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PDA TR 62-Recommended Practices for Manual Aseptic Processes

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重要Aseptic-Process-Simulations-and-Risk-Analysis

重要Aseptic-Process-Simulations-and-Risk-Analysis
TR 44 : Quality Risk Management for Aseptic Processes (2008) TR 22 (draft): Process Simulation for Aseptically Fil Quality Risk Management for Aseptic Processes »
EU GMP's Annex 20 expectations
• EU GMP's Annex 20 : Quality Risk Management » approved March 1st, 2008
Makes Quality Risk Management become an integral part of a manufacturer’s quality system Does formalize existing practices, and provides examples of risk analysis methods which are likely to add value to the quality systems Establishes a structured and consistent risk evaluation process Is an encouragement for Companies to develop a risk management strategy Indicates who to participate, how to document, etc
EU GMP's Annex 20 statement
• Quality Risk Management as Part of Production

PDA TR1 湿热灭菌验证(CN2007)

PDA TR1 湿热灭菌验证(CN2007)
3.2 灭菌指示剂........................................................................................................................20 3.2.1 生物指示剂（BIs）................................................................................................20 3.2.2 化学监测器 .............................................................................................................21
2.0 术语.............................................................................................................................................5 3.0 灭菌科学...................................................................................................................................11
PDA
Parenteral Drug Association
湿热灭菌的验证：
灭菌程序的设计，开发，确认和日常监控 2007年增补，第一卷 N0.S-1
美国注射剂协会 制药科学及技术杂志
编写委员：中国医药设备工程协会技术委员会 发行单位：中国医药设备工程协会

PDA_TR11 中 伽马射线灭菌法(1988年)

PDA_TR11 中 伽马射线灭菌法(1988年)

1988 补充42卷3S号技术报告第11号肠道外用药的伽马射线杀菌《肠道外用药科学与技术》肠道外用药（也可以译为注射用药）协会出版物肠道外用药的伽马射线杀菌微生物小组委员会射线杀菌任务小组简介《美国药典》中经验证的有五种不同的灭菌方法：蒸汽灭菌法、干热灭菌法、环氧乙烷灭菌法、过滤灭菌法和电离辐射灭菌法(1)。

灭菌方法的选择基于产品的特性和生产过程。

选择一种合适的灭菌方法需要有熟知各种灭菌的过程和原理、灭菌设备的要求，同时也要考虑到产品的理化性质、功能兼容性（functional compatiblity）以及灭菌程序中的包装。

灭菌必须达到预设的灭菌级数并保证产品全部的质量属性（quality attibutes）这篇论文对采用同位素钴60和同位素铯70作为电离辐射源的伽马辐射灭菌法的发展和验证做了总结和说明。

对健康保健产品的委托灭菌（contract radiation facilities）的发展和验证做了特别关注。

在一个具备辐射灭菌能力的厂家里，灭菌承包方和生产厂家委托方各自的责任结合在了单一的组织里。

这篇论文假设雇佣第三方灭菌的情况，以便详细说明各方的责任。

伽马射线的微生物灭活能力得到充分证明(2-4)。

与其他灭菌方法一样，考察伽马照射作为一种灭菌方法的主要因素是产品兼容性（compatiblity）和稳定性，以及灭菌程序中的容器或材料。

肠道外用药的辐射兼容性（radiation compatibility）要求在接受灭菌时产品结构和/或产品完整性在物理、化学、微生物学、治疗学和毒理学上保持可接受限度。

确保产品在货架保质期（货架保质期由产品暴露于辐射程序后累积测算的数据得知）范围内的稳定性。

文献呈现出不同材料对伽马射线的兼容性（compatiblity）相关信息，可作为指南使用。

关于放射线灭菌法承包机构的考察室内辐射设施的投资成本高昂的结果导致承包机构对产品和材料反复进行辐射，而这些承包商本应在安全、环保和过程控制上进行必要控制。

PDA TR 33 微生物测试(中文)

PDA TR 33 微生物测试(中文)

Evaluation, V alidation and Implementation of New Microbiological Testing Methods新微生物测试方法的评估、验证和执行Technical Report No. 33 第33号技术报告PDA目录第一部分: 新微生物方法的选择1.0 简介. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11.1 文件范围. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.2 文件目的. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11.3 文件结构概览. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22.0 技术概要. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22.1微生物方法类型的一般说明. . . . . .. . . . . . . . . . .. . . . . . . . .. . 22.2 技术审核. . .. . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . .. . . . 32.3 基于生长的技术. . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . .. .32.3.1 ATP生物发光. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. ..32.3.2 CO2生产的色度检测. . . . . . . . . . . . . . . . . . . . . . . .. . . .42.3.3 顶部空间压力变更的测量. . . .. . . . . . . . . . . . . .. .. . . .. .42.3.4阻抗. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42.3.5 生物化学分析. . .. . . . . .. . . . . . .. . . . . . . . . . . . . . . .42.4 基于活性的技术. . .. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . 62.4.1 固相血细胞计数. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . 62.4.2 流式荧光细胞计. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62.5 人工技术. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.5.1 脂肪酸概要. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.5.2 质谱学. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72.5.3 ELISA酶联免疫吸附测定. . . . . . . . . . . . . . . . . .. . . . . . 72.5.4 荧光探针检测. . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . 72.5.5 细菌内毒素-鲎变形细胞溶解物测试. . . . . . . . . . . . . ..72.6 基于核酸的技术. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. (8)2.6.1 探针. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .82.6.2 核糖型/分子型. . .. . . . . . . . . . . . . . . . . . . . . . . . . . . 82.6.3 聚合酶链反应. . .. . . . . .. . . . . . . . . . . . . . . . . . . . . .93.0监管审查. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .103.1微生物测试总分类. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (10)3.1.1 加工过程中测试. . .. . . . . . . . . . . . . . . . . . . . . . (10)3.1.2 产品测试. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (10)3.1.3 定性测试. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (10)3.1.4 定量测试. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (10)3.2 药典微生物测试方法参考文件. . .. . . . . . . . . . . . . . . . . . . . 103.2.1 制药用水. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..103.2.2 抗菌效力测试. . . . .. . . . . . . . . . . . . . . . . . . . . . . (10)3.2.3 微生物限度测试. . . . . .. . . . . . . . . . . . . . . . . . (11)3.2.4 无菌测试. . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . (11)3.2.5 环境监测. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (11)3.2.6 微生物鉴定. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .113.3 改变微生物测试方法. . . . . . . . . . . . . . . . . . . . . . . . . . . . 113.3.1 新微生物测试方法介绍的监管观点 . . . . . . . . . . . . . ..113.3.2 药典观点. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (12)3.4 药典变更. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (13)3.5 新微生物方法的管理者评估. . . . . . . . . . . . . . . . . . . . .13 第二部分: 如何验证并执行新微生物测试方法4.0 验证流程. . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .154.1 设备确认模型. . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . .164.1.1 供应商/说明要求. . . . . . . . . . . . . . . . . . . . . . . . . . 164.1.1.1 测试方法选择. . . . . . . . . . . . . . . . . . . . .174.1.1.2 供应商选择. . . . . . . . . . . . . . . . . . . . . . .174.1.2 验证方法设计. . . . . . . . . . . . . . . . . . . . . . . . . . (18)4.1.3 安装确认. . . . . . . . . . . . . . . . . . . . . . . . . . . . (18)4.1.4 运行确认. . . . . . . . . . . . . . . . . . . . . . . . . . . . (20)4.1.5 性能确认. . . . . . . . . . . . . . . . . . . . . . . . . . ....... (20)4.2验证标准. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . (21)4.2.1测试样品制备. . .. . . . . . . . . . . . . . . . . ....... . . . (23)4.2.2 微生物方法的活性：特别注意. . . . . . . . . . . . . . . . 254.2.2.1 样品分布错误. . .. . . . . . . . . . . . . . . (25)4.2.2.2 细胞形态. . . . . . . . . . . . . . . . . . . . . . . . 254.2.2.3 代谢活动. . .. . . . . . . . . . . . . . . . . . . . . 254.2.3使用推荐验证标准的方案设计. .. . . . . . . . . . . . . . .264.3微生物方法验证的特殊考虑. . . . . . . . . . . . . . . . . . . . . . . 294.3.1在实验室和公司内使用多件相同设备. . . . . . . . . . . . 294.3.2微生物设备的独特测试要求. .. . . . . . . . . . . . . . . . . 305.0 术语. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32第一部分新微生物测量方法的选择1.0简介1.1文件范围本文件的目的是对制药、生物技术和医药设备工业为确保产品质量进行成功评估、验证和实施所需新微生物方法提供指南。

