11 Process validation -FDA and PICS
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Process Validation
Approval of protocol and report Execution of protocol
NPI or CP, QC, QA
NPI or CP, QC, QA CP, QC
Documented evidence (1)
Process as decribed in Manufacturing Instruction (Master Formula)
Documented evidence (2)
Validation Report Part 1 : data to release validation batches for use in next synthesis step
Validation Report Part 2 : results of additional validation studies evaluation data of next synthesis step final validation conclusion validation reports part 1 and 2 should be completed and approved prior to the release of the resulting final API
Responsibilities
Responsibility
Writing of protocol and report
Department
New Product Introduction (NPI) or Chemical Prod. (CP)
Review of protocol and report
15. Conclusion
15. Approval 16. Approval
NPI or CP, QC, QA
NPI or CP, QC, QA CP, QC
Documented evidence (1)
Process as decribed in Manufacturing Instruction (Master Formula)
Documented evidence (2)
Validation Report Part 1 : data to release validation batches for use in next synthesis step
Validation Report Part 2 : results of additional validation studies evaluation data of next synthesis step final validation conclusion validation reports part 1 and 2 should be completed and approved prior to the release of the resulting final API
Responsibilities
Responsibility
Writing of protocol and report
Department
New Product Introduction (NPI) or Chemical Prod. (CP)
Review of protocol and report
15. Conclusion
15. Approval 16. Approval
无菌原料药的工艺模拟
常见的无菌药用化学品
• • • • • • • • • • • Penicillins Cephalosporins Penems Monobactams Other antibiotics Corticosteroids Arginine HCl Sodium Carbonate Sodium Citrate Biological intermediates Other API’s • • • • • • • • • • • 青霉素 头孢菌霉素 青霉烯 单环β-内酰胺类 其它抗生素 皮质类固醇 盐酸精氨酸 碳酸钠 柠檬酸钠 生物中间体 其它原料药
• 材料
– 需大量的培养基 – 在工艺模拟以前，灭 菌工作量很大，这类 灭菌程序均须须证 – 对模拟后大量培养基 检测极为困难 – 用来中和青霉素的β内酰胺酶用量极大
无菌BPC模拟的难点-续
• 残留
– 有必要将模拟分段，因为在许多BPC生产中，同时 会有液体及粉未设备的处理。 – 常规生产工艺采用的温度及pH，它们本身可能抑制 微生物生长 – 许多无菌原料药抑菌性比较强，因此，模拟前须彻 底清洁，去除所有生产的残留物。 – 工艺模拟残留污染会导致产品失败，模拟后应须彻 底清洁，去除工艺模拟的残留物。
• 所开发的工艺必须是完 善的—先决条件！！ • 参与验证的人员必须经 过适当的培训 • 生产环境、设备、分析 方法必须经过验证，为 产品及工艺服务 • 工艺验证方案必须经过 批准并分发相关人员
工艺验证二大组成+三个阶段
• 二大组成：
– 厂房设计、设备及公用系统的确认； – PQ/性能确认（验证）….只有在完成性能确认以后，方可进 入商业性生产阶段。性能确认中生产的产品，如果合格，可 以放行
– Despite these difficulties FDA is largely inflexible with regard to expectations in this area
FDA Process Validation
Process Validation and GMP Overview
Requirements and Recommendations Charles Ahn, USFDA, Asst. Country Director, China
FD&C Act Defines
Adulteration and Misbranding of a Drug Product Section 501 Adulteration Section 502 Misbranding
Validation of Manufacturing Process
Is implied, in both general and specific terms, by the CGMP regulations in sections of the CFR part 211. The concept of process validation is derived from the section 211.100(a), which states that "[t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess"
Guidance for Industry, 2008
Process Validation is … the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.
Requirements and Recommendations Charles Ahn, USFDA, Asst. Country Director, China
FD&C Act Defines
Adulteration and Misbranding of a Drug Product Section 501 Adulteration Section 502 Misbranding
Validation of Manufacturing Process
Is implied, in both general and specific terms, by the CGMP regulations in sections of the CFR part 211. The concept of process validation is derived from the section 211.100(a), which states that "[t]here shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess"
Guidance for Industry, 2008
Process Validation is … the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.
