a Guidance for Industry:Investigating Out of Spec
22、ification (00S)Test Results for Pharmac-eutical Production in 2006 in response to the U.S.versus Barr Laboratories decision,which is applicable to laboratory testing results for products regulated by the Center for Drug Evaluation and Research (CDER)(1, 2).The FDA guidance does not extend to microbi
23、ological failure investigations,however.Consequently,PDA developed this technical report to provide approaches,specific to the pharmaceutical industry,for investigat- ing various types of microbial data deviations based on current scientific knowledge and modern testing tec- hnologies.The term “micr
24、obial data deviationis preferred to “out-of-specification”or“out-of-limit result”in this technical report,as most microbiological tests,especiallyin a sterile product manufacturing faciity,are inpro- cess tests,not finished-product tests that must meet a regulatoryapproved specification.For simplici
25、ty and consistency,the term “deviation”will be used throughout this document.FDA 于2006年发布了行业指南：调查药品生产的超规格(OOS) 测试结果，以回应美国与Bar 实验室的决定，适用于 药物评估中心监管的产品的实验室测试结果和研究(CDER)(1,2)。然而，FDA 指南并未延伸至微生物失效调查。因此， PDA 开发了这份技术报告，以提供特定于制药行业的方法，用于根据当前的科学知识和现代测试技术调查各种类型 的微生物数据偏差。在本技术报告中，术语“微生物数据偏差”优于“超标”或“超限结果”,因为大多数微生物
26、 测试，尤其是在无菌产品制造设施中，都是过程中测试，不是必须符合监管批准规范的成品测试。为简单起见，本 文档将使用术语“偏差”。Technical Report No.88 presents a holistic approach for performing a microbiological investigation.It provid-es a framework to assist with focusing on the investigational areas that may contain or contribute to the root cause of data de
27、viations,such as sampling,test methodology,and suitability of the test,as opposed to prov- iding methods for analysis of batch acceptability.(Batch acceptability determinations and release decisions are made by the quality control unit as required by FDA good manufacturing practice (GMP)regulations,
28、not by deviation investigation teams.)第88号技术报告提出了一种进行微生物研究的整体方法。它提供了一个框架来帮助关注可能包含或导致数据偏差根 本原因的研究领域，例如抽样、测试方法和测试的适用性，而不是提供分析批次可接受性的方法。(批次可接受性 确定和放行决定由质量控制部门根据FDA 良好生产规范(GMP) 法规的要求做出，而不是由偏差调查小组做出。)1.2.Scope范 围Each of the three sections of this document focuses on distinct areas where microbial data is
29、 collected andinspected for deviation investigations and with the following designated responsibilities:本文件的三个部分中的每一部分都侧重于收集和检查微生物数据以进行偏差调查的不同领域，并具有以下指定职责：Roles and Responsibilities-Focuses on personnel,especially microbiologists,in the laboratory investigations and cross-functional teams responsibl
30、e for manufacturing investigations.角色和职责-关注实验室调查中的人员，尤其是微生物学家，以及负责制造调查的跨职能团队。Conducting Laboratory Investigations (Phase I)-Provides additional details on how an investigation may be conducted to determine that the microbial test was valid and what is the root cause of a failure when the result is d
31、eemed invalid.Subsections focus on different microbiological tests conducted,with points for consideration in the final determination of the investigation.进行实验室调查(第一阶段)-提供有关如何进行调查以确定微生物测试是否有效以及当结果被视为无效 时失败的根本原因的更多详细信息。小节侧重于进行的不同微生物测试，并在最终确定调查时考虑要点。Conducting Manufacturing Investigations(Phase II)-Il
32、ustrates where a microbiologist,acting as a subject matter expert (SME),can contribute to the evaluation of personnel activities,environmental changes,utilities,materials,and process-related events and can assist in determining the probable cause of the deviation and the most appropriate corrective
33、and preventive actions (CAPA).进行制造调查(第二阶段)-说明微生物学家作为主题专家(SME) 可以对人员活动、环境变化、公用事业、 材料和过程相关事件的评估做出贡献，并可以帮助确定-找出偏差的可能原因以及最适当的纠正和预防措施 (CAPA)。lf needed and when appropriate,Phase I and Phase ll investigation activities can be conducted in parallel.如果需要并且在适当的时候，可以同时进行第一阶段和第二阶段的调查活动。The roles of other contr