无菌模拟灌装工艺验证[指南]

无菌模拟灌装工艺验证[指南]

无菌工艺模拟验证-培养基灌装试验王新峰QA/QC 厂房设施人员灭菌工艺无菌保证培养基灌装HVAC，水操作规程日常监控EM&PM内容1.培养基灌装的目的2.法规要求3.不同制剂工艺的培养基灌装（液体、冻干产品，干粉分装产品）4.风险分析5.实验设计6.审计要点培养基灌装试验的定义定义:培养基灌装－采用培养基代替产品，按照正常生产的程序来进行无菌灌装工艺验证。

培养基灌装试验目的目的：–评估在既定无菌生产环境和过程控制条件下生产无菌产品的能力–证明指定的无菌工艺设计和变更是否可行–证明无菌工艺过程中的相关操作是否可行–评估无菌工艺人员的操作水平（资格确认组成部分）– QAR调查的手段–证明符合cCMP的要求–发现无菌工艺过程中潜在的微生物污染因素培养基灌装试验应用范围•无菌药品和生物制剂的生产•用无菌工艺进行医疗器械，人和动物保健品的生产法规要求2010GMP•第四十七条无菌生产工艺的验证应当包括培养基模拟灌装试验。

•应当根据产品的剂型、培养基的选择性、澄清度、浓度和灭菌的适用性选择培养基。

应当尽可能模拟常规的无菌生产工艺，包括所有对无菌结果有影响的关键操作，及生产中可能出现的各种干预和最差条件。

•培养基模拟灌装试验的首次验证，每班次应当连续进行3次合格试验。

空气净化系统、设备、生产工艺及人员重大变更后，应当重复进行培养基模拟灌装试验。

培养基模拟灌装试验通常应当按照生产工艺每班次半年进行1次，每次至少一批。

•培养基灌装容器的数量应当足以保证评价的有效性。

批量较小的产品，培养基灌装的数量应当至少等于产品的批量。

培养基模拟灌装试验的目标是零污染，应当遵循以下要求：•（一）灌装数量少于5000支时，不得检出污染品。

•（二）灌装数量在5000至10000支时：•1.有1支污染，需调查，可考虑重复试验；•2.有2支污染，需调查后，进行再验证。

•（三）灌装数量超过10000支时：•1.有1支污染，需调查；•2.有2支污染，需调查后，进行再验证。

PDATR1湿热灭菌工艺验证

PDATR1湿热灭菌工艺验证

PDATR1湿热灭菌⼯艺验证PDA Technical Report No. 1 - Revised 2007PDA技术报告No. 1 –2007修订版Validation of Moist Heat Sterilization Processes:Cycle Design, Development, Quali?cation and Ongoing Control湿热灭菌⼯艺验证：周期设计，开发，验证和持续控制Contributors作者James P. Agalloco, Agalloco & AssociatesJames E. Akers, Ph.D., Akers Kennedy & AssociatesWilf Allinson, GlaxoSmithKlineThomas J. Berger, Ph.D., HospiraFrank Bing, Abbott Laboratories(retired)Go¨ran Bringert,GE KayeInstruments Gary Butler, SterisCorporationJean-Luc Clavelin, Eli Lilly & Co.Peter Cooney, Ph.D., FDA (retired)Phil DeSantis, Schering-PloughPeter Du¨rr,F.Hoffmann-La Roche AGKristen D. Evans, FDAJohn G. Grazal, AstraZenecaNigel Halls, Ph.D., IAGT. Ltd.Paul Hargreaves, MHRAAndrew D. Hopkins, MHRAMartin A. Joyce, Ph.D., GeneraMedix Inc.David Karle, Steris Corporation BernardKronenberg, Bakrona Basel AG John W.Levchuk, Ph.D., FDA (retired) RichardV. Levy, Ph.D., PDA Steen Loevtrup,Novo Nordisk A/S Timothy F. Lord, EliLilly & Co.Genevieve Lovitt-Wood, G.I. Lovitt & Associates, Project Manager and Technical Writer Russell E. Madsen, The Williamsburg Group, LLCVittorio Mascherpa, Ph.D., Fedegari Autoclavi Spa (retired)David W. Maynard, Maynard & AssociatesRobert B. Myers, PDAJames E. Owens, Baxter Healthcare (retired)Irving P?ug, Ph.D., University of Minnesota (retired)Dario Pistolesi, Ph.D., Fedegari Autoclavi Spa (retired)Anthony Pochiro, AG Edwards and Sons Jarmo Saari,Leiras OYMichael Sadowski, Baxter HealthcareJohn T. Shirtz, Baxter HealthcareKeith Shuttleworth, Keith Shuttleworth & Associates Ltd.Finlay Skinner, Skinner Pharm-AssistIan Symonds, GlaxoSmithKlineKevin D. Trupp, HospiraDieter Witthauer, Ph.D., NovartisRichard T. Wood, Ph.D. (retired)William Young, Baxter Healthcare (retired)Validation of Moist Heat Sterilization Processes:Cycle Design, Development, Quali?cation and Ongoing Control湿热灭菌⼯艺验证：周期设计，制定，验证和持续控制Technical Report No. 1 (Revised 2007) 技术报告No. 1（2007年修订）Supplement补充Vol. 61, No. S-12007 by PDATABLE OF CONTENTS⽬录1.0 INTRODUCTION简介 (2)1.1 Scope范围 22.0 GLOSSARY OF TERMS术语词汇 (4)3.0 STERILIZATION SCIENCE 灭菌科学 (8)3.1 Sterilization Models灭菌模式 (8)3.1.1 Resistance Value(Dr) 电阻值 (9)3.1.1.1 Direct Enumeration Method直接计算法 (9)3.1.1.2 Fraction-Negative Methods 负分数⽅法 (10)3.1.2 Temperature Coefficient(z-value)温度系数（Z值） (11)3.1.3 Lethal Rate(L) and Lethality (F) 致死率（L0和致死率（F） (12)3.1.3.1 Lethal Rate(L)致死率（L） (13)3.1.3.2 Fphysical Value(FPHY) Fphysical 值 (13)3.1.3.3 F0 (15)3.1.3.4 FBiological Value(FBIO) FBiological 值 (15)3.2 Process Indicators ⼯艺指⽰器 (15)3.2.1 Biological Indicators⽣物指⽰器 (15)3.2.2 Chemical Monitors 化学检测器 (16)3.2.2.1 Chemical Indicators化学指⽰器 (17)3.2.2.2 Chemical Integrators 化学集成 (17)3.3 Thermal Science and Steam Quality热科学和蒸汽质量 (17)3.3.1 Temperature and Heat温度和热 (17)3.3.1.1 Conduction传导 (19)3.3.1.2 Convection对流 (20)3.3.1.3 Radiation辐射203.3.1.4 H eat Transfer Rate and a Comparison of Heat Capacities of Heating Mediums热传递速率和加热介质的热能对照 (20)3.3.2 Steam蒸汽 (21)3.3.2.1 Plant Steam⼯⼚蒸汽 (21)3.3.2.2 Process Steam⼯艺蒸汽 (21)3.3.2.3 Pure Steam纯蒸汽 (21)3.3.3 Steam Quality Testing for Pure Steam 纯蒸汽的蒸汽质量测试 (22)3.3.3.1 Noncondensable Gases⾮凝性⽓体 (22)3.3.3.2 Dryness Fraction and Dryness Value⼲燥分数和⼲燥值 (22)3.3.3.3 Superheat过热 (23)4.0 STERILIZATION PROCESS DEVELOPMENT⽆菌⼯艺开发 (24)4.1 Design Approaches设计⽅法 (24)4 1.1 Use of Survivor Curve in Cycle Design Approaches周期设计⽅法使⽤⽣存曲线254.1.1.1 Overkill Design Approach有⼒的设计⽅法 (26)4.1.1.2 Product-specific Design Approach特定产品设计⽅法 (26)4.2 Load Types 负荷类型 (28)4.2.1 Defining Porous/ Hard Goods Loads定义多孔/硬货载负荷 (28) 4.2.2 Defining Liquid Loads定义液体负荷 (28)4.3 Sterilization Processes⽆菌⼯艺 (28)4.3.1 Saturated Steam Processes饱和蒸汽⼯艺 (29)4.3.1.1 Prevacuum Process预真空⼯艺 (29)。