欧洲药监局--工艺验证指南更新意向书
Concept Paper on the Revision of the Guideline on Process Validation工艺验证指南更新意向书欧洲药品管理局，2010年2月25日发布1. IntroductionThis concept paper addresses the need to update the guideline on Process Validation1. This guideline was originally adopted in February 2001. With the development of new ICH guidelines Q8, Q9 and Q10, this guideline is being reviewed in order to implement the concepts highlighted in the ICH guidelines.该指南旨在适应ICH不断提高的要求，改动后将Q8，Q9和Q10的一些理念也融合了进去。
2. Problem statementThe current guideline does not reflect the recent regulatory developments on Process Analytical Technology (PAT), Quality by Design (QbD) and Real-Time Release Testing (RTRT).当前的指南没有考虑目前生产过程控制技术、质量源于设计和实时放行测试方面的发展。
3. Discussion (on the problem statement) 讨论(基于上述问题)即将出台的这份指南是基于ICHQ8、Q9和Q10这些先进指南的综合考虑而出台的。
根据这些新指南的出台，对于工艺控制以及传统验证批的概念提出了全新的理解(根据这些指南的定义，可能颠覆对传统的工艺验证批次以及工艺过程控制的理解)。
FDA最新工艺验证指南(2011.1版)北大中英对译-已打印
/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
中文译稿：北京大学药物信息与工程研究中心 info@
另外的副本可从以下部门得到： 马里兰州银泉市新罕布什尔大道10193号2201室 药品信息处，对外信息办公室， 邮政编码：20993 电话：301-796-3400; 传真：301-847-8714
Guidance for Industry
行业指南 Process Validation: General Principles and Practices 工艺验证：一般原则与规范
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 美国卫生与人类服务部 食品药品管理局 药物评价和研究中心（CDER） 生物制品评价和研究中心（CBER） 兽药中心（CVM） 2011年1月 现行药品质量生产管理规范（CGMP） 修订版 1
/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 240-276-9300
中文译稿：北京大学药物信息与工程研究中心 info@
另外的副本可从以下部门得到： 马里兰州银泉市新罕布什尔大道10193号2201室 药品信息处，对外信息办公室， 邮政编码：20993 电话：301-796-3400; 传真：301-847-8714
Guidance for Industry
行业指南 Process Validation: General Principles and Practices 工艺验证：一般原则与规范
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 美国卫生与人类服务部 食品药品管理局 药物评价和研究中心（CDER） 生物制品评价和研究中心（CBER） 兽药中心（CVM） 2011年1月 现行药品质量生产管理规范（CGMP） 修订版 1
/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or Communications Staff, HFV-12 Center for Veterinary Medicine Food and Drug Administration 7519 Standish Place, Rockville, MD 20855 (Tel) 240-276-9300
PICS 对无菌药品生产重大变化的解释(032-2)
2. Basics 基础知识
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2.1 Legal requirements (binding) 法律规定（约束）
Refer to national legislation 参照国家立法
2.2 Regulatory guidance (to be justified if not applied) 监管指南（如果不适用要合理）
3
到鼓励。
3. Definitions and abbreviations 定义和缩写
Room Classification 房间分级
Room classification is part of the initial qualification of a facility and is also normally performed during routine re-qualification. Both, classification activities and the final / to be achieved classification status for clean rooms / clean air devices are meant. This Annex directly links to clean room / clean air device classification according to ISO 14644. For qualification and validation and re-qualification see also PIC/S GMP Guide Annex 15. 房间分级是设施预确认的一部分，通常也和常规的再确认同时进行。 这两种分级活动，都意味着最终将实现对洁净室/空气洁净设备的分 级。本附件与按照 ISO 14644 进行的洁净室/空气洁净设备分级直接 相关。对于确认和验证，以及再确认参见 PIC / SGMP 指南的附件 15。
