Joseph C. Famulare

Deputy Director, Office of Compliance FDA/CDER

副主任，FDA/CDER合规性办公室

PharmaceuticalManufacturing.comWebcast,

March 26, 2009

Overview总览

..Process Validation Stages工艺验证步骤

..Regulatory Consequences规范性后果

PV Guidance工艺验证指南

..Draft –November 2008

草案-2008年11月

http://www.fda.gov/cder/guidance/8019dft.pdf

..Comments accepted through 03/16/09 at Regulations.gov for docket FDA-2008-D-0559

评论可在09年3月16日前在Regulations.gov 上提交附加摘要FDA-2008-D-0559

Guidance Background指南背景

..Completed under auspices of CGMPs for the 21st Century initiative implementation phase in 2004 (CPQ)

2004年，在CGMP的21世纪初步实施阶段（CPQ）项目的协助下完成。

..foster innovation and advance the science of the pharmaceutical manufacturing.

促进创新和提升药品生产科学性

..Aligns Process Validation activities with the product lifecycle

工艺验证活动和产品生命周期一致

..Approach aligns with Pharmaceutical Quality System (PQS) initiatives

方法与制药业质量体系（PQS）精神一致。

..Builds on the concepts delineated in the 1987 Guideline

以1987年指导原则中描述的概念为基础

The Question of Process Validation工艺验证的问题

..Do I have confidence in my manufacturing process? Or, more specifically, what scientific evidence assures me that my process is capable of consistently delivering quality product?

我对我的生产工艺有信心吗？或者，更明确地，什么科学证据能确保我的工艺可以持续得生产出高质量的产品？

..How do I demonstrate that my process works as intended?

我如何论证我的工艺能按预期的运行？

..How do I know my process remains in control?

我如何知道我的工艺仍然处于受控状态？

The process of process validation工艺验证的过程

..Series of activities taking place over the lifecycle of the product/process.

产品/工艺的生命周期中所发生的一系列活动。

..Not a one-time events, but key milestones.

不是一次性的事件，而是关键的里程碑。

Process Lifecycle Stages工艺生命周期阶段

..Stage 1, Process Design:

第1阶段，工艺设计：

..Lab, pilot, small scale and commercial scale studies to establish process

实验室、中试、小规模和商业化研究，以确定工艺

..Stage 2, Process Qualification:

第2阶段，工艺确认：

..Facility, utilities and equipment

设施，公用工程和设备

..Performance Qualification (Confirm commercial process design)

性能确认（确认商业化工艺设计）

..Stage 3, Continued Process Verification:

第3阶段，继续工艺核实：

..Monitor, collect information, assess during commercialization

监控、收集信息、评估商业化过程

..Maintenance, continuous verification, process improvement.

维护、持续性的核实、工艺改进。

Stage Goals阶段目标

..Stage 1 -functional understanding between parameters (material and process) and quality attributes

第1阶段-参数（物料和工艺）与质量属性之间的功能性认识

..Stage 2 -Scientific measurable evidence that

第2阶段-科学的可测量的证据

..product meets specifications consistently

产品持续得符合标准

..process performance meets acceptance criteria; reproducible

工艺性能符合可接受的标准；可重现的

..Stage 3 -Maintain or improve control and reduction in product and process variability

第3阶段-维护或改进控制和减少产品与工艺的变异性。

Process Design工艺设计

..Propose process steps (unit operations) and operating parameters to be studied.

提议工艺步骤（单元操作）和需要研究的操作参数

..Identify sources of variability each unit operation is likely to encounter.

对于每个操作，确定可能遭遇到的变异的来源。

..Studies to identify multivariate interactions

用于确定多变量间相互影响的研究

Input Variability变异性的输入

..Manufacturers should

制造商应该

..understand the sources of variation,

理解变异的来源

..detect the presence and measure degree of variation,

发现存在的变异和测量其程度

..understand its impact on the process and ultimately product attributes, and

理解它对工艺和最终对产品属性的影响

..manage it in a manner commensurate with risk it represents to the process and product.

