cGMP for Sterile Drug Products and APIs 无菌药品和原料药的 cGMP

1. cGMP for Sterile Drug Products and APIs无菌药品和原料药的cGMP Presentation by Ira R. Berry International Regulatory Business Consultants, L.L.C. Maplewood, New Jersey, USA

2. Guidance for Industry Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice DRAFT GUIDANCE cGMP关于无菌工艺生产无菌药品的工业指南（讨论稿） Office of Regulatory Affairs (ORA) August 2003 Pharmaceutical cGMPs \\CDS029\REGAFF\!guidanc\J 874dft.doc 08/12/03

3. Draft Guidance – Aseptic ProcessingI. Introduction无菌工艺指南（讨论稿）介绍 • Use with 1994 guidance 使用1994版指南 • Covers facility design, equipment suitability, process validation, quality control 覆盖了设施设计、设备适用性、工艺验证、质量控制内容

4. Draft Guidance - II. Background指南讨论稿-II.背景 • Aseptic processing 无菌工艺 • Terminal sterilization 最终灭菌

5. Draft Guidance – III. Scope指南讨论稿- III. 范围 • Finished drug products 成品 • Upstream bulk processing steps 原料药上游的工艺步骤 • Terminal sterilization not covered 不包括最终灭菌

6. Draft Guidance – IV. Buildings and Facilities指南讨论稿- IV. 厂房和设施 • Separate and controlled areas 单独和控制区 • Microbiological and particle standards 微生物和尘埃粒子标准 • Evaluate under static and dynamic conditions 静态和动态条件下的评估

7. Critical Area = Class 100关键区域＝100级 • Sterilized drug product, containers, closures exposed to environment = maintain sterility 灭菌的药品、容器、密封暴露于环境＝保持无菌 • Design air handling system 空调系统的设计 • Personnel practices and procedures 人员行为和操作程序 • Personnel flow 人流 • Monitor daily 每日的监控

8. Air Handling System 空调系统 • HEPA filtered and laminar flow (HEPA过滤和层流） • Retain NLT 99.97% particulates > 0.3 micron • Leak test – introduce upstream challenge – installation, every 6 months – dioctylphthalate (DOP) and polyalphaolefin (PAO) aerosols • 泄漏测试－－上游挑战性试验： 用邻苯二甲酸二辛脂或聚α烯烃气溶胶每半年测定。 • Monitor face velocity检测表面速率

9. Air Handling System 空调系统 • Carry particles from closing area从密封区携带微粒 • Unidirectional air flow 单向流 • Constant flow 恒流 • Conduct air pattern analysis气流样式分析 • HEPA（HIGH EFFCIENCY PARTICULATE AIR ） HEPA（高效空气微粒子过滤）是具有世界统一标准的过滤器，对0.3微米以上的微粒子的过滤效率达到99.97%以上。

10. Supporting Clean Area =Class 100,000支持性的洁净区＝100000级 • Non-sterile components, products, materials, equipment, containers and closures - prepared, stored or transferred 非无菌组分、产品、材料、设备、容器和密封材料－－制备、贮存或转移 • Minimize particle contamination 将粒子污染减至最小 • Control microbiological content = bioburden 控制微生物量 ＝生物负荷

11. Adjacent Area = Class 10,000 or Class 1,000相邻区域＝10,000级或1,000级

12. Air and Compressed Gas Filtersand Membrane Filters空气、压缩气体过滤器和膜过滤器 • Free from oil and water 无油无水 • Microbiological and particle quality = environment air 微生物和粒子质量＝环境空气 • Prevent backflow 防止回流 • Integrity test = installation, after use 完整性测试＝使用后，安装后

13. Design Factors设计因素 • Personnel flow and number of people 人流和人数 • Material flow and number of transfers 物流和转移次数 • Equipment layout 设备布局 • Equipment design – curtains, plastic shields, double door sterilizers 设备设计－门帘、塑料护罩、双扉灭菌器 • Minimize movement 将移动减至最小