FDA Guidance Process Validation
Process Validation: General Principles and Practices Guidance for Industry1工艺验证一般原则与规范2011/01本指南代表了FDA目前对于此主题的看法。
它不创造或赋予任何人任何权利，也并不束缚FDA 或公众行为。
可以使用满足适用的法令和法规的要求的替代性方法。
如需讨论替代方法，请联系负责本指南实施的FDA工作人员。
如果不能确认恰当的FDA工作人员，请拨打本指南扉页所列出的适当的电话号码。
目录[隐藏]一. 介绍二. 背景o A.工艺验证与药品质量o B. 工艺验证方法三. 对工艺验证的法规和监管要求四. 建议o A. 对工艺验证的总体考虑o B. 第一阶段- 工艺设计▪ 1. 建立和捕获工艺知识与理解▪ 2. 建立工艺控制策略o C. 第二阶段- 工艺确认▪ 1. 厂房设施设计以及公用设施与设备确认▪ 2. 工艺性能确认▪ 3. PPQ方案▪ 4. PPQ方案的执行与报告o D. 第三阶段- 持续工艺验证五. 工艺性能确认批次的同时放行六. 文件记录七. 分析方法术语表参考资料一. 介绍本指南概述了FDA认为是包括原料药在内的人与动物用药和生物制品（在本指南中合称为药品或制品）生产工艺验证相应要素的一般原则和方法。
该指南收编了所有生产商可用于验证生产工艺的多种原则和方法。
本指南工艺验证活动与产品生命周期的概念和现有FDA指南一致，包括FDA/ICH行业指南，Q8(R2)《药品研发》、Q9《质量风险管理》和Q10《药品质量体系》2。
尽管本指南不复述那些指南解释的概念或原则，但FDA鼓励在药物工艺生命周期所有阶段使用现代药物研发概念、质量风险管理和质量体系。
生命周期概念衔接产品和工艺开发、商业化生产工艺确认3、以及日常商业化生产中处于受控状态的过程维护。
本指南支持通过合理的科学对工艺进行改进和创新。
本指南涵盖下列类别的药物：•人用药•兽用药•生物和生物技术制品•制剂产品和活性药物成分（原料药或药用物质）4•组合产品（药物和医疗器械）的药品本指南不涵盖下列类型产品：•A类添加药物产品或添加药物饲料•医疗器械5•膳食补充剂•受《公共卫生服务法》第361节监管的拟用于移植的人体组织6本指南没有详细说明哪些信息应该包括在监管提交文件部分中。
FDA分析方法验证指南(中英文对照版)
一旦FDA有要求，则NDA或ANDA的申请者必须提交制剂，原料药，非药典对照品和空白以使FDA实验室能对申请者所用分析方法进行评审(21 CFR 314.50(e) and 314.94(a)(10))。
The FDA laboratory analysis demonstrates that the analytical procedures are reproducible by laboratory testing. The review chemists and laboratory analysts determine the suitability of the analytical procedures for regulatory purposes.
尽管本指南并不专门叙述原料，中间体，赋形剂，包装材料及原料药和制剂生产中所用的其它物料的分析方法及分析方法验证资料的递交，但是应该应用验证过的分析方法来分析检测这些物质。
For questions on appropriate validation approaches for analytical procedures or submission of information not addressed in this guidance, applicants should consult with the appropriate chemistry review staff at FDA.
本指南中所述的分析方法验证的原则适用于各种类型的分析方法。但是，本指南中特定的建议可能不适用于有些产品所用的特殊分析方法，如生物药，生物技术药，植物药或放射性药物等。
For example, many bioassays are based on animal challenge models, 39 immunogenicity assessments, or other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information.
The FDA laboratory analysis demonstrates that the analytical procedures are reproducible by laboratory testing. The review chemists and laboratory analysts determine the suitability of the analytical procedures for regulatory purposes.
尽管本指南并不专门叙述原料，中间体，赋形剂，包装材料及原料药和制剂生产中所用的其它物料的分析方法及分析方法验证资料的递交，但是应该应用验证过的分析方法来分析检测这些物质。
For questions on appropriate validation approaches for analytical procedures or submission of information not addressed in this guidance, applicants should consult with the appropriate chemistry review staff at FDA.
本指南中所述的分析方法验证的原则适用于各种类型的分析方法。但是，本指南中特定的建议可能不适用于有些产品所用的特殊分析方法，如生物药，生物技术药，植物药或放射性药物等。
For example, many bioassays are based on animal challenge models, 39 immunogenicity assessments, or other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information.
