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Guidance for Industry
Process Validation: General Principles and Practices
Final Version January 2011 Draft 2008
I. INTRODUCTION
I. INTRODUCTION
简介
This guidance outlines the general principles
and approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this
guidance as drugs or products. This guidance
incorporates principles and approaches that
all manufacturers can use to validate manufacturing processes.
本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。本指南整合了一般的原则和方法，所有的生产企业都可以将这些原则和方法应用于生产工艺的验证。 This guidance outlines the general principles and approaches that FDA considers to be appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (API or drug substance),
collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use in validating a
manufacturing process. 本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。本指南整合了一般的原则和方法，所有的生产企业都可以将这些原则和方法应用于生产工艺的验证。
This guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.2 Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk man- agement, and quality systems at all stages of the manufacturing process lifecycle. 本指南将工艺验证活动与产品生命周期概念以及现有FDA 相关指南进行了协调；这些存在的FDA指南包括FDA/ICH指南，Q8(R2)药品研发指南、Q9质量风险管理指南和Q10制药质量体系指南。尽管本指南没有重复上述指南解释的概念和This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance.2 2 See the FDA/International Conference on Harmonisation (ICH) guidances for industry: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and when finalized, Q10 Pharmaceutical Quality System (a notice of availability for the May 2007 ICH draft guidance, Q10 Pharmaceutical Quality System, published in the Federal Register on July 13, 2007 (72 FR 38604)). We update guidance documents periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at https://www.doczj.com/doc/2b9096736.html,/cder/guidance/index.htm, the CBER guidance page at
原则，FDA鼓励在药品制造工艺生命周期的各个阶段使用现代药品研发概念、质量风险管理和质量体系概念。 注释2To make sure you have the most recent version of a guidance, check the CDER guidance page at https://www.doczj.com/doc/2b9096736.html,/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/default.htm, the CBER guidance page at
https://www.doczj.com/doc/2b9096736.html,/BiologicsBloodVaccines/Guida nceComplianceRegulatoryInformation/
Guidances/default.htm, or the CVM guidance page at
https://www.doczj.com/doc/2b9096736.html,/AnimalVeterinary/GuidanceCo mplianceEnforcement/
GuidanceforIndustry/default.htm
https://www.doczj.com/doc/2b9096736.html,/cber/guidelines.htm, or the CVM guidance page at https://www.doczj.com/doc/2b9096736.html,/cvm/Guidance/published.htm . 本指南将工艺验证活动与产品生命周期概念以及现有FDA 相关指南（这里指得是Q8、Q9和Q10指南）进行了协调。 The lifecycle concept links product and process development, qualification of the commercial manufacturing process,3 and
maintenance of the process in a state of control
during routine commercial production.
This guidance supports process improvement
and innovation through sound science.
生命周期概念将产品与工艺开发、商业生产工艺
的确认以及维护工艺在日常商业生产中处于受
控状态连结在一起。本指南通过足够科学知识来
支持工艺优化和革新。
注释 3 In this guidance, the term commercial
manufacturing
process refers to the manufacturing
process resulting in commercial product (i.e., drug
that is marketed, distributed, and sold or intended to be sold). For the purposes of this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material. The lifecycle concept links product and
process development, qualification of the
commercial manufacturing process, and
maintenance of the process in a state of control
during routine commercial production.
This guidance promotes modern manufacturing
principles, process improvement, innovation,
and sound science.
生命周期概念将产品与工艺开发、商业生产工艺
的确认以及维护工艺在日常商业生产中处于受控
状态连结在一起。本指南可促进现代生产的原则、
工艺改进、创新并且形成完善的科学。
This guidance covers the following categories of drugs: H uman drugs V eterinary drugs
B iological and biotechnology products F inished products and active pharma ceutical ingredients (APIs or drug sub stances)4
The following categories of drugs are within the scope of this guidance: H uman dr ugs V eterinary drugs
B iological and biotechnology products
F inished products and active pharmaceutical ingredients (API or drug substance) 3
T he drug constituent of a combination (drug and medical device) product 以下类别的药品在本指南范围之内： ? 人用药物 ? 兽药 ? 生物制品和生物技术产品 ? 制剂产品与活性药物成分(API 或药用物质)3? 复合产品(药物和医疗设备)中的药物成分 注释4 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug substances) and intermediates have not published as of the date of this guidance, but these components are subject to the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7), available on the Internet at https://www.doczj.com/doc/2b9096736.html,/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/default.htm.
Section XII of ICH Q7 describes in detail the
principles for validating API processes.
T he drug constituent of a combination (drug and medical device) product 3 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug substances) and intermediates have not published as of the date of this guidance, but these components are subject to the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7A), available on the Internet at https://www.doczj.com/doc/2b9096736.html,/cder/guidance/index.htm. Section XII of ICH Q7A describes in detail the principles to be followed in validating API processes. 以下类别的药品在本指南范围之内： ? 人用药物 ? 兽药
? 生物制品和生物技术产品
? 制剂产品与活性药物成分(API 或药用物质)3? 复合产品(药物和医疗设备)中的药物成分 This guidance does not cover the following types of products: T ype A medicated articles and medicated feed M edical devices5 D ietary supplements H uman tissues intended for transplantation regulated under section 361 of the Public Health Service Act6 本指南不适用于以下类别的产品： ? A 型含药产品与含药饲料 ? 医疗器械 ? 膳食补充剂 ? 公共卫生服务法361 节下的移植用人体组织 注释5 Guidance on process validation for medical devices is provided in a separate document, Quality Management Systems –Process Validation,
edition 2, available at
The following categories of products are not covered by this guidance: T ype A medicated articles and medicated feed M edical devices D ietary supplements H uman tissues intended for transplantation regulated under section 361 of the Public Health Service Act4. 4 See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for Transplantation, available on the Internet at
https://www.doczj.com/doc/2b9096736.html,/cber/guidelines.htm . 本指南不适用于以下类别的产品： ? A 型含药产品与含药饲料
? 医疗设备 ? 膳食补充剂
https://www.doczj.com/doc/2b9096736.html,/sg3/sg3-final.html. See infra note 6.