PDA TR1 湿热灭菌工艺验证

PDA TR1 湿热灭菌工艺验证

PDA Technical Report No. 1 - Revised 2007PDA技术报告No. 1 –2007修订版Validation of Moist Heat Sterilization Processes:Cycle Design, Development, Qualification and Ongoing Control湿热灭菌工艺验证：周期设计，开发，验证和持续控制Contributors作者James P. Agalloco, Agalloco & AssociatesJames E. Akers, Ph.D., Akers Kennedy & AssociatesWilf Allinson, GlaxoSmithKlineThomas J. Berger, Ph.D., HospiraFrank Bing, Abbott Laboratories(retired)Go¨ran Bringert,GE KayeInstruments Gary Butler, SterisCorporationJean-Luc Clavelin, Eli Lilly & Co.Peter Cooney, Ph.D., FDA (retired)Phil DeSantis, Schering-PloughPeter Du¨rr,F.Hoffmann-La Roche AGKristen D. Evans, FDAJohn G. Grazal, AstraZenecaNigel Halls, Ph.D., IAGT. Ltd.Paul Hargreaves, MHRAAndrew D. Hopkins, MHRAMartin A. Joyce, Ph.D., GeneraMedix Inc.David Karle, Steris Corporation BernardKronenberg, Bakrona Basel AG John W.Levchuk, Ph.D., FDA (retired) RichardV. Levy, Ph.D., PDA Steen Loevtrup,Novo Nordisk A/S Timothy F. Lord, EliLilly & Co.Genevieve Lovitt-Wood, G.I. Lovitt & Associates, Project Manager and Technical WriterRussell E. Madsen, The Williamsburg Group, LLCVittorio Mascherpa, Ph.D., Fedegari Autoclavi Spa (retired)David W. Maynard, Maynard & AssociatesRobert B. Myers, PDAJames E. Owens, Baxter Healthcare (retired)Irving Pflug, Ph.D., University of Minnesota (retired)Dario Pistolesi, Ph.D., Fedegari Autoclavi Spa (retired)Anthony Pochiro, AG Edwards and Sons Jarmo Saari,Leiras OYMichael Sadowski, Baxter HealthcareJohn T. Shirtz, Baxter HealthcareKeith Shuttleworth, Keith Shuttleworth & Associates Ltd.Finlay Skinner, Skinner Pharm-AssistIan Symonds, GlaxoSmithKlineKevin D. Trupp, HospiraDieter Witthauer, Ph.D., NovartisRichard T. Wood, Ph.D. (retired)William Young, Baxter Healthcare (retired)Validation of Moist Heat Sterilization Processes:Cycle Design, Development, Qualification and Ongoing Control湿热灭菌工艺验证：周期设计，制定，验证和持续控制Technical Report No. 1 (Revised 2007) 技术报告No. 1（2007年修订）Supplement补充Vol. 61, No. S-1© 2007 by PDATABLE OF CONTENTS目录1.0 INTRODUCTION简介 (2)1.1 Scope范围 22.0 GLOSSARY OF TERMS术语词汇 (4)3.0 STERILIZATION SCIENCE 灭菌科学 (8)3.1 Sterilization Models灭菌模式 (8)3.1.1 Resistance Value(Dr) 电阻值 (9)3.1.1.1 Direct Enumeration Method直接计算法 (9)3.1.1.2 Fraction-Negative Methods 负分数方法 (10)3.1.2 Temperature Coefficient(z-value)温度系数（Z值） (11)3.1.3 Lethal Rate(L) and Lethality (F) 致死率（L0和致死率（F） (12)3.1.3.1 Lethal Rate(L)致死率（L） (13)3.1.3.2 Fphysical Value(FPHY) Fphysical 值 (13)3.1.3.3 F0 (15)3.1.3.4 FBiological Value(FBIO) FBiological 值 (15)3.2 Process Indicators 工艺指示器 (15)3.2.1 Biological Indicators生物指示器 (15)3.2.2 Chemical Monitors 化学检测器 (16)3.2.2.1 Chemical Indicators化学指示器 (17)3.2.2.2 Chemical Integrators 化学集成 (17)3.3 Thermal Science and Steam Quality热科学和蒸汽质量 (17)3.3.1 Temperature and Heat温度和热 (17)3.3.1.1 Conduction传导 (19)3.3.1.2 Convection对流 (20)3.3.1.3 Radiation辐射203.3.1.4 H eat Transfer Rate and a Comparison of Heat Capacities of Heating Mediums热传递速率和加热介质的热能对照 (20)3.3.2 Steam蒸汽 (21)3.3.2.1 Plant Steam工厂蒸汽 (21)3.3.2.2 Process Steam工艺蒸汽 (21)3.3.2.3 Pure Steam纯蒸汽 (21)3.3.3 Steam Quality Testing for Pure Steam 纯蒸汽的蒸汽质量测试 (22)3.3.3.1 Noncondensable Gases非凝性气体 (22)3.3.3.2 Dryness Fraction and Dryness Value干燥分数和干燥值 (22)3.3.3.3 Superheat过热 (23)4.0 STERILIZATION PROCESS DEVELOPMENT无菌工艺开发 (24)4.1 Design Approaches设计方法 (24)4 1.1 Use of Survivor Curve in Cycle Design Approaches周期设计方法使用生存曲线254.1.1.1 Overkill Design Approach有力的设计方法 (26)4.1.1.2 Product-specific Design Approach特定产品设计方法 (26)4.2 Load Types 负荷类型 (28)4.2.1 Defining Porous/ Hard Goods Loads定义多孔/硬货载负荷 (28)4.2.2 Defining Liquid Loads定义液体负荷 (28)4.3 Sterilization Processes无菌工艺 (28)4.3.1 Saturated Steam Processes饱和蒸汽工艺 (29)4.3.1.1 Prevacuum Process预真空工艺 (29)。

PDA TR3-1981 干热灭菌

PDA TR3-1981 干热灭菌

24 6.0 Biological Validation .................................. 6.1 Biological Intent ................................... 24 6.2 Laboratory Studies ................................. 27 6.3 Plant Studies ...................................... 44
Technical Report No. 3
VAEIDATION OF DRY HEA T PROCESSES USED FOR STERILIZATION AND DEPYROGENA TION
PARENTERAL DRUG ASSOCIATION, Inc.
L i . p d a -
lo FDA
PREFACE
IS THE THIRD Technical Report dealing with sterilization THIS validation(1s2). Specifically, this report presents a review of validation for processes that use dry heat to achieve sterilization and/or depyrogenation.
Task Group 16, under the co-chairmanship of William Frieben and Thomas Lypka, has developed a discussion of various biological and engineering parameters which may be considered in validation. Sol Motola-1980 R. Michael Enzinger-1981 Chairman Research Committee

PDA TR29(1998)中英文对照版[1]

PDA TR29(1998)中英文对照版[1]
This Technical Report was disseminated in draft for public review and comment prior to publication. Many of the submitted comments have been included in the final document. We
清洁剂 4.3 Microbiological Contaminants
微生物污染 4.4 Other Contaminants to be Removed
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次要设备——主要设备 Materials of Construction 构造材质 2.4 Product Attributes 产品属性 Low Risk——High Risk Drugs 低风险——高风险药物 Highly Characterized——Poorly Characterized 高度特性化——缺乏特性化 Non-Sterile——Sterile 非无菌——无菌 2.5 Formulation Attributes 配方属性 Solids——Liquids 固体——液体 Soluble (Active or Excipient)——Insoluble (Active or Excipient) 可溶活性成分或赋形剂——难溶活性成分或赋形剂 2.6 Operational Issues 操作上的问题 Single Product Facility——Multiple Product Facility 单品种设施——多品种设施 Campaign Production——Batch Production 连续生产——批次生产 Simple Equipment Train——Complex Equipment Train 简单设备组合——复杂设备组合

