(仅供参考)PDA TR42 蛋白产品工艺验证(中英文)

Technical Report No.42
Process Validation of Protein Manufacturing
技术报告42号
蛋白制造工艺验证
PDA Journal of Pharmaceutical Science and Technology
注射用药物协会杂志-制药科学与技术
2005年9/10
增刊
59卷
S-4 蛋白制造工艺验证工作组成员：
Chris Bussineau, Ph.D., Chiron Corporation, Co-Chair
Robert Seely, Ph.D., Amgen, Inc., Co-Chair
Genevieve Lovitt, G.I. Lovitt& Associates, Project Manager/Technical Editor
James Fernandez, Fernandez and Associates, PDA Liaison
Greg Blank, Ph.D., Genentech, Inc.
E.J. Brandreth, Favrille, Inc.
Chris Bussineau, Ph.D., Chiron Corporation
Doris Conrad, Consultant, GlaxoSmithKline Biologicals
Rebecca A. Devine, Ph.D., Independent Regulatory Consultant
Robert J. Ferris, Ph.D., Chiron Corporation
Koen de Heyder, GlaxoSmithKline Biologicals
Robert W. Juffras, M.S., Wyeth BioPharma
Peter Levy, Millennium Pharmaceuticals, Inc.
Wolfgang List, Ph.D., Aventis Behring
Morten Munk, CMC Biopharmaceuticals A/S
Brian C. Neely, Don Hill and Associates, Inc.
Stephen Notarnicola, Ph.D., Biogen Idec
Rhona O’Leary, Ph.D., Genentech, Inc.
Harold van Deinse, Baxter Healthcare Corporation
Table of Contents目录
1 Introduction简介 (3)
1.1 Purpose目的 (3)
1.2 Scope范围 (3)
2 Definitions定义 (4)
3 Process Validation Prerequisites 工艺验证前提条件 (8)
3.1 Introduction 简介 (8)
3.2 Planning 计划制定 (9)
3.3 Process Development 工艺开发 (10)
3.3.1 Sequence of Activities Leading Up to Formal Process Validation 正式工艺验证的准备活动顺序 (11)
3.3.2 Raw Materials 原材料 (12)
3.3.3 Process Description 工艺描述 (13)
3.3.4 Analytical Methods 分析方法 (13)
3.3.5 Risk Assessment 风险评估 (15)
3.3.6 Process Characterization 工艺特性 (15)
3.3.7 Cell Line and Expression Construct Characterization 细胞系和表达载体特性 (20)
3.3.8 Extractables from Product-contact Surfaces 产品接触面萃取物 (20)
3.3.9 Development Documentation 开发文档 (21)
3.4 Equipment and Facilities 设备设施 (21)
3.5 Training 培训 (22)
4 Process Validation 工艺验证 (22)
4.1 Introduction 简介 (22)
4.2 Process Validation Options 工艺验证选项 (22)
4.3 Validation Approaches 验证方法 (23)
4.3.1 Unit Operation Validation 单元操作验证 (23)
4.3.2 Family and Matrix Validation 群体和矩阵验证 (24)
4.4 Scale of Studies 规模研究 (24)
4.5 Process Validation Studies 工艺验证研究 (25)
4.5.1 Viral Clearance 病毒清除 (26)
4.5.2 Impurity Clearance 杂质去除 (28)
4.5.3 Process Consistency 工艺的一致性 (29)
4.5.4 Process Intermediate Stability 工艺中间产物稳定性 (30)
4.5.5 Process Solution Stability 工艺溶液稳定性 (31)
4.5.6 Drug Substance Fill/Freeze/Thaw/Storage 药品配制/冻结/解冻/储存 (32)
4.5.7 Mixing Studies 混合研究 (33)
4.5.8 Chromatography Resin and Reusable Membrane Lifetime Validation 层析介质和膜包寿命验证 (34)
5 Post-Validation Activities 再验证 (35)
5.1 Change Control(58,59) 变更控制 (35)
5.2 Ongoing Process Monitoring 持续工艺监测 (36)
6 Documentation 文件 (38)
6.1 Introduction 介绍 (38)
6.2 Validation Protocols 验证方案 (38)
6.3 Validation Reports 验证报告 (40)
6.4 Compliance Program合规项目 (41)
7 Appendices 附录 (41)
7.1 Idealized Process Validation Workflow 理想工艺验证流程 (41)
7.2 Process Description Example 工艺描述举例 (41)
7.2.1 Cell Culture Process Description 细胞收获工艺描述 (44)
7.2.2 Downstream Purification Process Flow 下游纯化工艺流程 (45)
1 Introduction简介
Significant advancement in the design and implementation of effective validation programs has been made since the 1987 Food and Drug Administration (FDA) Guideline on General Principles of Process Validation. (1) Open, candid discussions at conferences, many of which were dedicated specifically to process validation, and at other open forums have resulted in common practices.
自1987年食品药品管理局提出工艺验证基本原理的指导方针一来，制定在设计和实施过程中都有效的验证程序已经取得了重大进展。