注释6 See the FDA guidance for industry, Validation of
Procedures for Processing of Human Tissues Intended for Transplantation, available on the Internet at
https://www.doczj.com/doc/2b9096736.html,/BiologicsBloodVaccines/Guida nceComplianceRegulatoryInformation/ Guidances/default.htm.
? 公共卫生服务法361 节下的移植用人体组织 This guidance does not specify what information should be included as part of a regulatory submission. Interested persons can
refer to the appropriate guidance or contact the appropriate Center in determining the
type of information to include in a submission. 本指南没有具体说明哪些信息应包括在药政提交文件中，有兴趣的人士可以参照适当的指南或与适当的中心联系，以确定哪些类型的信息应包括在申报文件中。
This guidance does not specify what information should be included as part of a regulatory submission. Interested persons can refer to the appropriate guidance or contact the
appropriate Center in determining what information should be included in a submission.
本指南没有具体说明哪些信息应包括在药政提交文件中，有兴趣的人士可以参照适当的指南或与适当的中心联系，以确定哪些信息应包括在提交中。
This guidance also does not specifically discuss the validation of automated process
control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. This guidance is relevant, however, to the validation of processes that include automated equipment in processing.
本指南也没有专门讨论自动化工艺控制系统的验证(即计算机硬件和软件界面)，这些常整合到现代药物生产设备中。当然，本指南也是与那些在生产中包括自动化设备在内的工艺验证相关的。
This guidance also does not specifically discuss the validation of automated process
control systems (i.e., computer hardware and software interfaces), which are commonly integrated into modern drug manufacturing equipment. This guidance is relevant, however, to the validation of processes that include automated equipment in processing.
本指南也没有专门讨论自动化工艺控制系统的验证(即计算机硬件和软件界面)，这些常整合到现代药物生产设备中。当然，本指南也是与那些在生产中包括自动化设备在内的工艺验证相关的。
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
FDA 的指南文件，包括本指南在内，并无法定的强制执行要求。相反地，指南描述的是官方目前对某一问题的考虑与观点，除非引入了具体的药政或法定要求，否则应仅视为建议。官方指南中所用的“应当”一词意味着建议或推荐某种情况，但并非必需。 FDA 的指南文件，包括本指南在内，并无法定的强制执行要求。相反地，指南描述的是官方目前对某一问题的考虑与观点，除非引入了具体的药政或法定要求，否则应仅视为建议。官方指南中所用的“应当”一词意味着建议或推荐某种情况，但并非必需。
II. BACKGROUND II. BACKGROUND
In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance).7 Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDA’s current thinking on process validation and is consistent with basic principles first introduced in the 1987 guidance. The revised guidance also provides recommendations
that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical CGMPs for the 21st Century ― A Risk-Based Approach,” particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system tools and concepts.8 This revised guidance replaces the 1987 guidance. II.背景
在1987 年5 月11 日的联邦公报(52 FR 17638)上，FDA 发布了一个通告，宣布了题为工艺验证的一般原则指南(1987 年指南)的问世5。自那以来，通过我们的药政监管获得的额外经验，使得我们能够为业界更新我们关于这一议题的推荐建议。本修订指南传达了FDA 关于工艺验证的目前思考，并与1987 年指南最早引入的基本原则相一致。本修订后的指南同样提供了能反映FDA 倡议的“21 世纪制药cGMP－基于风险的办法”中某些目标的建议，特别是关于在药品生产中使用先进技术，以及实施现代风险管理和质量管理体系的工具和概念。当最终完成后，本修订后的指南将取代1987 年的指南。 In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the availability of a guidance entitled Guideline on General Principles of Process Validation (the 1987 guidance). 5 Since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic. This revised guidance conveys FDA’s current thinking on process validation
and is consistent with basic principles first introduced in the 1987 guidance. This guidance also provides recommendations that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical CGMPs for the 21st Century – A Risk-Based Approach,” particularly with regard to the use of technological advances in pharmaceutical manufacturing, as well as implementation of modern risk management and quality system tools and
concepts. When finalized, this guidance will replace the 1987 guidance.
5 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and Radiological Health (CDRH). Since that time, CDRH elected to publish its own process validation guidance through the Global Harmonization Task Force. The principles and
recommendations in that document, Quality Management Systems – Process Validation, edition 2 (available on the Internet at
https://www.doczj.com/doc/2b9096736.html,/sg3/sg3final.html), are also useful to consider for drug manufacturing
注释7 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and Radiological Health (CDRH). Since that time, CDRH elected to reference a process validation guidance prepared in coopera- tion with the Global Harmonization Task Force
(GHTF). The principles and recommendations in that document, Quality Management Systems –
Process Validation, edition 2 (available on the
Internet at https://www.doczj.com/doc/2b9096736.html,/sg3/sg3-final.html)are also useful to consider for drug manufacturing processes.