用于它对工艺和产品产生的风险相匹配的方式来管理。

Process Design & Managing Variability

工艺设计和变异性的管理

..Lab scale, small scale, pilot scale studies

实验室规模、小规模、中试规模研究

..Designed experiments

设计的实验

..Modeling

建模

..Mechanisms for managing variability is part of the control strategy

管理变异性的机制是控制策略的一部分。

..e.g., may choose advanced manufacturing technologies that employ detection, analysis and control feedback loops to react to input variability.

如选择先进的生产技术，采用侦查、分析和反馈控制循环来对输入的变异性做出反应。

Process Design Outputs & Process Qualification

工艺设计输出和工艺确认

..Master production and control records

主生产和控制记录

..Overall control strategy

全面控制策略

..Operational limits/ranges

操作限度/范围

..Specifications

规格

..Process Qualification: provides confirmation that the process design is functional for commercial scale manufacturing.

工艺确认：提供工艺设计对商业化生产有用的确认

..Transfer process design knowledge to production, i.e., technology transfer

工艺设计知识到生产的转移。如技术转移。

Process Qualification工艺确认

..Two Aspects

两个方面

1.      Qualification of equipment, utilities and facilities

设备、公用工程和设施的确认

..Consider user requirements, use risk analysis to identify studies/ tests needed and chose criteria to assess outcomes

考虑用户的要求，用风险分析的方法来识别所需要的研究/测试和选择标准来评估产出。

2.      Performance qualification

性能确认

..Performance qualification protocol(s)

性能的确认方案

Performance Qualification Protocols

性能确认方案

..Must go beyond just a particular number of batches made

必须在所做的几个特定数目的批次（基础上）走得更远

..Criteria, including statistical, that—if met—leads to the conclusion that process consistently produces a quality product

标准，包括统计学的，如果符合-得出工艺能持续得生产出高质量产品的结论

..Leverage previous experience and knowledge if the data is relevant to the commercial scale process

如果数据与商业化工艺有关，补充支持前面的经验和知识

..Typically will include:

典型地包括：

..Commercial batches manufactured with the qualified utilities, facilities, production equipment, approved components, master production and control record, and trained production personnel in place.

用确认过的公用工程、设施、生产设备、批准的组分、主工艺和控制记录和培训过的人员生产的商业化批次

..Usually run at target/nominal operating parameters within proven acceptable range or design space.

通常在目标/名义的操作参数处于证实过的可接收范围或设计空间内的情况下生产的

..Extensively tested, i.e., combination of samples analytically tested and increased process control monitoring beyond typical routine QC levels.

扩展的测试，如在典型的日常QC水平上的样品分析测试和增加的工艺控制监控的组合

On What Basis Can Commercial Distribution Begin?

在什么基础上能开始商业化发货？

..Before commercial distribution begins, a manufacturer is expected to have accumulated enough data and knowledge about the commercial production process to support post-approval distribution.

在商业化发货之前，期望制造商能够积累商业化生产工艺方面的足够多的数据知识，以支持批准后销售

..Initial Process Qualification

签署工艺确认

Continued Process Verification继续的工艺确认

..Process Validation during commercial manufacturing

商业化生产过程中的工艺验证

..Activities to continually assure that the process remains in a state of control.

确保工艺仍处于受控状态的持续性活动。

Trend/Assess Data, Monitor趋势/评估数据，监控

..Evaluate periodically (at least annually per 21 CFR 211.180(e)) to determine the need for changes in drug product specifications or manufacturing and control procedures

进行周期性的评估(根据21CFR211.180(e))，以确定是否需要进行制剂产品质量标准或生产和控制程序的变更。

..Analyze data gathered from monitoring processes

分析工艺监控过程中收集到得数据

..Timely monitoring of critical operating and performance parameters

及时得监控关键操作和性能参数

..Investigate problems for root cause and implement corrective action.