（1）某些特定工艺验证在会议上或在论坛上公开、坦率的讨论已经成为一种大众的习惯。

The guidelines presented here are intended to assist in the design and execution of process validation studies to ensure the reproducibility and robustness of the process. Points to consider are provided to facilitate collection of data to support a regulatory filing for the approval of a drug substance intended to be used in a pharmaceutical product. The information provided in these guidelines is one technical approach to process validation activities and documentation based on the experiences and practices of a PDA Task Force that represents a cross-section of industry professionals.
这里所提到的指导方针是想协助设计和工艺验证研究的完成以确保整个工艺的可重复性和稳定性。

指导方针需要考虑的一点是汇编一种药品中批准使用的药物成份成档案，从而可以便利的收集数据。

这些方针中提供的信息是一种工艺验证行为和文件的技术方法，其有效性基于这些有经验的PDA工作人员的经验与实践，他们代表一个行业的专业人才。

The following guidelines represent what the authors believe to be best practices that are science-based and value-added and are believed to make good business sense as well as meet current regulatory expectations. The document does not contain isolated responses to individual inspections or reviews. Such responses are often driven by case-by-case requirements particular to specific organizational needs.
作者相信接下来的指导方针是以科学为基础、有价值、规范并且满足当前监管预期的最好的实践。

本文不包括个人视察和评论的回应，这些回复通常都是针对具体问题，部分是满足特殊组织的需要。

1.1 Purpose目的
This technical report provides practical guidance for compliance with current Good Manufacturing Practices (cGMP) and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidances for the validation of biopharmaceutical processes to the drug substance stage.
这份技术报告为实践提供指导，符合动态药品生产管理规范（cGMP）和人用药物注册技术要求国际协调会（ICH）对生物制药过程到药品的验证要求。

1.2 Scope范围
The focus of this technical report is validation of biopharmaceutical processes used to manufacture therapeutic proteins and polypeptides. These proteins and polypeptides are produced from recombinant or non-recombinant cell-culture expression systems and can be characterized using an appropriate set of analytical procedures. Selected principles outlined in this document may also apply to other product types, such as proteins and polypeptides isolated from tissues and body fluids. The intent is to provide clear technical guidance for the development and design of a process validation plan and provide a comprehensive overview of strategies that may be used to validate a manufacturing process or unit operation.
这份技术报告的重点是用于生产治疗性蛋白和多肽的生物制药工艺验证。

这些蛋白和多肽来自于重组或非重组的细胞培养表达系统，并且可以被一系列适当的分析方法所鉴定。

本文大纲选择的原则也可以运用到其它产品类型，比如从组织和血液中分离蛋白和多肽。

目的是为开发和设计工艺验证方案提供明确的技术指导，并阐述一套或许可以应用于生产工艺或操作单元验证的综合性策略。

The strategies contained in this document primarily focus on the validation of non-sterile, low bioburden, protein-based drug substances. The guidelines do not cover validation as it relates to reprocessing, reworking, aseptic processing of drug
products, Process Analytical Technologies (PAT), facilities, design qualification, stability, cleaning, or shipping. These topics are either covered in depth elsewhere or are in the early stages of definition.
报告中策略主要针对非最终灭菌和低生物负荷的蛋白药品验证。