注释8 See “Pharmaceutical cGMPS for the 21st Century
— A Risk-Based Approach: Second Progress Report and Implementation Plan,” available at https://www.doczj.com/doc/2b9096736.html,/Drugs/DevelopmentApprovalP rocess/
Manufacturing/QuestionsandAnswersonCurr entGoodManufacturingPracticescGMPfor- Drugs/ucm071836.htm.
processes. II.背景
在1987 年5 月11 日的联邦公报(52 FR 17638)上，FDA 发布了一个通告，宣布了题为工艺验证的一般原则指南(1987 年指南)的问世5。自那以来，通过我们的药政监管获得的额外经验，使得
我们能够为业界更新我们关于这一议题的推荐建议。本修订指南传达了FDA 关于工艺验证的目前
思考，并与1987 年指南最早引入的基本原则相一致。本指南同样提供了能反映FDA 倡议的“21 世纪制药cGMP－基于风险的办法”中某些目标的建议，特别是关于在药品生产中使用先进技术，以
及实施现代风险管理和质量管理体系的工具和概念。当最终完成后，本指南将取代1987 年的指南。FDA has the authority and responsibility to
inspect and evaluate process validation performed by manufacturers. The CGMP regulations for validating pharmaceutical (drug)
manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)).
FDA 有权力和责任来检查和评估生产厂家所实施的工艺验证。用于药品生产验证的cGMP 法规要求药品应具有高度保证来生产以符合其预期拥有的所有属性(见21CFR211.100(a)与211.110(a))。
FDA has the authority and responsibility to
inspect and evaluate process validation performed by manufacturers. The CGMP regulations for validating pharmaceutical (drug)
manufacturing require that drug products be produced with a high degree of assurance of meeting all the attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)).
FDA 有权力和责任来检查和评估生产厂家所实施的工艺验证。用于药品生产验证的cGMP 法规要求药品应具有高度保证来生产以符合其预期拥有的所有属性(见21CFR211.100(a)与211.110(a))。A. Process Validation and Drug Quality A 工艺验证和药品质量
Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug Effective process validation contributes significantly to assuring drug quality. The basic principle of quality assurance is that a drug
should be produced that is fit for its intended
use. This principle incorporates the understanding that the following conditions exist: Q uality, safety, and efficacy are designed
or built into the product.
Q uality cann ot be adequately assured merely by in-process and finishedproduct
inspection or testing.
E ach step of a manufacturing process
is controlled to assure that the finished product meets all quality attributes including specifications.有效的工艺验证为保证产品质量发挥了重大作用。质量保证的基本原则是药物生产应符合其预期使用目的；这一原则整合了对下列情况的理解： ? 产品质量、安全性和有效性系由设计而得，或融入产品。 ? 仅仅对中控和成品进行监控或检测，质量不能得到充分的保证。 ? 对每一步的生产工艺进行控制，以确保成品符合所有设计特性与质量属性，包括规格标准。有效的工艺验证为保证产品质量发挥了重大作用。质量保证的基本原则是药物生产应符合其预期使用目的；这一原则整合了对下列情况的理解：? 产品质量、安全性和有效性系由设计而得，或融入产品。 ? 仅仅对中控和成品进行监控或检测，质量不能得到充分的保证。 ? 对每一步的生产工艺进行控制，以确保成品符合所有质量属性，包括质量标准。 should be produced that is fit for its intended use; this principle incorporates the understanding that the following conditions exist:
Q uality, safety, and efficacy are designed or built into the product. Q uality cannot be adequately assured
merely by in-process and finishedproduct inspection or testing. E ach step of a manufacturing process is controlled to assure that the finished product meets all design characteristics
and quality attributes including specifications. 有效的工艺验证为保证产品质量发挥了重大作用。质量保证的基本原则是药物生产应符合其预期使用目的；这一原则整合了对下列情况的理解：? 产品质量、安全性和有效性系由设计而得，或融入产品。 ? 仅仅对中控和成品进行监控或检测，质量不能得到充分的保证。 ? 对每一步的生产工艺进行控制，以确保成品符合所有设计特性与质量属性，包括规格标准。有效的工艺验证为保证产品质量发挥了重大作用。质量保证的基本原则是药物生产应符合其预期使用目的；这一原则整合了对下列情况的理解： ? 产品质量、安全性和有效性系由设计而得，或融入产品。 ? 仅仅对中控和成品进行监控或检测，质量不能得到充分的保证。 ? 对每一步的生产工艺进行控制，以确保成品符合所有设计特性与质量属性，包括规格标准。 B. Approach to Process Validation 工艺验证方法
For purposes of this guidance, process validation is defined as the collection and evaluation of data, from the process design stage
through commercial production, which establishes scientific evidence that a process is
capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process. This guidance describes process validation activities in three stages.
For purposes of this guidance, process validation is defined as 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. Process validation involves a series of activities taking place over the lifecycle of the
product and process. This guidance describes the process validation activities in three stages.
本指南将工艺验证定义为收集并评估从工艺设计阶段一直到商业化生产的数据，用这些数据来确立科学证据，证明该工艺能够始终如一地生产出优质产品。工艺验证涉及到了在产品生命周期及生产中所发生的一系列活动。本指南将工艺验证活动描述为三个阶段。
S tage 1
– Process Design: The commercial manufacturing process is defined
during this stage based on knowledge
gained through development and
scale-up activities.
S tage 2
– Process Qualification: During
this stage, the process design is evaluated
to determine if the process is
capable of reproducible commercial manufacturing.
S tage 3
– Continued Process Verification: Ongoing assurance is gained during
routine production that the process
remains in a state of control.