14. Design Factors (continued) • Minimize manual activities 将人工活动减至最小 • Product transfers under appropriate conditions 在适合条件下的产品传输 • Airlocks and interlocking doors 空气锁和联锁的门 • Written procedures for personnel and materials 人员和物料的书面规程 • Change control 变更控制 • Air handling shutdown 空调关闭 • Construction 建筑

15. Cleanroom Design洁净室设计 • Facilitate cleaning and sanitizing 设施的清洁和消毒 • Seamless and rounded floor-wall junctions 地面和墙角无缝隙、圆弧型 • Floors, walls, ceilings – smooth, hard surfaces 地面、墙、天花板－－表面光滑、坚硬 • Ceilings and HEPA filter banks prevent contamination 天花板和HEPA过滤器组避免污染 • No unused equipment, fixtures or materials 无没用的设备、固定物或材料

16. Processing Equipment Design工艺设备的设计 • Sanitary fittings and valves 卫生设施和阀门 • No drains 无排水口 • Ease of sterilization 容易消毒 • Facilitate aseptic setup 设施无菌安装 • No flat surfaces or ledges 无平面或壁架 • Should not interfere with airflow不干扰气流

17. Draft Guidance – V. Personnel – Procedures指南讨论稿－V.人员、规程 • Use sterile instruments to contact sterile materials 使用无菌工具接触无菌原料 • Move slowly and deliberately 缓慢和有目的的移动 • Avoid the unidirectional airflow path 避开单向流通道 • Do not compromise product sterility 不要危及产品无菌安全 • Follow proper gown control 遵从正确的更衣控制 • Laboratory personnel – use aseptic technique 实验室人员－－使用无菌技术 • Personnel monitoring and training program 人员监控和培训程序。

18. Draft Guidance – VI. Components, Containers, Closures指南讨论稿－VI.成分、容器、密封材料 • Characterize microbial content 微生物的鉴别 • Establish acceptance limits based on bioburden 基于生物负荷建立可接受限度 • Sterilization methods 灭菌方法 • Filtration – membrane or cartridge 过滤－膜或滤芯 • Steam 蒸汽 • Dry heat 干热 • Ethylene oxide 环氧乙烷

19. Draft Guidance – VII. Endotoxin Control指南讨论稿－VII. 内毒素控制 • Control bioburden – prevent endotoxin load • Clean, dry, store equipment properly • 生物负荷控制－－避免带入内毒素 • 洁净、干燥、设备的正确保存 • Dry heat endotoxin inactivation on equipment surfaces 在仪器表面的内毒素干热灭活 • Validate cleaning procedures – remove endotoxins from equipment surfaces 清洁规程的验证－－从设备表面除去内毒素

20. Draft Guidance – VIII. Time Limitations指南讨论稿－VIII. 时间限制 • Establish limits for each processing phase 建立每个工序阶段的时间限度 • Assess bioburden and endotoxin load at each stage 评价生物风险和每个步骤可能带入的内毒素数量 • Replace filters after each product lot 每个生产批结束更换过滤器。

21. Draft Guidance – IX. Validation of Aseptic Processing and Sterilization指南讨论稿－IX.无菌工艺和灭菌的验证 • Sterilization and aseptic processing operations 灭菌和无菌工艺操作 • Aseptic processing = media fill (process simulation) 无菌工艺＝培养基灌装（工艺模拟）

22. Aseptic Processing Validation Runs无菌工艺验证的运行 • Design worst-case media fill program – mimic commercial production conditions 设计最差的培养基灌装程序－－模拟商业生产条件 • Three consecutive runs for initial qualification 开始的确认采用3个连续批号 • Routine semi-annual requalification 常规每半年重新确认 • 5,000 to 10,000 units 5000至10000个单位包装 • Bracket vial sizes and fill volumes – worst case line speed 按瓶子的尺寸和填充体积分级－最差的在线速度 • Actual manufacturing conditions 实际的生产条件

23. Aseptic Processing Validation Controls无菌工艺验证的控制 • Microbiological growth medium 培养基 • Positive controls with <100 CFU challenge 阳性检查 • Incubation time 14 days minimum, 20-35 ℃ 20－35℃最少培养14天。 • Investigate any contaminated unit 调查任何污染的单元 • Microbiological challenges to filters 对过滤器的微生物挑战试验 • Determine bioburden of unsterilized bulk solutions 测定未灭菌原料药溶液的微生物负荷。