FDA无菌生产指南-中英文对照版.doc

FDA无菌生产指南-中英文对照版.doc

FDA无菌生产指南-中英文对照版Translated from / 译自：Guidance for IndustrySterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice行业指南无菌加工生产的无菌药品—现行的生产质量管理规范(cGMP）U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Office of Regulatory Affairs (ORA)September 2004Pharmaceutical CGMPsCopyright SCI Version 1Copyright SCI Version 1Copyright SCI Version 1TABLE OF CONTENTSI. INTRODUCTION (1)简介II. BACKGROUND (2)背景A.Regulatory Framework (3)法规架构B.Technical Framework (3)技术架构III. SCOPE (5)适用范围IV. BUILDINGS AND FACILITIES (6)厂房和建筑A.Critical Area – Class 100 (ISO 5) (8)关键区域– 100级(ISO 5)B. Supporting Clean Areas (11)辅助洁净区域C. Clean Area Separation (11)净化区的隔离D.Air Filtration (13)空气过滤1.Membrane (13)膜过滤2.High-Efficiency Particulate Air (HEPA) (14)高效颗粒空气过滤器(HEPA)E.Design (17)设计V. PERSONNEL TRAINING, QUALIFICATION, & MONITORING (21)人员的培训，资格认定和监控A.Personnel (22)人员boratory Personnel (26)实验室人员C.Monitoring Program (26)监控程序VI. COMPONENTS AND CONTAINER/CLOSURES (28)药品成分和容器/密封A. Components (28)Copyright SCI Version 1药品成分B. Containers/Closures (31)容器/密封1.Preparation (31)准备2. .................................................................................. Inspection of Container Closure System33容器密封系统的检查VII. ENDOTOXIN CONTROL (35)内毒素控制VIII. TIME LIMITATIONS (37)时间限制IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION (38)无菌加工和灭菌的验证A. Process Simulations (38)工艺模拟1.Study Design (39)研究设计2.Frequency and Number of Runs (41)运行频率和次数3.Duration of Runs (42)运行时间4.Size of Runs (43)批量5.Line Speed (44)运行速度6.Environmental Conditions (44)环境质量7.Media (45)培养基8.Incubation and Examination of Media-Filled Units (46)培养基灌装单位的培养和检查9.Interpretation of Test Results (48)试验结果解释B. Filtration Efficacy (50)过滤功效C. Sterilization of Equipment, Containers, and Closures (53)设备、容器和密封的灭菌1.Qualification and Validation (54)确认和验证2.Equipment Controls and Instrument Calibration (56)设备控制和仪器校准X. LABORATORY CONTROLS (59)实验室控制Copyright SCI Version 1A. Environmental Monitoring (61)环境监测1. ...................................................................................................... General Written Program61书面程序2.Establishing Levels and a Trending Program (63)建立监测标准和趋势分析程序3.Disinfection Efficacy (64)消毒功效4.Monitoring Methods (64)监测方法B. Microbiological Media and Identification (66)微生物培养基及微生物的鉴定C. Prefiltration Bioburden (67)过滤前的生物负荷D. Alternate Microbiological Test Methods (68)可替代的微生物测试方法E. Particle Monitoring (68)颗粒监测XI. STERILITY TESTING (69)无菌试验A. Microbiological Laboratory Controls (71)微生物实验室控制B. Sampling and Incubation (71)取样和培养C. Investigation of Sterility Positives (72)无菌试验阳性结果的调查XII. BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION (77)批生产纪录审核：工艺控制文件化APPENDIX 1: ASEPTIC PROCESSING ISOLATORS (79)附录1: 无菌隔离装置APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY (87)附录2：吹-灌-封技术APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS (91)附录3：灌装和密封前的工艺REFERENCES (94)参考文献RELEVANT GUIDANCE DOCUMENTS (95)相关指南文件GLOSSARY (96)Copyright SCI Version 1术语表Copyright SCI Version 1Guidance for Industry1Sterile Drug Products Produced byAseptic Processing — Current Good Manufacturing PracticeI.INTRODUCTION简介This guidance is intended to help manufacturers meet the requirements in the Agency's current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic processing. This guidance replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing (Aseptic Processing Guideline). This revision updates and clarifies the 1987 guidance.本指南旨在帮助生产商在应用无菌工艺制造无菌药品和生物制剂时，达到FDA cGMP规章(美国联邦法规的第210及第211节)要求。

WHO使用风险评估的方法对无菌生产进行检查

WHO使用风险评估的方法对无菌生产进行检查

你是怎样认为的？
|
5|
FMEA : 模式的准备(1)
成功的关键 : 输入质量从而使之更加客观和有效 确定问题：范围是从无菌工艺生产的厂房，设备，系统或工艺需 要被评估的方面。 管理支持： 召集组成一个由多种学科专家组成的小组，确立领 导者和各自相应的职责并指配必要的资源
文件: 假设 (手动分装, 半自动或自动传统工艺A/B, RABS, 隔离器 | ), 范围, 边界界限背景和原始资料。工艺流程图
PDA TR 44, 无菌工艺的质量风险管理（Quality Risk Management for Aseptic Processes, Vol. 62, No. S-1, 2008）
2|
FMEA :失败模式与影响分析
FMEA : 是一种对无菌工艺进行评估和做决定的方法。
关键质量属性 (CQAs)：产品的 CQAs 能够对患者（接种者）的安全产生影 响或对患者（接种者） 产生伤害，包括特性，纯度，安全和剂型，这些直接 和QRM相关联。
使用风险评估的方法对无菌生产进行检查
使用风险评估的方法对无菌工艺进行检查
FMEA（失败模式与影响分析） : 无菌工艺 QRM 模式 例子 1 定性评级 RPR（风险优先等级）: 西林瓶冻干后开始压盖的QRM（质量风险管理） 例子2 定量评级 RPN（风险优先数量）:
无菌分装的QRM（质量风险管理） |
| 注意:可发现性与危害性和发生的可能性成反比：可发现性越高＝ 风险等级越低。
11 |
FMEA 模型中每栏标题的含义3
RPR 或RPN : = 风险优先等级或者数量= 工艺步骤的总体风险 - 定量或数字系统RPN= 计算数值 - 定性系统RPR = 综合的描述性评价，带有些直觉因素，应当在开 始评估开始前作出判断。 以无菌工艺模型来举例，严重性始终都是一个高风险等级因此它始 终是一个常数或恒量。而RPR 或 RPN 就要结合其发生的可能性和 可发现性。