第1 阶段―工艺设计：在该阶段，基于从开发和放大试验活动中得到的知识确定商业化生产工艺。
第2 阶段―工艺确认：在这一阶段，对已经设计的工艺进行评估，以确定这个工艺是否能够进行重复性的商业化生产。
第3 阶段―持续工艺核实：工艺的受控状态在日常生产中得到持续地保证。本指南将工艺验证定义为收集并评估从工艺设计阶段一直到生产的数据，用这些数据来确立科学证据，证明该工艺能够始终如一地生产出优质产品。工艺验证涉及到了在产品生命周期及生产中所发生的一系列活动。本指南将工艺验证活动描述为三个阶段。
S tage 1
– Process Design: The commercial process is defined during this
stage based on knowledge gained
through development and scale-up activities.
S tage 2
– Process Qualification: During
this stage, the process design is confirmed
as being capable of reproducible
commercial manufacturing.
S tage 3
– Continued Process Verification: Ongoing assurance is gained during
routine production that the process
remains in a state of control.
第1 阶段―工艺设计：在该阶段，基于从开发和放大试验活动中得到的知识确定工业化生产工艺。
第2 阶段―工艺确认：在这一阶段，对已经设计的工艺进行确认，证明其能够进行重复性的商业化生产。
第3 阶段―持续工艺核实：工艺的受控状态在日常生产中得到持续地保证。
This guidance describes activities typical of
each stage, but in practice, some activities
might occur in multiple stages.
本指南描述了每一阶段的典型活动，但在实践中，有些活动可能在多个阶段出现。This guidance describes activities typical in
each stage, but in practice, some activities in different stages might overlap.
本指南描述了每一阶段的典型活动，但在实践中，有些活动在不同的阶段可能会重叠。
Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree
of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products
meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-, Before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree
of assurance in the performance of the manufacturing process such that it will consistently produce APIs and drug products
meeting those attributes relating to identity, strength, quality, purity, and potency. The assurance should be obtained from objective information and data from laboratory-, pilot-,
and/or commercial-scale studies. Information
and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions.
从某工艺商业化销售给消费者使用前的任何一批，生产企业应该已经获得对该生产工艺性能的高度保证，即它将始终如一地生产出能满足关于鉴别、含量、质量、纯度和效价属性要求的原料药与制剂产品。这些保证应该从产品小试、中试和/或大生产研究的客观信息和数据中得到。这些信息和数据应该能够证明该商业化生产工艺有能力在其商业生产条件下，持续地生产出可接受的优质产品。and/or commercial scale studies. Information
and data should demonstrate that the commercial manufacturing process is capable of consistently producing acceptable quality products within commercial manufacturing conditions, including those conditions that
pose a high risk of process failure.
从某工艺商业化销售给消费者使用前的任何一批，生产企业应该已经获得对该生产工艺性能的高度保证，即它将始终如一地生产出能满足关于鉴别、含量、质量、纯度和效价属性要求的原料药与制剂产品。这些保证应该从产品小试、中试和/或大生产研究的客观信息和数据中得到。这些信息和数据应该能够证明该商业化生产工艺有能力在其商业生产条件，也包括那些造成工艺失败的高风险条件下，一贯地生产出可接受的优质产品。
A successful validation program depends
upon information and knowledge from product and process development. This knowledge
and understanding is the basis for establishing
an approach to control of the manufacturing process that results in products
with the desired quality attributes. Manufacturers should:
U nderstand the sources of variation
D etect the presence and degree of variation
U nderstand the impact of variation on
the process and ultimately on product
attributes
C ontrol the variation in a manner commensurate
with the risk it represents to
the process and product
一个成功的验证程序取决于来自产品与工艺开发的信息与知识，这种知识与理解是建立适合于生产工艺的某一控制方法的基础，而这个工艺可以生产出具有期望质量属性的产品。
生产企业应当：
? 了解变异来源
? 检测变异是否存在以及发生的程度
? 理解变异对工艺，以及最终对产品属性的影响? 使用与工艺和产品风险相适应的方法来控制变异A successful validation program depends
upon information and knowledge from product and process development. This knowledge
and understanding is the basis for establishing
an approach to control that is appropriate
for the manufacturing process.
Manufacturers should:
u nderstand the sources of variation
d etect th
e presence an
d degre
e o
f variation
u nderstand the impact of variation on
the process and ultimately on product
attributes
c ontrol the variation in a manner commensurate
with the risk it represents to
the process and product
一个成功的验证程序取决于来自产品与工艺开发的信息与知识，这种知识与理解是建立适合于生产工艺的某一控制方法的基础。生产企业应当：? 了解变异来源
? 检测变异是否存在以及发生的程度
? 理解变异对工艺，以及最终对产品属性的影响? 使用与工艺和产品风险相适应的方法来控制变异
Each manufacturer should judge whether it
has gained sufficient understanding to provide
a high degree of assurance in its manufacturing
process to justify commercial distribution
of the product. Focusing exclusively
on qualification efforts without also understanding
the manufacturing process and associated
variations may not lead to adequate
assurance of quality. After establishing and
confirming the process, manufacturers must
maintain the process in a state of control
over the life of the process, even as materials,
equipment, production environment,
personnel, and manufacturing procedures
change.9
每个生产企业应当判断是否已经对此获得了足
够的理解，即对其生产工艺提供一个高度保证，
从而证明其产品商业化销售的正当性。没有对生
产工艺和相关变异的理解而仅仅注重于资质性
的成果，不可能带来对质量的足够保证。在工艺
建立并确认后，生产企业必须保证该工艺在其工
艺生命周期内处于受控状态，既使是在材料、设
备、生产环境、人员和生产工艺变更的条件下。
注释9 The statute and regulations described in
section
III of this guidance explain the requirement that
the methods and facilities used for the
manufacturing
of drugs be operated and administered
under control sufficient to assure that the identity,
strength, purity, and quality of a drug are as they
purport or are represented to possess.