此指南不涵盖返工、重新加工、无菌工艺有关的药品验证，过程分析技术、设施、设计规格、稳定性、清洁和运输也没有涉及到。

这些主题在早期的指南或其它地方有阐述。

The guidelines are not intended to establish mandatory standards for process validation; they are intended to be a single-source overview that complements existing guidance documents listed in the reference section. For greater detail on various topics throughout this technical report, references to published documents are provided. It is always advisable to consult with the appropriate regulatory authority for agreement on the strategies employed for process validation studies.
指导方针并不是有意建立强制性的工艺验证标准，而是想对参考资料中所列的指导文档给予独立补充。

技术报告中各种论题的更详细内容在出版物中有提供。

与合适的监管机构商讨并形成对工艺验证研究策略的一致性是明智之举。

2 Definitions定义
Current FDA, ICH, and other regulatory definitions are used except when more clarity is added by the Task Force. In some instances two definitions used in current guidances are provided where both are considered applicable. Regulatory guidelines offer other definitions that may be considered.
只有工作组明确指出，现行FDA、ICH和其它机构的规定才可以使用。

在一些实际应用中，现行的指导方针中出现对同一种事物不同的两种定义，而且都具有应用价值。

所以会考虑调整指导方针，重新予以定义。

Variations in the usage of some terms may differ from company to company, and some may be subject to change in the future. However, the terms used in a validation program must be clearly defined and well understood within the company and clearly defined in internal Standard Operating Procedures (SOPs), standards, and in regulatory filings. For the purposes of this technical report, the following definitions are used.
一些术语在使用过程中，不同的公司之间会有一定的差异，甚至在将来会面临彻底改变。

然而，每个公司在工艺验证中的术语必须有明确的定义，且易于理解，在标准操作程序和规程中描述清楚。

基于技术报告的目的，以下定义将被使用。

Action Limit: An internal (in-house) value used to assess the consistency of the process. The cause of the excursion should be investigated and documented and corrective action is generally required. Action limits are not specifications. (Synonym: action level)
行动界限：用于评估工艺一致性的限值（内部标准），通常要求对偏差的原因进行调查、证明并矫正行动。

行动界限并非产品指标（同义词：行动标准）。

Acceptance Criteria: Numerical limits, ranges, or other suitable measures for acceptance of test results. (2) Exceeding the acceptable range for a critical parameter during subsequent validation studies may result in questionable product quality
that would require initiation of an investigation. Exceeding the operating range should be documented and explained in the validation report and evaluated for validation study impact.
接受标准：用数字限度、范围或其它适宜方法来规定检测结果的可接受性。

当后续验证研究表明关键参数超过可接受范围可能造成产品质量问题，就要求开始调查。

超过操作范围要记录并在验证报告中说明原因并评估对验证结论的影响。

Active Pharmaceutical Ingredient (API): See Drug Substance. 活性药物成分（API）：见原料药。

Characterization Study: A late-stage study that evaluates the process to increase process knowledge and examines proposed operational ranges and their individual and/or combined impact on target protein quality. (Synonyms: evaluation studies, process justification studies, engineering studies, development studies, robustness studies)
鉴别研究：在研究后期，对过程进行评价以提高对工艺的认识，调查预期操作范围，以及它们独自或相互作用对目
标蛋白质量的影响。

（同义词：评价研究、过程调整研究、工程研究、开发研究、稳定性研究）
Conformance Lots: A pre-determined number of production lots, typically three, that represent the licensed process and are evaluated to demonstrate consistency. (Synonyms: validation, consistency, demonstration, or qualification lots).
批次一致性：预先设定的生产批次，通常三批，用以代表批准工艺并评估证明稳定性。

（同义词：验证、稳定性、证明、或确认批次）
Contaminant: Any adventitiously or externally introduced material(s) (e.g., chemical, biochemical, or microbial species) not intended to be part of the process. (3) An undesired impurity of a chemical or microbiological nature that is introduced into a raw material, intermediate, or API [drug substance] during manufacture. (4)
污染物：工艺中任何一种非预期的外源或内源物质（如化学试剂、生物分子或微生物物种）（3）在药品制造过程中原材料、中间样品或成品阶段引入的不期望出现的化学或生物杂质。