24. Material viscosity 原料的粘度 pH Filter compatibility 过滤器的兼容性 Pressures 压力 Flow rates 流速 Maximum filtration time 最大过滤时间 Temperature 温度 Osmolality 渗透性 Effects of hydraulic shock液压的影响 Filter Performance Factors过滤器性能因素

25. Sterilization Qualification and Validation灭菌确认和验证 • Qualification – empty chamber 确认－空载 • Validation – loaded chamber/configuration 验证－负载/配置 • Equipment and instrument calibration 设备和仪器的校验

26. Change Control Program变更控制程序 • Written procedures 书面规程 • Equipment, process, test methods, systems 设备、工艺、分析方法、系统 • Revalidate 再验证

27. Draft Guidance –X. Laboratory Controls指南讨论稿－X.实验室控制Environmental Monitoring 环境检测

28. Product Development Activities产品发展活动 • Microbial limits and bioburden 微生物限度和含量 • Raw materials, packaging components, product 原料、包装材料、产品 • Endotoxin limits 内毒素限度 • Antimicrobial effectiveness for preservatives 防腐剂的抗菌效力 • Container-closure integrity 容器密封的完整性 • Bacterial challenge testing for sterilizing filters 除菌过滤器的细菌挑战性测试 • Process validation 工艺验证 • Aseptic or terminal sterilization process 无菌和终端灭菌工艺

29. Environmental Monitoring Program环境检测程序 • Written procedures 书面规程 • All production shifts 生产的更换 • Air 空气 • Floors, walls 地面、墙壁 • Equipment surfaces 设备表面 • Sample locations, timing, frequency 取样位置、时间、频次 • Sample points of contamination risk 有污染风险的取样点 • Track data trends 数据的趋势

30. Microbiological Levels and Reporting微生物水平和报告 • Establish microbiological monitoring levels 建立微生物监控水平 • Alert levels 警戒水平 • Action levels 行动水平 • Issue environmental trend reports 签发环境趋势报告 • Assess suitability, efficacy, limitations of sanitization agents and procedures 评价灭菌试剂和规程的适用性、效力、局限性。

31. Methods for Monitoring监测方法 • Surface monitoring 表面监测 • Active air monitoring 主动的空气监控 • Passive air monitoring 被动空气监控 • Characterize recovered microorganisms 检测出的微生物的鉴定 • Minimize bioburden, eg, prefiltration 生物负荷的最小化，如预过滤 • Monitor air particles 监控空气粒子

32. Draft Guidance – XI. Sterility Testing指南讨论稿－XI.无菌测试 • Identify organisms in positive results 阳性结果中微生物的鉴别 • Review trends in laboratory results 回顾实验室结果的趋势 • Monitor and trend production area environment 生产区域环境的监控和趋势 • Trend daily monitoring of personnel人员每日监控的趋势 • Trend product bioburden 产品生物风险的趋势 • Review batch and production control records 批生产控制记录的回顾 • Trend manufacturing history 生产历史的回顾

33. Draft Guidance – XII. Batch Record Review – Process Control Documentation指南讨论稿－XII. 批记录的回顾－工艺控制文件 • Establish daily process and environmental controls 建立每日的过程和环境控制 • Review all batch records and data for batch release 回顾所用的批记录和批放行数据

34. Guidance for Industry, Submission Documentation for Sterilization Process Validation, November 1994 无菌工艺验证申报资料的工业指南 1994年11月

35. Introduction to the Guidance指南的介绍 • Submission of information and data上报的信息和资料 • Relates to sterilization processes灭菌工艺相关的 • Aseptic processing 无菌工艺 • Terminal sterilization 终端灭菌 • Evaluate process by series of protocols and scientific experiments 通过一系列验证和科学试验评价工艺