调查问题的根本原因和推行纠正措施。

Establish Process History & Process Monitoring

建立工艺历史和工艺监控(制度)

..Measurements of process variability

工艺变异性的测量

..Only have estimates for new processes

仅对新工艺进行评估

..Measurements of process performance over time

随着时间的流逝，对工艺性能进行测量

..Will reveal opportunities for improving the process and the control strategy to better detect and reduce variability

愿意展现工艺改进和控制策略的机会，以便更好地发现和减少变异性。

Changes to the Process工艺变更

..U.S. Statutory and GMP References:

美国法律和GMP参考

..21 CFR 211.100(a) “…written procedures, including any changes, shall be drafted, reviewed and approved…”

21 CFR 211.100(a) “应该起草、审核和批准包括任何变更的书面程序”

..21 CFR 211. 180(e) –Annual review to determine whether changes in specifications or manufacturing or control procedures are needed”

21 CFR 211. 180(e) –年度评审要确定是否需要进行规格或生产或控制程序的变更。

..Q10 –A formal change management system should be in place for commercial manufacturing with appropriate science and risk-based assessments.

Q10- 对于商业化生产，应该有正式的变更管理体现。它以适当的科学的和基于风险的评估为基础。

Periodic Evaluation周期性评估

..Re-validation –not using this term in the revised Process Validation Guidance

再验证-修改后的工艺验证指南中不使用这个术语。

..Production phase (continual verification) monitoring will evaluate quality indicator data, changes and adverse trends and should be used to periodically decide if new studies, e.g., conformances batches or other verification experiments, need to be done.

将采用生产阶段(持续性的确认)监控来评估质量指示性数据、变更和不利的趋势。生产阶段监控应该用于周期性决定是否需要进行新的研究，如适应性批次或其它确认实验。

Continuous Processing 连续作业

..Use of PAT systems to detect input and output variability of the material and react in real time to prevent sub-quality product

使用PAT体系来检查物料和实时反应的变异性的输入和输出以防止低质量的产品。

..Scale-up issues may not be as relevant as with batch manufacturing.

放大问题与批生产也许没有相关性

..Combination of real time detection of material attribute quality (particle size, uniformity) as well as process drift or change in performance (e.g. flow rates, power)

将物料质量属性(粒度、均一性)的实时检查与工艺漂移或性能变更(如流速、动力)一起考虑

..Monitoring quality on a continuous basis.

以连续的方式监控质量

..Continuous processing utilizing PAT systems allows product testing requirements to be moved up stream.

使用PAT系统的连续作业允许产品测试要求在通量之上。

..Superior statistical power obtained by advanced technologies which provide parameter monitoring and material interrogation at frequent intervals.

由先进技术得到的高级的统计能力，在很短时间间隔内，提供了参数监控和物料询问。

..Performance criteria in protocols and studies for continuous processing are likely to be different than those for batch manufacturing.

方案和研究中的关于连续作业的性能标准可能不同于批生产中的那些情况。

Summary总结

..Lifecycle approach links product/process development to the commercial manufacturing process, and maintains the process in a state-of-control during routine production.

生命周期方法将产品/工艺发展同商业化生产工艺联系在一起，并维持日常生产工艺处于受控状态。

..Consistent with Pharmaceutical Quality Systems (PQS)

与制药业质量体系(PQS)一致

Q10 Annex 1 -Opportunity to:

Q10附件1-有机会

..increase use of risk based approaches for regulatory inspections;

在药政检查中，增加基于风险的方法的使用

..facilitate science based pharmaceutical quality assessment;

促进基于科学的制药业质量评估

..optimise science and risk based post-approval change processes to maximise benefits from innovation and continual improvement;

优化基于科学和风险的批准后的工艺变更，最大限度地受益于创新和持续改进

..enable innovative approaches to process validation;

允许工艺验证中的创新性的方法

..establish real-time release mechanisms.