Documentation: 文件：
Development Reports: Documentation and description of work done during the early phases of development. The goal is to document information about the way the process works and to document why key choices were made in selecting the specifics of the process (e.g., flow rate or temperature). These documents can serve as a reference during investigations of discrepancies and during the design of specific validation and characterization studies.
研制报告：在研制早期阶段对工作怎样完成写下的说明和描述。

目标是记录工艺路线信息，并阐述工艺关键决定是如何确定的（如流速和温度）。

在对偏差进行调查或是进行特殊验证和特性研究的设计时，这些文件可以作为参考标准。

Process Characterization Report: A report that includes results from a study characterizing the performance of a unit operation and/or operations conducted in a process characterization study. The report describes process characteristics, the operational parameters (e.g., critical, key, and non-key) and their acceptable ranges (limits), and acceptance criteria for validation protocols. Proces s Validatio n Maste r Plan: A document that defines the process validation scope and rationale and that contains the list of process validation studies to be performed. Proces s Validatio n Protocol: A written plan
pre-approved by the quality unit that specifies critical steps, controls, and measurements. The Process Validation Protocol states how validation will be conducted, identifying sampling, assays, specific acceptance criteria, production equipment, and operating ranges. Results obtained for each study described in the protocol should be evaluated in an associated process validation report. Proces s Validatio n Report: A report approved by the quality unit that summarizes specific tests performed, compares the test results with the protocol acceptance criteria, and addresses deviations encountered during the study.
工艺特性报告：特性研究中对单元操作及连续操作性能的结果描述。

报告描述了工艺特性、操作参数（比如关键的、主要的和次要的）及其可接受范围（限度）、验证方案的接受标准。

工艺验证主计划：定义工艺验证范围、原理的文件，包括将要执行的工艺验证研究明细表。

工艺验证记录：质量单位在获得批准前把关键步骤、控制和测量方法列入书面计划。

工艺验证记录陈述了怎样执行验证、明确取样、分析、可接受标准、生产设备和操作范围。

记录中描述的每个研究获得的结果应该被相关的工艺验证报告评估。

工艺验证报告：质量单位批准的总结报告，包括各项测试性能、比较测试结果是否与记录中的可接受标准一致，并指明研究过程中的偏差情况。

Drug Product: A pharmaceutical product that contains a drug substance, generally in association with excipients. (5)
The dosage form in its final immediate packaging intended for marketing. (6) (Synonyms: dosage form; finished product, medicinal product)
制药产品：一种含有药物成份的药剂，通常添加相关的赋形剂。

（5）最后直接做成供市场销售的剂型。

（6）（同
义词：剂型、成品、药品）
Drug Substance: The active ingredient that is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, product-related substances, and product-and process-related impurities. It may also contain excipients, including other components such as buffers. (7) (Synonyms: bulk drug substance, bulk material, active pharmaceutical ingredient (API))
药物成份：有效成分依据配方添加辅料制成药品。

它可以由目的产品、产品相关物质、产品及工艺相关的杂质组成。

它也包括辅料和其它的成分如缓冲液等。

（7）（同义词：主要药物成分、主要原材料、活性药物成分（API）Impurity: Any component present in the drug substance or drug product that is not the desired product, a product-related substance, or excipient. Impurities are to be distinguished from contaminants, which are defined above.
杂质：任何药物成分或药品中出现的非目的成分，包括不希望得到的产品相关物质或赋形剂。

杂质区别于前面提到的污染物的定义。

In-process Control: Checks performed during production to monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API [drug substance] conforms to its specifications and/or other defined quality criteria (e.g. limits for bioburden and endotoxin). (8) (Synonym: process control)
工艺内部控制：产品生产过程中采用监控设备对性能检查，如果合适，需要调整工艺以确保中间产物或药品成分与技术指标和其他形式定义的质量标准相符。