36. Terminal Moist Heat Sterilization Process终端的湿热灭菌工艺 • Describe the product and process 产品和工艺描述 • Drug product, container-closure system 药品、容器密封系统 • Sterilization process 灭菌工艺 • Autoclave process and cycle, loading patterns 高压釜灭菌工艺和循环、装填模式 • Controls to monitor production 生产监控的检查 • Requalification requirement 再确认的要求 • Reprocessing 返工

37. Terminal Moist Heat Sterilization Process终端的湿热灭菌工艺 • Thermal qualification of the cycle循环的热量确认 • Heat distribution and penetration 热分布和热穿透 • Thermal monitors 温度监控 • Thermal input for minimum and maximum loads 最小和最大负载的热量输入 • Master batch record based on validation studies 基于验证研究的主批记录

38. Terminal Moist Heat Sterilization Process终端的湿热灭菌工艺 • Microbiological efficacy of the sterilization cycle 灭菌循环的微生物灭菌效果 • Sterility assurance of 10-6 or better灭菌保证10-6 • Identify and characterize bioburden organisms对微生物鉴定 • Bioburden specifications微生物含量的标准 • Biological indicator identification, resistance, stability生物学指示剂的鉴定，耐受性，稳定性 • Microbiological challenge studies微生物挑战试验

39. Terminal Moist Heat Sterilization Process终端的湿热灭菌工艺 • Container-closure integrity 容器包装的完整性 • Simulate processing stress 模拟工艺 • Demonstrate integrity following maximum exposure 根据最大暴露证明完整性 • Evaluate each of multiple sterility barriers 对多重微生物屏障的评估 • Specify sensitivity of the integrity test确定完整性测试的灵敏度 • Demonstrate microbial integrity over the product shelf life 在整个产品的货架寿命期证明微生物方面的完整性

40. Terminal Moist Heat Sterilization Process终端的湿热灭菌工艺 • Laboratory controls 实验室控制 • Bacterial endotoxins 细菌内毒素 • Sterility testing 无菌测试

41. Terminal Moist Heat Sterilization Process终端的湿热灭菌工艺 WRITTEN PROCEDURES 书面规程

42. Ethylene Oxide Sterilization Process环氧乙烷灭菌工艺 • Describe the sterilizer 灭菌器的描述 • Cycle parameters 周期参数 • Prehumidification, gas concentration 预湿 ，气体的浓度 • Vacuum and gas pressure cycles 真空和气压循环 • Exposure time, temperature, humidity 暴露的时间、温度和湿度 • Degassing and aeration 脱气和通风 • Determination of residuals 残留物的测定 • Microbiological testing methods 微生物测试方法 • Stability 稳定性 • Packaging 包装 • Container-closure integrity 容器包装的完整性

43. Radiation Sterilization Process射线灭菌工艺 • Describe the facility and process 设施和工艺的描述 • Radiation source 辐射源 • Method of exposure 暴露的方法 • Type and location of dosimeters to monitor 放射剂量测定仪的类型和位置 • Describe product packaging 产品标准的描述 • Multiple dose mapping studies 多剂量图 研究 • Microbiological methods and controls 微生物方法和控制 • Stability 稳定性 • Packaging 包装 • Container-closure integrity 容器包装的完整性

44. Aseptic Fill Manufacturing Process无菌灌装生产工艺 • Updated in August 2003 Draft Guidance 在2003年8月版指南讨论稿中升级

45. Microbiological Control and Quality: Stability Considerations微生物控制和质量－稳定性考虑 • Container-closure integrity 容器包装的完整性 • Microbial barrier 微生物 • Shelf life 货架寿命 • Sensitivity of the integrity test 完整性测试的灵敏度 • Preservative effectiveness 防腐剂的效力 • Beginning and end of stability period 稳定性周期的开始和结束 • Microbial challenge and chemical assays 微生物挑战和化学测定 • Pyrogen or endotoxin testing 热原和内毒素测试 • Beginning and end of stability period 稳定性周期的开始和结束

46. References 参考文献 U.S. FDA GUIDANCES • Draft Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, August 2003 • Guidance for Industry, Submission Documentation for Sterilization Process Validation, November 1994