PDA_Technical_Reports_list

PDA_Technical_Reports_list
PDA TECHNICAL REPORTS
TECHNICAL REPORT
Paper Version
Digital Version
01001
43381
01004 01005 01007 01009 01010 01011 01012
43208 43209 43210 43212 43214 43215 43216 43217 43218
43486 43487
43488
TITLE
36 Current Practices in the Validation of Aseptic Processing -- 2001
38
Manufacturing Chromatography Systems Post-Approval Changes: (ChromPAC): Chemistry, Manufacturing and Controls Documentation
30 Parametric Release of Pharmaceuticals Terminally Sterilized by Moist Heat
31 Validation and Qualification of Computerized Laboratory Data Acquisition Systems
49 Points to Consider for Biotechnology Cleaning Validation
DATE OF PUBLICATION
2002 2006 2007 2005 2008 2005 2007 2008 2008 2009 2010 2010 2010
01060 01061
56
Application of Phase-Appropriate Quality Systems and CGMP to the Development of Therapeutic Protein Drug Substance

PDA TR29(1998)中英文对照版[1]

PDA TR29(1998)中英文对照版[1]
2. The Cleaning Continuum 清洁操作的连贯性 2.1 Use of the Cleaning Continuum 清洁操作连贯性的运用 2.2 Cleaning Program Criteria 清洁程序标准 Automated Cleaning——Manual Cleaning 自动清洁——手工清洁. . . . . . . . . . . . . . 5 Clean-In-Place (CIP)——Clean-Out-of-Place (COP) 在线清洗——离线清洗 2.3 Equipment Characteristics / Materials of Construction 设备特色与构造材质 Dedicated—— Non-Dedicated Manufacturing Equipment 专用——非专用生产设备 Dedicated—— Non-Dedicated Cleaning Equipment 专用——非专用清洁设备 Non-Product Contact——Product Contact Surfaces 非产品接触——产品接触表面 Non-Critical Site—— Critical Site 非关键位置——关键位置 Minor Equipment——Major Equipment
3.5 Cleaning Agent Groupings 清洁剂分类
4. Residues and Residue Removal 残留物与残留物的清除
4.1 Types of Residue 残留物的类别
4.2 Cleaning Agents
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Our goal had always been to outline cleaning validation practices across a range of equipment, process, and product applications and the inclusion of this flexibility was certainly a factor in the length of time it took to complete this effort. During the course of assembling this document, we recognized the commonality of certain themes, issues, and concerns relative to cleaning and cleaning validation across the industry. We also realized that in order to apply the principles in different operating settings, that some narrowing of the document would be necessary. As a result, we have included perspectives on the application of the guidance in various areas: finished pharmaceuticals, bulk pharmaceutical chemicals, biopharmaceuticals and clinical products. Inclusion of biopharmaceuticals in this effort is not intended to replace the more comprehensive coverage provided by our partner committee, but rather to provide greater insight regarding the broad application of the guidance provided herein. 我们的目标一直都是着眼于如何描述清洁验证的操作，以适应一系列设备、工艺及产品 的应用，另外，在完成本工作之前耗时不少，是以运作的弹性度也自然的进行了考虑。 在编制本文件的过程中，我们了解工业界在清洁方法与清洁验证方面若干共同的主题、 争议及关注点。我们也知道如要讲相关的原则用于不同的现状，本文件中有些部分涉及 的内容有必要加以量化的必要。基于这些原因，我们对本文件在各种领域方面的应用， 如一般制剂、原料药、生物制剂及临床有关产品等，分别加以研究描述。生物药学制剂 的列入，目的不在于取代我们的队友已提供的较为广泛而深入的资料，而在于本资料更 能令人深入了解，以使其广泛的应用。

PI_007-6_无菌工艺验证的建议(中英文对照)

PI_007-6_无菌工艺验证的建议(中英文对照)
2.3 General information 综述
2.3.1 The basic principles and application of process validation are described in Annex 15 to the EU/PIC/S Guide to GMP and are further elaborated in PIC/S Document PI 006 (Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation) and apply also to aseptic processing. Annex I to the EU/ PIC/S Guide to GMP provides the basic requirements for the manufacture of sterile products including those aseptically processed. The Annex includes requirements, standards and recommendations, for example, for monitoring of the environment and of personnel. 工艺验证的基本原则及其应用在 EU/PIC/S GMP 指南附录 15 中进行了描述，在 PIC/S 文件 PI 006（验证总计划、IQ、OQ、非无菌工艺验证、清洁验证）中有了更为详尽的 说明，该说明也适用于无菌工艺。EU/ PIC/S 的 GMP 指南附录 1 对无菌产品的生产提 出了基本要求，包括那些无菌生产的工艺。该附录包含了要求、标准以及建议，例如， 对环境和人员的监测。

pdatr13环境监控

pdatr13环境监控

[翻译] PDA TR13 环境监控2015-09-21文章来源：北京齐力佳整理INTRODUCTION简介The purpose of this document is to identifymicrobiological and particulate control concepts and principles as they relateto the manufacture of sterile pharmaceutical products. It expandssubstantially upon the first edition of Technical Report No. 13, Fundamentalsof a Microbiological Environmental Monitoring Program, published by PDA in1990. While this publication cannot possibly supplant the wealth ofinformation published on this subject, it provides summary information andappropriate references for the reader to consult, if necessary. The objectivewas to contemporize the first edition through the utilization of current definitions,recognition of improved environmental monitoring procedures, and equipment. 本文件目的是确定微生物和微粒控制的概念和原则，因为这涉及到无菌药品的生产。