Each manufacturer should judge whether it
has gained sufficient understanding to provide
a high degree of assurance in its manufacturing
process to justify commercial distribution
of the product. Focusing on qualification
efforts without understanding the manufacturing
process may not lead to adequate
assurance of quality. After establishing and
confirming the process, manufacturers must
maintain the process in a state of control
over the life of the process, even as materials,
equipment, production environment,
personnel, and manufacturing procedures
change.6
6
The statute and regulations described in section
III of this guidance explain the requirement that
the methods and facilities used for the
manufacturing
of drugs be operated and maintained under
control sufficient to assure that the identity,
strength, purity, and quality of a drug are as they
purport or are represented to possess.
每个生产企业应当判断是否已经对此获得了足够
的理解，即对其生产工艺提供一个高度保证，从
而证明其产品商业化销售的正当性。没有对生产
工艺的理解而仅注重于资质性的成果，不可能带
来对质量的充足保证。在工艺建立并确认后，生
产企业必须保证该工艺在其工艺生命周期内处于
受控状态，既使是在材料、设备、生产环境、人
员和生产工艺变更的条件下。
Manufacturers should use ongoing programs to collect and analyze product and process data to evaluate the state of control of the process. These programs may identify
process or product problems or opportunities for process improvements that can be evaluated
and implemented through some of the activities described in Stages 1 and 2.
制造商应该采用持续项目来收集和分析产品和工艺数据，以便评估工艺受控状态。这些项目可能确认工艺或者产品的缺陷，或者工艺改进的机会，这些问题或者机会可以通过阶段2和阶段3描
述的活动来评估和实施。
Manufacturers of legacy products can take advantage of the knowledge gained from the original process development and qualification work as well as manufacturing experience to continually improve their processes. Implementation of the recommendations in this guidance for legacy products and processes would likely begin with the activities described in Stage 3.
已有产品的制造商可以利用从原有工艺研发和确认工作中获得的知识，也包括制造经验来持续改进工艺。在本指南中，对于已有产品和工艺实施这些建议可以从阶段3描述的活动开始。
III. STATUTORY AND REGULATORY
REQUIREMENTS
FOR PROCESS VALIDATION
第三部分：工艺验证的法规和法规要求
III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS VALIDATION 第三部分：工艺验证的法规和法规要求 Process validation for drugs (finished
pharmaceuticals and components) is a legally
enforceable requirement under section
501(a)(2)(B) of the Act (21 U.S.C.
351(a)(2)(B)), which states the following:
对药品（制剂和组分）进行工艺验证是法案（21
U.S.C.351(a)(2)(B)）的501(a)(2)(B)部分的法定要
求，描述如下：
Process validation for drugs (finished
pharmaceuticals and components) is a legally
enforceable requirement under section
501(a)(2)(B) of the Act, which states the following:
III.工艺验证的法规和法规要求
药品(制剂与其成分)的工艺验证是食品、药品与
化妆品法之501(a)(2)(B)节规定的一个法定的、
强制性的要求，其规定如下：
A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess. 某一药品…，如果在其生产、加工、包装或持有中所使用的方法、设施或管理控制不符合cGMP 要求，或未按照cGMP 要求来操作或管理，以便A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.
某一药品…，如果在其生产、加工、包装或持有中所使用的方法、设施或管理控制不符合cGMP 要求，或未按照cGMP 要求来操作或管理，以便保证
保证药品符合本法规所要求的安全性、鉴别、含量并符合其声称的质量与纯度特性，该药品将被视为伪劣药品。 药品符合本法规所要求的安全性、鉴别、含量并符合其声称的质量与纯度特性，该药品将被视为伪劣药品。 FDA regulations describing current good
manufacturing practice (CGMP) for finished
pharmaceuticals are provided in 21 CFR
parts 210 and 211.
FDA 法规描述的cGMP 即是21CFR 的210 与211
部分。
FDA regulations describing current good
manufacturing practice (CGMP) are provided
in 21 CFR parts 210 and 211.
cGMP 的第210 和211 部分对工艺验证进行了一
般性和特殊性的要求。
The CGMP regulations require that manufacturing processes be designed and controlled to assure that in-process materials and the finished product meet predetermined quality
requirements and do so consistently and
reliably. Process validation is required, in
both general and specific terms, by the
CGMP regulations in parts 210 and 211. The
foundation for process validation is provided in § 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...” (emphasis added). This regulation requires manufacturers to design a process, including operations and controls, which results in a product meeting these attributes. CGMP 法规要求制造工艺应该被设计和控制来确保中控物料和最终产品符合预先确定的质量要求，而且工艺被持续和有效的控制。 §211.100(a)提供了工艺验证的基础，其指出，“应当有设计的书面的用于生产与工艺控制的程序，用以保证其声称或代表拥有的药品鉴别、含量、质量和纯度”(重点强调)。该法规要求生产企业设计一个能使产品符合这些特质的工艺，包括操作与控制。
Process validation is required, in both general and specific terms, by the CGMP regulations in parts 210 and 211. The foundation
for process validation is provided in § 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" (emphasis added). This regulation requires that manufacturers design a process including operations and controls that will result in a product meeting these attributes. Product quality in the context of process validation means that product performance is consistent from batch-tobatch and unit-to-unit. Many products are single-source or involve complicated processes to manufacture. Validation also offers assurance that a process is reasonably safeguarded from sources of variability affecting production output, the loss of which
can cause supply problems, thereby negatively affecting public health. §211.100(a)提供了工艺验证的基础，其指出，“应当有设计的书面的用于生产与工艺控制的程序，用以保证其声称或代表拥有的药品鉴别、含量、质量和纯度”(重点强调)。该法规要求生产企业设计一个能使产品符合这些特质的工艺，包括操作与控制。在工艺验证中产品质量意味着产
品性能在批与批之间、单位与单位之间是一致的。许多产品为单一来源或涉及复杂的生产工艺。验证还提供了另一种保证，即工艺被适度地保护，远离了可能会影响生产产量的变异性来源，产量
的损失可能会造成市场供应问题，进而影响到公众健康。
Other CGMP regulations define the various aspects of validation. For example, §
211.110(a), Sampling and testing of inprocess materials and drug products, requires
that control procedures “. . . be established to monitor the output and to validate
the performance of those manufacturing
processes that may be responsible for causing
variability in the characteristics of inprocess
material and the drug product” (emphasis
added). Under this regulation, even
well-designed processes must include inprocess
control procedures to assure final
product quality. In addition, the CGMP regulations
regarding sampling set forth a number
of requirements for validation: samples must
represent the batch under analysis (§
211.160(b)(3)); the sampling plan must result
in statistical confidence (§ 211.165(c) and
(d)); and the batch must meet its predetermined
specifications (§ 211.165(a)).