34、ibutors to deviation investigations required for effective root cause analysis,such as representatives from manufacturing,process engineering,and quality assurance,will also be briefly descri- bed.The composition of the investigation team will depend on the nature of the investigation.还将简要介绍有效根本原因分析
35、所需的偏差调查的其他贡献者的角色，例如来自制造、工艺工程和质量保证的代表。 调查小组的组成将取决于调查的性质。This technical report promotes a lifecycle approach,but greater emphasis is placed on laboratory and manu- facturing investigations of marketed drug products.The approaches described may be suitable during resea- rchand product development and t
36、he manufacture of clinical supplies,as well as the manufacture and testing of regulatoryapproved products.The microbial tests discussed in this technical report include microbial attrib- ute testing of nonsterile products,components,sterility testing,bacterial endotoxin assay,mycoplasma test- ing,en
37、vironmental and personnel monitoring,and microbial monitoring of utilities including pharmaceutical- grade water and compressed gases.本技术报告提倡生命周期方法，但更加强调对已上市药品的实验室和制造调查。所描述的方法可能适用于研究和产 品开发以及临床用品的制造，以及监管批准产品的制造和测试。本技术报告中讨论的微生物测试包括非无菌产品、 组件的微生物属性测试、无菌测试、细菌内毒素测定、支原体测试、环境和人员监测，以及包括医药级水和压缩气 体在内的公用设施的微生物监
38、测.Microbial assays of antibiotics and vitamins and the detection and enumeration of protozoans,viruses,and prions are not included in the scope of this report.Additionally,batch disposition is separate from the outco- me of a microbial investigation report.This document is directed specifically to p
39、harmaceutical manufacturing; however,the industry practices may be suitable for deviation investigations in the biological,consumer health, medical devices,and cosmetic industries.In addition,these can be extended to contract manufacturing andtesting organizations supporting pharmaceutical companies
40、.抗生素和维生素的微生物测定以及原生动物、病毒和朊病毒的检测和计数不包括在本报告的范围内。此外，批次处 置与微生物调查报告的结果是分开的。本文件专门针对药品生产；然而，行业实践可能适用于生物、消费者健康、 医疗器械和化妆品行业的偏差调查。此外，这些可以扩展到支持制药公司的合同制造和测试组织。While this document provides a framework illustrating how deviations and the resulting investigations might be conducted,each company is responsible for d
41、eveloping their internal policies and procedures suitable for its specific needs that also meets current GMPs.虽然本文件提供了一个框架，说明了如何进行偏差和由此产生的调查，但每家公司都有责任制定适合其特定需求的 内部政策和程序，同时满足当前的GMP。2.0 Glossary of Terms术语表Action Limit行动限制A microbial or total airborne particulate limit that,wh-en exceeded,indicates a
42、process is outside of its no-rmal operating range.A response to such an excur-sion should involve a documented investigation andinvestigation (3-6).corrective actions based on the results of that微生物或空气中的总颗粒物限值，当超过该限值时，表 明过程超出其正常操作范围。对此类偏差的响应应包括 记录在案的调查和基于调查结果的纠正措施(3-6)。Alert Level警报级别An established
43、value that when exceeded,provides an early warning of potential drift from normal oper- ating conditions and validated state,which does not necessarily give grounds for corrective action but triggers appropriate scrutiny and followup to address the potential problem (3,4,7).一个既定值，当超过该值时，可提供与正常操作条件和
44、验证状态的潜在偏差的早期警告，这不一定为纠正措施 提供依据，但会引发适当的审查和后续处理以解决潜在 问题(3,4,7)。AdverseTrend不利趋势An increase in the frequency of alert level or action limit excursions or repeated recovery of low levels of microorganisms below the alert level during microb- ial monitoring or of pharmaceutical ingredient or fin- ished pr
45、oduct failure that is indicative of a loss of pr- ocess control.在微生物监测期间，警报级别或行动限制偏离或重复恢 复低于警报级别的低水平微生物或药物成分或成品失效 的频率增加，这表明失去了过程控制。Batch Record Review批记录审核Review by the quality control unit of the batch manu- facturing record for accuracy and completeness and for absence of derivation from the approvedmanufacturing and testing processes.The batch re-