文件全称为第13号技术报告第一版，微生物的环境监测计划基础，PDA于1990年出版。

FDA无菌生产指南-中英文对照版

FDA无菌生产指南-中英文对照版

Translated from / 译自：Guidance for IndustrySterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice行业指南无菌加工生产的无菌药品—现行的生产质量管理标准(cGMP〕U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Office of Regulatory Affairs (ORA)September 2004Pharmaceutical CGMPsGuidance for Industry Sterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing PracticeAdditional copies are available from:Office of Training and CommunicationDivision of Drug Information, HFD-240Center for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573orOffice of Communication, Training andManufacturers Assistance, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448(Tel) Voice Information System at 800-835-4709 or 301-827-1800U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Office of Regulatory affairs (ORA)September 2004Pharmaceutical CGMPsTABLE OF CONTENTSI.INTRODUCTION (1)简介II.BACKGROUND (2)背景A.Regulatory Framework (2)法规架构B.Technical Framework (3)技术架构III.SCOPE (4)适用范围IV.BUILDINGS AND FACILITIES (6)厂房和建筑A.Critical Area – Class 100 (ISO 5) (8)关键区域– 100级 (ISO 5)B. Supporting Clean Areas (10)辅助洁净区域C. Clean Area Separation (11)净化区的隔离D.Air Filtration (12)空气过滤1.Membrane (12)膜过滤2.High-Efficiency Particulate Air (HEPA) (13)高效颗粒空气过滤器(HEPA)E.Design (16)设计V.PERSONNEL TRAINING, QUALIFICATION, & MONITORING (20)人员的培训，资格认定和监控A.Personnel (21)人员boratory Personnel (24)实验室人员C.Monitoring Program (25)监控程序VI. COMPONENTS AND CONTAINER/CLOSURES (26)药品成分和容器/密封A. Components (26)药品成分B. Containers/Closures (29)容器/密封1.Preparation (29)准备2. Inspection of Container Closure System (31)容器密封系统的检查VII. ENDOTOXIN CONTROL (33)内毒素控制VIII. TIME LIMITATIONS (35)时间限制IX.VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION (36)无菌加工和灭菌的验证A. Process Simulations (36)工艺模拟1. Study Design (37)研究设计2.Frequency and Number of Runs (39)运行频率和次数3.Duration of Runs (40)运行时间4.Size of Runs (41)批量5.Line Speed (41)运行速度6.Environmental Conditions (42)环境质量7. Media (42)培养基8.Incubation and Examination of Media-Filled Units (43)培养基灌装单位的培养和检查9.Interpretation of Test Results (45)试验结果解释B. Filtration Efficacy (47)过滤成效C. Sterilization of Equipment, Containers, and Closures (50)设备、容器和密封的灭菌1.Qualification and Validation (51)确认和验证2.Equipment Controls and Instrument Calibration (53)设备控制和仪器校准BORATORY CONTROLS (55)实验室控制A. Environmental Monitoring (56)环境监测1. General Written Program (57)书面程序2.Establishing Levels and a Trending Program (58)建立监测标准和趋势分析程序3.Disinfection Efficacy (59)消毒成效4. Monitoring Methods (60)监测方法B. Microbiological Media and Identification (62)微生物培养基及微生物的鉴定C. Prefiltration Bioburden (63)过滤前的生物负荷D. Alternate Microbiological Test Methods (63)可替代的微生物测试方法E. Particle Monitoring (63)颗粒监测XI.STERILITY TESTING (65)无菌试验A. Microbiological Laboratory Controls (67)微生物实验室控制B. Sampling and Incubation (67)取样和培养C. Investigation of Sterility Positives (68)无菌试验阳性结果的调查XII.BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION (73)批生产纪录工艺控制文件化APPENDIX 1: ASEPTIC PROCESSING ISOLATORS (75)附录 1: 无菌隔离装置APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY (82)附录2：吹-灌-封技术APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS (86)附录3：灌装和密封前的工艺REFERENCES (89)参考文献RELEVANT GUIDANCE DOCUMENTS (90)相关指南文件GLOSSARY (91)术语表Guidance for Industry1Sterile Drug Products Produced byAseptic Processing — Current Good Manufacturing PracticeI.INTRODUCTION简介This guidance is intended to help manufacturers meet the requirements in the Agency's current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic processing. This guidance replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing (Aseptic Processing Guideline). This revision updates and clarifies the 1987 guidance.本指南旨在帮助生产商在应用无菌工艺制造无菌药品和生物制剂时，到达FDA cGMP规章(美国联邦法规的第210及第211节)要求。