（例如生物负荷和内毒素的界限）（8）（同义词：过程控制）Information-only Tests: Tests that provide data that are collected without pre-established acceptance criteria to further evaluate the process.
最佳数据确定试验：收集预先设定可接受标准之外的数据，以进一步评价工艺。

Installation Qualificatio n (IQ): Documented verification that the equipment or systems, as installed or modified, comply with the approved design, the manufactur er’s recommendations, and/or user requirements. (9) Intermediate: A material produced during steps of the processing of a drug substance that undergoes further molecular change or purification before it becomes a drug substance. (10)
安装确认（IQ）：证明设备或系统的原始装备及改良装备符合已批准设计、制造商推荐和用户要求的文件。

（9）中间产物：在药品生产工艺中产生的物质，需要分子结构改变或是进一步纯化才能成为成品。

（10）Operational Qualification (OQ): Documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. (11)
操作确认（OQ）：证明设备或系统的原始装备及改良装备的运行自始自终按预期操作范围执行的文件。

（11）Parameters: Operational Parameter: An input variable or condition of the manufacturing process that can be directly controlled in the process. Typically, these parameters are physical or chemical (e.g., temperature, process time, column
flow rate, column wash volume, reagent concentration, or buffer pH). (Synonym: process parameter)
参数：操作参数：指生产过程中可以被直接控制的输入变量或条件。

一般来说，这些参数都是理化参数（如温度、
加工时间、柱流速、柱清洗体积、试剂浓度、或缓冲液pH值）。

（同义词：工艺参数）
Critical Operational Parameter: An input process parameter that should be controlled within a meaningful, narrow operating range to ensure that drug substance quality attributes meet their specifications. Although, parameters with wide operating ranges may also impact product quality, they are generally easily controlled and not as likely to result in excursions that impact quality and are therefore low risk. [For further discussion see Sub-section 3.3.6] (Synonym:
critical process parameter (CPP))
关键操作参数：指一个输入的工艺参数，应控制在一个有意义、较窄的操作范围内，以确保药物成分的质量属性
符合其要求。

尽管，较宽操作范围的参数也可能影响产品质量，但一般这样的参数较容易控制，也不大可能导致
产品质量的偏离，所以具有较低的风险。

（详见3.3.6）（同义词：关键工艺参数（CPP））
Non-critical Operational Parameter: All input process parameters that fall outside the definition for critical operational parameter are non-critical. Noncritical operational parameters are divided into key and non-key operational parameters. [For further explanation, see Sub-section 3.3.6]
非关键工艺参数：关键操作参数定义之外的所有输入工艺参数都被定义为非关键操作参数。

非关键操作参数又被分为重要操作参数和非重要操作参数。

（详见3.3.6）
Key Operational Parameter: An input process parameter that should be carefully controlled within a narrow range and
is essential for process performance. A key operational parameter does not affect critical product quality attributes. If the acceptable range is exceeded it may affect the process (e.g., yield, duration) but not product quality. [For further explanation, see Sub-section 3.3.6]
重要操作参数：应谨慎的控制在狭窄范围内，并且是工艺性能必不可少的输入工艺参数。

重要操作参数不会影响关键的产品质量属性，如果超过接受范围，其可能会影响工艺（如收率，持续时间）但不会影响产品质量。

（详见3.3.6）
Non-key Operational Parameter: An input process parameter that has been demonstrated to be easily controlled or has
a wide acceptable limit. Non-key operational parameters may have an impact on drug substance quality or process performance if acceptable limits are exceeded. [For further explanation, see Sub-section 3.3.6]
非重要操作参数：经过证明的容易控制或有较宽接受限度的输入工艺参数。

如果超出了非重要操作参数的运行范围，可能对药物成分的质量或工艺性能有影响。

（详见3.3.6）
Performance Parameter: An output variable or outcome that cannot be directly controlled but is an indicator that the process performed as expected. (Synonym: performance attribute)
性能参数：不能够直接控制但是可以指示工艺按预期完成的输出变量参数。