其它的cGMP 法规界定了验证的不同方面。例如，
第211.110(a)节中控物料与药品的取样和检测，
要求控制程序“…应该建立，以便监控产品的输
出并对有可能造成中控物料与药品特性变异的
那些生产工艺的性能进行验证”(重点强调)。该
法规建立了这样的要求，既使是精心设计的工艺
也必须包括中间工艺控制程序，以保证最终成品的质量。另外，CGMP法规设定了针对验证的一系列取样要求：需要分析的样品必须具有批次代表性（§211.160(b)(3)）；取样计划必须具有统计置信限（§ 211.165(c) 和(d)）；批次必须符合预先确定的标准（§ 211.165(a)）。
Other CGMP regulations define the various
aspects of validation. Section 211.110(a),
Sampling and testing of in-process materials
and drug products, requires that control procedures
“. . . be established to monitor the
output and to validate the performance of
those manufacturing processes that may be
responsible for causing variability in the
characteristics
of in-process material and the
drug product" (emphasis added). This regulation
establishes the requirement that even well-designed
processes must include inprocess
control procedures to assure final product quality.
其它的cGMP 法规界定了验证的不同方面。第
211.110(a)节中控物料与药品的取样和检测，要
求控制程序“…应该建立，以便监控产品的输出
并对有可能造成中控物料与药品特性变异的那些
生产工艺的性能进行验证”(重点强调)。该法规
建立了这样的要求，既使是精心设计的工艺也必
须包括中间工艺控制程序，以保证最终成品的质
量。
In addition to sampling requirements, the CGMP regulations also provide norms for establishing in-process specifications as an aspect of process validation. Section
211.110(b) establishes two principles to follow when establishing in-process specifications. The first principle is that “. . . in-process
specifications for such characteristics [of inprocess
CGMP regulations require that batch samples represent the batch under analysis (see, e.g., § 211.160(b)(3)) and that the sampling plan result in statistical confidence (§
211.165(c) and (d)) that the batch meets its predetermined specifications (§ 211.165(a)). Section 211.110(b) provides two principles to
follow when establishing in-process specifications.
material and the drug product] shall be consistent with drug product final specifications . . . .” Accordingly, in-process material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation further requires that in-process specifications “. . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.” This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability.10 除了取样要求，CGMP 法规也提供了建立中控标准的要求，这也是工艺验证的一部分。 cGMP 法规要求，批样品代表的是所分析的批号(参见§211.160(b)(3))，取样计划可带来统计上的信心(§211.165(c)与(d))，即该批符合其预定的规格标准(§211.165(a))。第211.110(b)提供了在建立中控标准时要遵守的两个基本原则，第一项，“中间物料的规格标准应该与最终产品的规格标准相一致”，相应地，对中间物料应当进行控制以确保成品能符合其要求的质量。本法规第二项原则进一步要求中控标准，“应该来自于先前可接受的工艺平均值及可能的工艺变量估计，而且应该用合适的统计方法进行确定”。这项要求，部分地确立了生产企业分析工艺性能并控制批与批之间变异的必要性。 注释10 The Agency further explains this principle in the preamble to the final rule on “Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding” (43 FR 45013 at 45052, September 29, 1978) (available on the Internet at https://www.doczj.com/doc/2b9096736.html,/cder/dmpq/ preamble.txt).
The first principle is that “. . . inprocess specifications for such characteristics [of in-process material and the drug product] shall be consistent with drug product final specifications . . . .” Accordingly, inprocess material should be controlled to assure that the final drug product will meet its quality requirements. The second principle in this regulation further requires that in-process specifications “. . . shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.” This requirement, in part, establishes the need for manufacturers to analyze process performance and control batch-to-batch variability.77In the Federal Register of September 29, 1978 (43 FR 45013 at 45052), FDA published a final rule on “Current Good Manufacturing Practice in Manufacture, Processing, Packing, or Holding” (available on the Internet at https://www.doczj.com/doc/2b9096736.html,/cder/dmpq/preamble.txt). In the preamble of the final rule, the Agency further explains this principle.