FDA无菌生产指南-中英文对照版.doc

FDA无菌生产指南-中英文对照版.doc

FDA无菌生产指南-中英文对照版Translated from / 译自：Guidance for IndustrySterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice行业指南无菌加工生产的无菌药品—现行的生产质量管理规范(cGMP）U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)Office of Regulatory Affairs (ORA)September 2004Pharmaceutical CGMPsCopyright SCI Version 1Copyright SCI Version 1Copyright SCI Version 1TABLE OF CONTENTSI. INTRODUCTION (1)简介II. BACKGROUND (2)背景A.Regulatory Framework (3)法规架构B.Technical Framework (3)技术架构III. SCOPE (5)适用范围IV. BUILDINGS AND FACILITIES (6)厂房和建筑A.Critical Area – Class 100 (ISO 5) (8)关键区域– 100级(ISO 5)B. Supporting Clean Areas (11)辅助洁净区域C. Clean Area Separation (11)净化区的隔离D.Air Filtration (13)空气过滤1.Membrane (13)膜过滤2.High-Efficiency Particulate Air (HEPA) (14)高效颗粒空气过滤器(HEPA)E.Design (17)设计V. PERSONNEL TRAINING, QUALIFICATION, & MONITORING (21)人员的培训，资格认定和监控A.Personnel (22)人员boratory Personnel (26)实验室人员C.Monitoring Program (26)监控程序VI. COMPONENTS AND CONTAINER/CLOSURES (28)药品成分和容器/密封A. Components (28)Copyright SCI Version 1药品成分B. Containers/Closures (31)容器/密封1.Preparation (31)准备2. .................................................................................. Inspection of Container Closure System33容器密封系统的检查VII. ENDOTOXIN CONTROL (35)内毒素控制VIII. TIME LIMITATIONS (37)时间限制IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION (38)无菌加工和灭菌的验证A. Process Simulations (38)工艺模拟1.Study Design (39)研究设计2.Frequency and Number of Runs (41)运行频率和次数3.Duration of Runs (42)运行时间4.Size of Runs (43)批量5.Line Speed (44)运行速度6.Environmental Conditions (44)环境质量7.Media (45)培养基8.Incubation and Examination of Media-Filled Units (46)培养基灌装单位的培养和检查9.Interpretation of Test Results (48)试验结果解释B. Filtration Efficacy (50)过滤功效C. Sterilization of Equipment, Containers, and Closures (53)设备、容器和密封的灭菌1.Qualification and Validation (54)确认和验证2.Equipment Controls and Instrument Calibration (56)设备控制和仪器校准X. LABORATORY CONTROLS (59)实验室控制Copyright SCI Version 1A. Environmental Monitoring (61)环境监测1. ...................................................................................................... General Written Program61书面程序2.Establishing Levels and a Trending Program (63)建立监测标准和趋势分析程序3.Disinfection Efficacy (64)消毒功效4.Monitoring Methods (64)监测方法B. Microbiological Media and Identification (66)微生物培养基及微生物的鉴定C. Prefiltration Bioburden (67)过滤前的生物负荷D. Alternate Microbiological Test Methods (68)可替代的微生物测试方法E. Particle Monitoring (68)颗粒监测XI. STERILITY TESTING (69)无菌试验A. Microbiological Laboratory Controls (71)微生物实验室控制B. Sampling and Incubation (71)取样和培养C. Investigation of Sterility Positives (72)无菌试验阳性结果的调查XII. BATCH RECORD REVIEW: PROCESS CONTROL DOCUMENTATION (77)批生产纪录审核：工艺控制文件化APPENDIX 1: ASEPTIC PROCESSING ISOLATORS (79)附录1: 无菌隔离装置APPENDIX 2: BLOW-FILL- SEAL TECHNOLOGY (87)附录2：吹-灌-封技术APPENDIX 3: PROCESSING PRIOR TO FILLING AND SEALING OPERATIONS (91)附录3：灌装和密封前的工艺REFERENCES (94)参考文献RELEVANT GUIDANCE DOCUMENTS (95)相关指南文件GLOSSARY (96)Copyright SCI Version 1术语表Copyright SCI Version 1Guidance for Industry1Sterile Drug Products Produced byAseptic Processing — Current Good Manufacturing PracticeI.INTRODUCTION简介This guidance is intended to help manufacturers meet the requirements in the Agency's current good manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) when manufacturing sterile drug and biological products using aseptic processing. This guidance replaces the 1987 Industry Guideline on Sterile Drug Products Produced by Aseptic Processing (Aseptic Processing Guideline). This revision updates and clarifies the 1987 guidance.本指南旨在帮助生产商在应用无菌工艺制造无菌药品和生物制剂时，达到FDA cGMP规章(美国联邦法规的第210及第211节)要求。