（同义词：性能属性）Performance Qualification (PQ): Documented verification that the equipment and ancillary systems, as connected together, can perform effectively and reproducibly based on the approved process method and specifications. (12)
性能确认：证明设备和附属系统连接在一起后，能够有效的、可重复的实现工艺过程和技术指标。

（12）Process Validation: The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce an intermediate or API [drug substance] meeting its predetermined specifications and quality attributes. (13)
工艺验证：证明工艺的操作按照已制定参数有效、稳定地执行，能够生产出符合预定指标和质量属性的中间产物或药物的文件。

（13）
Concurrent Process Validation: Validation that occurs during manufacturing of drug substance for batches that can be released and used in a final drug product for commercial distribution based on thorough monitoring and heightened testing of the drug substance batches. (14)
同步工艺验证：发生在药品生产过程中的验证，药品经过全面监测和充分测试的基础上可以签发和销售。

Prospective Process Validation: Validation conducted prior to the distribution of either a new product or a product made under a revised manufacturing process where the revisions may affect the product’s char acteristics. (15)
前瞻性工艺验证：新产品正式生产销售之前或者制造工艺变更有可能影响产品性质的情况下进行的验证。

Retrospective Process Validation: Validation of an existing manufacturing process that occurs by reviewing data from relevant historical and test production records.
回顾性工艺验证：指以历史数据的统计分析为基础的旨在证实正式生产工艺条件适用性的验证。

Re-validation: Repeating partial or full validation of a process after a process change is implemented. Re-validation is change-based, not time-based.
再验证：当生产工艺改变时，需要重复部分或全部工艺验证。

再验证基于工艺改变而不是生产周期。

Qualified Assay: An assay that is not fully validated but is documented to be suitable for its intended use, including sample collection and handling procedures. Such an assay should be demonstrated to be accurate, precise, linear within the range of use, and show no interference from process stream components (i.e., spike recovery). (16)
确认方法：用于证明预期的分析方法是合适的，包括取样和操作步骤。

这样的分析方法应该被证明是精确的、严谨的，在使用范围内具有线性关系，同时没有来自于工艺组分的干扰。

（如回收率）（16）
Specification: A list of tests, references to analytical procedures, and appropriate acceptance criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. (17)
规格：检测清单，包括分析项目和接受标准，用数字来规定界限、范围或其它用以描述结果的指标。

标准的建立和设定应当考虑到原材料的充分利用价值。

Set Point: The target for an operational parameter. The range around the set point is commonly stated in the manufacturing procedures or batch records.
设定值：指操作参数的目标值。

设定值的波动范围通常需要在操作程序或批记录中规定清楚。

Unit Operation: A discrete step or manipulation in a manufacturing process where process and operating parameters are
defined to achieve a specific process objective. (Synonym: process step)
操作单元：生产过程中独立的操作步骤，定义工艺参数和操作参数以达到特定工艺目标。

（同义词：工艺步骤）Validation: A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting predetermined acceptance criteria. (18)
验证：证明特定工艺、方法或系统能够稳定地生产出满足预定接受标准的产品的有文件记录的一系列活动。

3 Process Validation Prerequisites 工艺验证前提条件
3.1 Introduction 简介
There are several aspects of cGMP and development that should be completed prior to validation of the manufacturing process. Process validation requires that validated assays, calibrated instruments, and qualified production support systems are already established with documentation completed prior to execution of process validation studies. Furthermore, the process should be fully developed, characterized and documented in a development report. (19) These and other specific supporting activities are briefly described in the following subsections. (20)
生产工艺验证开始之前，cGMP若干部分和研究应该先行完成。