建立实时的放行机制

Truth & Consequences事实和后果

UNITED STATES DISTRICT COURT美国联邦地方法院

United States of America )

Plaintiff, 原告)

v. )

_________________ )        Civil Action No.民事诉讼号

corporation,法人 )

and 和)

______________________ )

Individuals个人的 )

Defendants,被告

CONSENT DECREE FOR PERMANENT INJUNCTION

永久性禁令的同意法令

COMPLAINT FOR PERMANENT INJUNCTION

关于永久性禁令的控诉

Adulterated Drugs假药

13. The United States Food and Drug Administration’s inspections of the Defendant’s facilities have established that the drugs manufactured by the Defendants are adulterated..., in that the methods used in, and the facilities and controls used for, the manufacture, processing, packing, labeling, holding, and distribution of drugs and components are not in compliance with CGMP.

美国FDA对被告的设施的检查确定被告生产的药品是掺假的 ……在那里生产、加工、包装、贴签、贮存和销售药品和组分用到的方法、设施和控制不符合CGMP要求。

15. Failure to

不能

A…follow the responsibilities and procedures applicable to the quality control unit

遵循适用于质量控制部门的职责和程序

B…establish control procedures to validate the performance of those manufacturing process that may be responsible for causing variability in the characteristics of in-process material and the drug product

对于可能引起中间体和制剂产品特性的变异的生产工艺，建立控制程序来验证其性能。

Failure to

不能

C…make written records of investigations into unexplained discrepancies [or] ..of a batch or any of its components to meet specifications

建立关于没有解释的偏差的书面调查记录[或]….一个批次或任何组分符合规格

D…review and approve drug product production and control records by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed

在一个批次放行和销售前，质量部门审核和批准制剂生产和控制记录，以决定是否符合所有建立的、批准的书面程序。

E...review and approve changes to written procedures by the quality control unit

质量控制部门审核和批准书面程序的变更。

Failure to

不能

F...

G…follow written procedures and process control procedures in the execution of production and process control functions

在生产和工艺控制运作中，遵循书面程序和工艺控制程序。

CONSENT DECREE OF PERMANENT INJUNCTION

永久性禁令的批准法令

Upon entry of this decree, Defendents

根据本法令条目，被告

…are permanently restrained and enjoined

被永久性地限制和禁止

…from directly of indirectly, doing or causing: the manufacture, processing, packaging, labeling, holding, introduction or delivery for introduction into interstate commerce at or from any of the [Defendant] facilities, of any drug…, unless and until:

直接地或者非直接地做成或促成：被告的任何设施和任何药品的生产、加工、包装、贴签、贮存、上市或州际贸易的运转……除非和直到：

unless and until:

除非和直到

C…Defendants establish and follow scientific product development and manufacturing process design procedures at all facilities to control all significant variables (including material attributes and processing parameters) affecting in-process materials and final drug product specifications and quality attributes

在所有设施中，被告建立并遵循科学的产品发展和生产工艺设计程序来对影响中间体和最终制剂规格和质量属性的所有重要变更(包括物料属性和工艺参数)进行控制。

Protecting the Public Health保护公众健康

“The FDA requires companies to manufacture drugs in accordance with the current good manufacturing practice standards and to comply with FDA approval requirements.”

FDA要求生产药品的公司符合CGMP标准和符合FDA批准的要求。

“Consumers need to be confident that drugs meet our manufacturing requirements for identity, strength, purity, and quality, and have been evaluated by the FDA for safety and efficacy.”

消费者应对符合我们在特性、剂量、纯度和质量方面的生产要求的，并进行了FDA安全性和有效性评估的药品充满信心。

Janet Woodcock, M.D., Director

Center for Drug Evaluation and Research (CDER).