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Creams (Homogenisation, mixing, filling, sealing，)
膏（均质，搅拌，灌装，封口...） Sterile products (sterilisation, filtration, aseptic filling.……)
消毒产品（消毒，过滤，无菌灌装... ）
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Pre-requisites for Process validation 工艺验证的先决条件
Facility and controlled environment (s) qualified 设施和环境控制合格 Critical services and utilities qualified 关键服务和设施合格 Equipment calibrated and qualified 设备校准和合格 Test methods validated 试验方法验证
Prolonged storage steps
长期储存的步骤
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Steps in Identifying Process Related Product risks 鉴定产品风险的步骤
List the possible potential hazards (to patients)
Scientific aim of process validation 工艺验证的科学目标
To provide documented evidence of control 提供控制的证据文件 To evaluate the Method of Manufacture 评估制造方法
理出可能的潜在危害（对病人）
Create a process map of unit operation by critical quality attribute 根据关键质量特性，创建一个单元操作工艺流程图 Identify the critical process parameters (CPPs) for each unit operation linked to the CQA 考虑关键质量特性，确定各单位运作的关键工艺参数 Conduct a risk analysis of the controls over the CPP based on
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Process validation generally applies to 工艺验证通常适用范围
All critic process steps e.g.: 所有关键工艺步骤如下： Tab letting (granulation, Mixing, Blending, compression...) 压片（造粒，混合，调匀，压缩...） Liquids (Mixing, storage, filtration, filling sealing.) 液体（混合，储存，过滤，灌装封口...）
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Process map summary 工艺图概述
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Exercise #1 Mapping a liquid manufacturing process 训练#1测绘生产过程中的液体 The presentation provided and example of constructing a process map for an oral solid dose (OSD) (generic) product. 提供的描述和创建口服固体剂量（OSD）产品工艺流程图的实例。 In groups of 4-5 repeat this exercise for the example liquid line. This should take approximately 60 minutes to complete 4-5处理组重复样品液体流程，这大约需要60分钟才能完成 ‘Step #1一Prepare a CQA by Unit operation matrix 步骤#1—准备单元操作矩阵的关键质量特性 Step#2一Use a fishbone diagram to identify CPPs for a number of steps 步骤#2—利用鱼骨图来确认一系列步骤的关键工艺参数 Step #3一Prepare a process map of inputs vs outputs 步骤#3—准备投入与产出的过程图
文件证实一个过程在已建立的参数下运行，能够持续有效地生产符 合预定规格及产品质量的医药产品。
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ICHQ9 quality risk management
ICHQ9 identifies the following potential uses of quality risk management principles and tools in process validation. ICHQ9确定了质量风险管理原则和工具在工艺验证的潜在用途。 一To identify the scope and extent of verification, qualification and validation activities (e.g., analytical methods, processes, equipment and cleaning methods; 确定了核查、确认和验证活动的范围和程度（例如，分析方法，工艺，设 备和清洁方法等） 一To determine the extent for follow-up activities (e.g. sampling, monitoring and re-validation}; 确定了后续活动（如采样，监测和再验证）的程度 一To distinguish between critical and non-critical process steps to facilitate design of a validation study. 要区分关键和非关键步骤，以方便验证研究设计
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NOVOZYMES PRESENTATION
Process validation-FDA and PIC/S
工艺验证FDA 和 PIC/S
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Modules outcomes 模块成果
On completion of this module the participant should be able to prepare a draft process validation protocol for a selected production line. 完成该本模块完成参与者必须能够为选定的生产线准备一份工艺验证方案草案。 The protocol should include the following features: 该方案应该包括以下特点： .Responsibilities 责任 Scope of the protocol (based on risk assessment) 方案的范围（基于风险评价） Typical tests and experimental plan for process validation 过程验证的典型测试和试验计划 Draft/example acceptance criteria 草案/实例接受标准
创建关键工艺参数控制的危险性分析，要根据： 如果关键工艺参数失败（失败类型），关键质量特性的严重程度。 关键工艺参数失败的可能性 可检测行（措施到位，能够检测关键工艺参数失败）
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Map of critical process parameters that could cause potential failure modes by unit operation 可能导致潜在的由运作单位导致的故障模式的关键工艺参数路线图
To demonstrate the process /product meets specifications consistently
表明过程/产品精确地符合规格 To demonstrate reliability (robustness to expected changes and challenges ) 证明可靠性（持久性—预期的变化和挑战） To demonstrate product uniformity /homogeneity 证明产品的一致性/同质化
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Prospective validation Protocol should include 准验证方案应当包括：
Short description of the process e.g. flowchart 过程如流程图的简短描述 Responsibilities工作职责 Summary of the critical processing steps to be investigated 进行调查的关键工艺步骤的概述 Details of the equipment /facilities to be used and calibration status 设备/设施的使用和校准状态的细节 Variables to be monitored 被监测的变量 Sampling plan 抽样计划 Product performance characteristics /attributes to be monitored 产品性能特点/属性被监控 List of test methods 测试方法清单 Proposed in-process controls and acceptances criteria 过程控制和可接受的标准的建议 Method for recording and evaluating results including statistical analysis, where applicable 在适用情况下，记录和评价结果的方法（包括统计分析） Proposed timetable 拟议的时间表