工艺验证开始前需要完成方法验证，仪器校准，生产辅助系统确认，并形成相应的支持性文件。

此外，工艺应该已经开发完成，并在开发报告中进行描述和记录。

（19）这些和其他特定的辅助活动在下面的章节中进行了简要介绍。

（20）
Fundamental to process validation is process knowledge and full understanding of the equipment and technology to be used in the process. The process must show consistency and be well defined, controlled, and reproducible. Operational (input) parameters and performance (output) parameters should be identified, with appropriate operating limits or acceptance criteria defined for both parameters. Process characterization studies performed during process development and scale-up establish this process knowledge database. Final written reports should include discussion, justification or rationale, details of the study, resulting data, recommendations, and cautions. These reports should be internally approved and controlled. (21) Regulators may review development documentation containing the justification for operational parameter ranges. For full-scale conformance lots, process validation usually focuses on process performance at the set-point of each operating parameter range. Justification of the operating range for each operation may not be demonstrated during full-scale process validation; therefore, the ranges should be justified during the development phase using appropriate process characterization studies, which for practical reasons are usually done at lab-scale.
工艺验证的基础是工艺知识，及对工艺中所使用到的设备、技术的充分理解。

工艺必须具有良好的一致性，能很好
的被定义，可控性和可重复性。

操作（输入）参数及性能（输出）参数应该定义清楚，并定义清楚各自适当的操作范围或可接受标准。

在工艺开发和规模放大过程中所进行的工艺特性研究应当建立起工艺知识数据库。

最终形成的书面报告应包括讨论，判断及理由，研究的细节，得出的数据，建议和注意事项。

这些报告应在内部进行审批和控制。

（21）监管机构可能会审查工艺开发文档中对操作参数范围是如何判定的。

对于实际商业化生产规模，工艺验证通常会关注各操作参数在设定点的工艺性能。

在完整规模的工艺验证过程中，每一操作的范围判定未必都会被证实，因此，这些操作范围，应该在工艺的开发阶段，用合适的工艺特征研究来确定，而这些为获得真实推理的工艺特性研究活动通常在实验室规模下进行。

Process validation studies that are performed at lab-scale should be done with pre-approved protocols that contain predetermined acceptance criteria and final validation reports. For example, spiking studies may demonstrate impurity removal that requires a scale-down model study because they cannot be conducted at full, commercial scale. Any scaled-down model used in process characterization or validation should be justified as being representative of the full-scale unit operation; this may include demonstrating that the resultant intermediate or drug substance is comparable. Some differences in performance are unavoidable; these are acceptable as long as they are understood and considered when interpreting the results. (22)
实验室规模进行的工艺验证研究应该按照预先批准的方案来执行，方案中应包含预定的接受标准和最终验证报告。

例如，峰形研究需要一个缩小模型来证明杂质去除，由于它们不能在完整的商业化规模下进行。

用于工艺鉴定或验证的每一个缩小模型，都应该判断是否能代表完整规模下的单元操作，这判断过程应该包含所得到的中间体或药物的性质具有可比性。

当然性能上有些差异是不可避免的；只要在对结果解释时有考虑到，能够被理解，这些差异是可以接受的。

Central to defining the process is a documented change control program, which should be in place throughout clinical product development. (23) Change control ensures that proposed changes are justified, examined, and documented so that the process is not altered without a thorough review and proper documentation. (24) Information about changes during development may affect the product application review process, as some clinical trials may have been conducted with material made prior to a change that took place during development. Change control should also be in place for equipment. 工艺确定的关键是贯穿于整个临床产品开发过程中的文件变更控制程序。

(23)变更控制确保拟定变更是合理的、经过审核的，并记录在案，以防止工艺在没有经过全面审核和适当参考资料的情况下发生改变。

(24)工艺开发过程中的变更信息可能会影响到产品注册申请审查的过程，如可能用一些原材料开展了一些临床试验，而这些原材料在工艺开发过程中又发生了变更。

变更控制同样会发生在设备上。

3.2 Planning 计划制定
A successful validation program is one that is initiated early in the product life cycle and is completed only when the process or product reaches the end of its life cycle. The foundation of a successful validation program begins with implementation of a comprehensive corporate policy that defines the organization’s expectations and commitment to process validation principles. This policy should define the corporation’s quality management philosophy, components of validation, periodic review or re-qualification time-frames, documentation requirements (including a validation master plan), (25) validation protocols and reports, and responsibilities of key stakeholders within the organization.
一个成功的验证程序应该从产品的早期开始着手，直至整个产品或工艺生命周期的终点。