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Technical Report No. 62Recommended Practices for Manual Aseptic ProcessesPDA Recommended Practices for Manual Aseptic Processes Technical Report TeamAuthorsOlivia A. Henderson, Ph.D., Biogen Idec (co-Chair)Carol Lampe, J.M. Hansen & Associates, Inc. (co-Chair)James Agalloco, Agalloco and Associates, Inc.Edward A. Fitzgerald, Fitzgerald ConsultingThomas Genova, Ph.D., Johnson & JohnsonJohn W. Levchuk, Food and Drug Administration (retired)John M. Lindsay, Aseptic Solutions, Inc. Jeanne E. Moldenhauer, Excellent Pharma ConsultingRobert J. Nolly, University of Tennessee, Pharmaceutical Sciences

Laura A. Thoma, Pharm. D., University of Tennessee, Pharmaceutical Sciences

ContributorsMark Birse, Medicines and Healthcare Products Regulatory Agency

Mark Ellison, Medicines and Healthcare Products Regulatory Agency

Andrew Hopkins, Medicines and Healthcare Products Regulatory Agency

Ian Jackson, Medicines and Healthcare Products Regulatory Agency

Terry E. Munson, PAREXEL ConsultantsMichelle Rowson, Medicines and Healthcare Products Regulatory Agency

Disclaimer: The content and views expressed in this Technical Report are the result of a consensus achieved by the Task Force and are not necessarily views of the organizations they represent.Recommended Practices for Manual Aseptic Processes

Technical Report No. 62

ISBN: 978-0-939459-57-5© 2013 Parenteral Drug Association, Inc. All rights reserved.1.0 INTRODUCTION ..................................................12.0 GLOSSARY OF TERMS ........................................33.0 BUILDINGS AND FACILITIES ..............................64.0 OPERATIONAL PERSONNEL TRAINING AND QUALIFICATION ...................................................8

4.1 Personnel Training and Qualification ..............84.2 Gowning Qualification ...................................84.3 Risk Management ..........................................84.4 Aseptic Handling Challenges .........................9

5.0 EQUIPMENT, COMPONENTS AND CONTAINER/CLOSURE ..............................10

6.0 PROCESS TIME LIMITATIONS ...........................117.0 DESIGN OF MANUAL ASEPTIC PROCESSES ....127.1 Manual Aseptic Process Design Principles in Unidirectional Air Flow Hoods .....................127.2 Manual Aseptic Process Design Principles in Isolators and RABS ..................................14

8.0 EVALUATION OF MANUAL ASEPTIC PROCESSING–PROCESS SIMULATION .............16

8.1 Simulation Design .......................................16

8.1.1 Compositing/Assembly Activities ...........168.1.2 Formulation/Compounding Activities ......168.1.3 Filling/Subdivision Activities (Including Lyophilization if Needed) .......168.1.4 Manual Manipulation Steps Performed in Conjunction with Other Processes .........168.2 Media Sterilization ......................................178.3 Frequency and Number of APS Runs ..........178.3.1 Duration of Runs ....................................178.3.2 Size of Runs ............................................178.4 Observation of the Process Simulation ........178.5 Media Fill Volume ........................................188.6 Anaerobes/Inert Gassing ............................188.7 Environmental Monitoring ............................188.8 Execution of the Simulation .........................188.9 Pre-Incubation Inspection ............................188.10 Incubation Time/Temperature .....................198.11 Post-Incubation Inspection .........................198.12 Growth Promotion........................................198.13 Interpretation of Test Results ......................19

9.0 CONCLUSION .....................................................2110.0 REFERENCES ...................................................2211.0 ADDITIONAL READING ...................................23

Table of Contents

TABLE INDEXTable 3.0-1 Cleanroom Standards Airborne Particulate Limits ................................................................................61.0 Introduction 简介 The purpose of this technical report is to outline methods and approaches for control and evaluation of aseptic processing operations for drug products/medicinal products which use all or partially manual procedures. The goal of aseptic processing is to prevent the contamination of sterile materials during their processing. The goal of evaluating any aseptic process is to demonstrate that aseptic processing can be achieved and maintained successfully under the specified operational configuration, activities, and conditions. These goals are the same for manual or automated aseptic operations, and for small-scale or large-scale operations. 这份报告的目的就是介绍用于评价和控制全部使用或部分使用手动操作生产的药品和医疗用品的无菌操作过程的方法。无菌操作的目的是阻止无菌物料在工艺过程中不会污染。评估无菌操作的目的就是为了证明通过规定的操作配置、行为和条件，能够成功实现并维持无菌工艺。这些目标对于人工操作、自动操作，大批量小批量操作都是一样的。