cGMP 法规要求，批样品代表的是所分析的批号(参见§211.160(b)(3))，取样计划可带来统计上的信心(§211.165(c)与(d))，即该批符合其预定的规格标准(§211.165(a))。第211.110(b)提供了在建立中控标准时要遵守的两个基本原则，第一项，“中间物料的规格标准应该与最终产品的规格标准相一致”，相应地，对中间物料应当进行控制以确保成品能符合其要求的质量。本法规第二项原则进一步要求中控标准，“应该来自于先前可接受的工艺平均值及可能的工艺变量估计，而且应该用合适的统计方法进行确定”。这项要求，部分地确立了生产企业分析工艺性能并控制批与批之间变异的必要性。 The CGMP regulations also describe and
define activities connected with process design, development, and maintenance. Section 211.180(e) requires that information and
The CGMP regulations also describe and
define activities connected with process design, development, and maintenance. Section 211.180(e) requires that information and
data about product quality and manufacturing experience be periodically reviewed to determine whether any changes to the estab-
lished process are warranted. Ongoing feedback about product quality and process performance
is an essential feature of process maintenance.
cGMP 法规中同样描述并定义了与过程设计、开发与维护相关的活动。第211.180(e)要求，产品质量与生产经验的资料和数据要进行定期审核，以确定是否与已经批准的工艺有任何变更。产品质量和工艺性能的持续反馈是工艺维护的本质特点。data about product performance and manufacturing experience be periodically reviewed
to determine whether any changes to the established process are warranted. Ongoing feedback about product performance is an essential feature of process maintenance.
cGMP 法规中同样描述并定义了与过程设计、开发与维护相关的活动。第211.180(e)要求，产品性能与生产经验的资料和数据要进行定期审核，以确定是否与已经批准的工艺有任何变更。产品性能的持续反馈是工艺维护的本质特点。
In addition, the CGMP regulations require
that facilities in which drugs are manufactured
be of suitable size, construction, and
location to facilitate proper operations (§
211.42). Equipment must be of appropriate design, adequate size, and suitably located
to facilitate operations for its intended use (§ 211.63). Automated, mechanical, and electronic equipment must be calibrated, inspected,
or checked according to a written
program designed to assure proper performance (§ 211.68).
此外，cGMP 法规还要求生产药品的设施应当有合适的尺寸、材质以及布局以利于适当地操作(21CFR211.42)。设备必须是适当的设计，足够的尺寸，并适当地布局以方便其预定的操作用途(21CFR211.63)。自动化、机械以及电子设备必须根据书面程序进行校验、检查或核实以便保证其合适的性能。 In addition, the CGMP regulations require
that facilities in which drugs are manufactured
be of suitable size, construction, and
location to facilitate proper operations (21
CFR 211.42). Equipment must be of appropriate design, adequate size, and suitably
located to facilitate operations for its intended
use (21 CFR 211.63). Automated, mechanical, and electronic equipment must be calibrated, inspected, or checked according to a
written program designed to assure proper performance (21 CFR 211.68).
此外，cGMP 法规还要求生产药品的设施应当有合适的尺寸、材质以及布局以利于适当地操作(21CFR211.42)。设备必须是适当的设计，足够的尺寸，并适当地布局以方便其预定的操作用途(21CFR211.63)。自动化、机械以及电子设备必须根据书面程序进行校验、检查或核实以便保证其合适的性能。
In summary, the CGMP regulations require
that manufacturing processes be designed
and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so
consistently and reliably.
总之，cGMP 法规要求应当对生产工艺进行设计和控制，以确保工艺中间物料与成品满足其预定的质量标准，而且应当一贯如此。In summary, the CGMP regulations require
that manufacturing processes be designed
and controlled to assure that in-process materials and the finished product meet predetermined quality requirements and do so
consistently and reliably.
总之，cGMP 法规要求应当对生产工艺进行设计和控制，以确保工艺中间物料与成品满足其预定的质量标准，而且应当一贯如此。
IV. RECOMMENDATIONS IV建议IV. RECOMMENDATIONS IV.建议
In the following sections, we describe general considerations for process validation, the recommended stages of process validation,
and specific activities for each stage in the product lifecycle.
在随后的部分，我们描述了工艺验证的一般考虑点、工艺验证的推荐阶段和产品生命周期中每个阶段的特定活动。
A. General Considerations for Process Validation
工艺验证的一般考虑A. General Considerations for Process Validation
A.工艺验证的一般考虑
In all stages of the product lifecycle, good
project management and good archiving that capture scientific knowledge will make the process validation program more effective
and efficient. The following practices should ensure uniform collection and assessment of information about the process and enhance
the accessibility of such information later in
the product lifecycle.
在产品生命周期的各个阶段，旨在捕捉科学知识的良好的项目管理与归档将使得工艺验证更加有效和高效率。这些惯例应确保统一收集并评估有关工艺信息，在后面的产品生命周期里加强利用这些资料。
W e recommend an integrated team
approach11 to process validation that
includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing,
and quality assurance). Project plans,
along with the full support of senior management, are essential elements
for success.
我们建议以整合团队的方式来进行工艺验证，其中包括来自于各不同的专门学科的专家，包括工艺工程、工业药学、分析化学、微生物学、统计学、生产和质量保证。项目计划，以及来自于高级管理层的全力支持，是必不可少的成功要素。In all stages of the product lifecycle, good
project management and good archiving that capture scientific knowledge will make the process validation program more effective
and efficient. These practices should ensure uniform collection and assessment of information about the process, reduce the chance for redundant information gathering and
analysis, and enhance the accessibility of
such information later in the product lifecycle.
在产品生命周期的各个阶段，旨在捕捉科学知识的良好的项目管理与归档将使得工艺验证更加有效和高效率。这些惯例应确保统一收集并评估有关工艺信息，减少多余信息的收集与分析机会，在后面的产品生命周期里加强利用这些资料。 · We recommend an integrated8team
approach to process validation that includes expertise from a variety of disciplines,
including process engineering,
industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing,
and quality assurance. Project
plans, along with the full support of senior management, are essential elements
for success.