成功验证程序的基础从全面贯彻企业政策开始，该项政策中定义了企业对于工艺验证准则的预期和承诺，并定义公司的质量管理体系，验证的内容，阶段性检查或重验证的时限，文件要求（包括验证主计划），（25）验证方案和报告，和组织内主要股东（法人）的责任。

Successful process validation begins early in the development phase of a product with acquisition of preliminary process
data and knowledge. Although formal process validation is not generally required in Phase 1, some exceptions are made for product safety issues (e.g., viral clearance validation for mammalian cell products). After Phase 1 and the decision to continue product development, efforts to develop a commercial process must ensure that the process meets all validation requirements. During the commercial development phase, more detailed process knowledge should be collected that de-scribes critical and key operational parameters; normal, maximum, and minimum operating ranges; performance parameters with acceptance criteria where appropriate; and product impurity profiles as a function of each individual unit operation and the process as a whole. This information, together with the history of the process, should be captured in a series of development reports and/or process characterization reports. These documents will serve as the repository of key development information;they are critical to assembling subsequent process validation plans and protocols, as well as providing ancillary process support during pre-approval inspections.
成功的工艺验证应当在产品开发早期，即初步工艺数据和知识收集的过程中过就开始了。

虽然正式的工艺验证一般不要求在I期临床就进行，但为了产品的安全问题，也有一些列外的验证需要提前进行（如哺乳动物细胞产品中病毒清除的验证）。

在I期临床之后，如果决定继续进行产品开发，必须确保后续的工艺严格符合商业化验收标准。

在商业开发的阶段，必须收集更加详细的描述关键和重要操作参数的工艺数据；正常，最大和最小的操作范围；性能参数和适用的验收标准，每一个单元操作和整个工艺中产品杂质的概述。

这些信息和工艺建立过程都应该在一系列的工艺开发报告和（或）工艺鉴定报告中获得。

这些报告文件将应当作为工艺开发的关键信息资源库；它们对于后续的工艺验证计划和试验设计至关重要，同时为注册批准前检查（PAI）提供辅助性的工艺支持。

A multi-function process validation team should be assembled prior to manufacture of conformance lots. The team should minimally consist of members from validation, process development, quality assurance, regulatory affairs, manufacturing, and technical operations and/or engineering departments. The team’s first assignment is to design and assemble the validation master plan. This high-level document is a blueprint for process validation activities and describes the required content of the individual process validation protocols (e.g., the need for test requirements and acceptance criteria and the responsibilities of various groups for protocol implementation). The validation master plan also includes requirements for implementation of the individual process validation protocols, including starting material requirements, execution of consecutive conformance lots, status of analytical methods (validated versus qualified), and procedures for handling deviations and revisions. Criteria for determining acceptance or failure of the validation program should also be defined.
在多批次的稳定性生产前，一个多功能的工艺验证团队应该先组建起来。

该小组成员至少应包含来自验证、工艺开发、质量保证、注册事务、制造和工艺操作以及工程部门的人员。

该小组的首要任务是设计和制定验证主计划。

这个最高水平的文件是工艺验证活动的一个蓝图，他描述了每个工艺验证方案的必要内容（例如，测试条件的必要性和验收标准，各方案实施团队的职责）。

验证主计划还包括每个工艺验证方案实施的需求，包括原材料要求，连续批生产一致性，分析方法的情况（验证并且合格），用于偏差处理和修订的程序。

验证计划成功或失败的标准也将在此定义。

Following assembly of the validation master plan, process validation protocols should be written describing in detail the procedures to be followed to produce documented evidence that the process has been validated. The protocols must specify critical and key operational parameters and their respective ranges, acceptance criteria, procedures required to perform the validation (including the sampling plan), and responsibilities of various functional team members participating in the validation.
验证主计划的制定后，应当制定工艺验证方案，详细描述应遵循的程序，执行并形成书面证据，证明工艺已经被验证过。

该方案必须指定关键和重要的操作参数和它们各自的范围，接受标准，实施验证的程序（包括取样计划），和参与验证的各团队成员的职责。

3.3 Process Development 工艺开发。