我们建议以整合团队的方式来进行工艺验证，其中包括来自于各不同的专门学科的专家，包括工艺工程、工业药学、分析化学、微生物学、统计学、生产和质量保证。项目计划，以及来自于高
T hroughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and approved in accordance with the established procedure appropriate for the stage of the lifecycle. 在整个产品生命周期中，可以开展各种研究以便发现、观察、联想或确认有关产品和工艺的信息。所有研究应该按照可靠的科学原则进行策划、实施并妥善记录，并且应当按照在适当的生命周期阶段建立的书面程序进行审批。 T he terms attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process, operating, and equipment) are not categorized with respect to criticality in this guidance. With a lifecycle approach to process validation that employs risk based decision making throughout that lifecycle, the perception of criticality as a continuum rather than a binary state is more useful.
在这个指南中，没有对属性术语（例如质量、产品和组分）与参数术语（例如工艺、操作和设备）进行涉及关键性的分类。对于工艺验证采用以风险为基础的生命周期方法，在整个生命周期中，把关键性看作连续的比看作间断的更有用。 All attributes and parameters should be evaluated in terms of their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those attributes or parameters should be commensurate with their risk to the process and process output. In other words, a higher degree of control is appropriate for attributes or parameters
that pose a higher risk. The Agency recognizes that terminology usage can
级管理层的全力支持，是必不可少的成功要素。· Throughout the product lifecycle, various studies can be initiated to discover, observe, correlate, or confirm information about the product and process. All studies should be planned and conducted according to sound scientific principles, appropriately documented, and should be approved in accordance with the established procedure appropriate for the stage of the lifecycle.在整个产品生命周期中，可以开展各种研究以便发现、观察、联想或确认有关产品和工艺的信息。所有研究应该按照可靠的科学原则进行策划、实施并妥善记录，并且应当按照在适当的生命周期阶段建立的书面程序进行审批。 8 This concept is discussed in more detail in FDA’s guidance for industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations, available on the Internet at https://www.doczj.com/doc/2b9096736.html,/cder/guidance/ index.htm.
vary and expects that each manufacturer
will communicate the meaning
and intent of its terminology and categorization to
the Agency.
应该评估所有属性或参数对工艺的作用和对产
品或者中控物料的影响，重新评估的新信息也可
以使用。对那些属性或参数的控制力度应该和它
们对工艺的风险影响以及对工艺输出量的影响
相匹配。换句话说，对于产生较高风险的属性或
参数，实施较高程度的控制是合适的。FDA认为
术语使用在不同场合是不同的，期望每个制造商
和FDA进行关于术语定义和用途的交流。
Many products are single-source or involve
complicated manufacturing
processes. Homogeneity within a batch
and consistency between batches are
goals of process validation activities.
Validation offers assurance that a
process is reasonably protected
against sources of variability that could
affect production output, cause supply
problems, and negatively affect public
health.
很多产品来源单一，或者涉及复杂的制造工艺。
工艺验证活动的目的是证明一批产品内部和在
批与批之间是均质的。验证还提供了另一种保
证，即工艺被适度地保护以避免可能会影响产品
产量的变异性来源，产量的损失可能会造成市场
供应问题，进而影响到公众健康。
注释11This concept is discussed in more detail in
FDA’s guidance for industry, Quality Systems
Approach to Pharmaceutical Current Good
Manufacturing Practice Regulations, available at
https://www.doczj.com/doc/2b9096736.html,/Drugs/GuidanceComplianceR
egulatoryInformation/Guidances/default.htm.
B. Specific Stages and Activities of Process
Validation in the Product Lifecycle
B.产品生命周期里工艺验证的阶段与活动
The following subsections describe the
recommended
stages and specific activities.
下面的小节描述了建议的阶段与具体活动。
Stage 1– Process Design 阶段1-工艺设计Stage 1– Process Design 阶段1-工艺设计
Process design is the activity of defining the commercial manufacturing process that will
be reflected in planned master production
and control records. The goal of this stage is
to design a process suitable for routine commercial manufacturing that can consistently deliver a product that meets its quality attributes.
工艺设计是确定商业化工艺的活动，工艺将体现在预期的主生产记录和主控制记录上。这个阶段的目的是确定适用于例行商业化生产的工艺，可以持续的生产出符合质量属性的产品。
Building and Capturing Process Knowledge and Understanding
建立和捕获工艺知识与理解Building and Capturing Process Knowledge
and Understanding
a. 建立和捕获工艺知识与理解
Process design is the activity of defining the commercial manufacturing process that will
be reflected in the master production and
control records. The goal of this stage is to design a process suitable for routine commercial manufacturing that can consistently
deliver a product that meets its critical quality attributes. 工艺设计是定义商业化生产工艺的活动，这个工艺将反映在主生产和控制记录里。这个阶段的目标是设计一个适合于日常商业化生产的工艺，能够始终如一地生产出满足其关键质量属性的产品。
Generally, early process design experiments
do not need to be performed under the
CGMP conditions required for drugs intended
for commercial distribution that are manufactured during Stage 2 (process qualification)
and Stage 3 (continued process verification). They should, however, be conducted in accordance with sound scientific methods and
principles, including good documentation practices. This recommendation is consistent with ICH Q10 Pharmaceutical Quality System12. Decisions and justification of the controls should be sufficiently documented and Generally, early process design experiments
do not need to be performed under CGMP conditions. They should, however, be conducted
in accordance with sound scientific
methods and principles, including good documentation
practices. This recommendation
is consistent with ICH guidance for industry,
Q10 Pharmaceutical Quality System.9
Decisions and justification of the controls should
be sufficiently documented and internally
reviewed to verify and preserve their value
for use later in the lifecycle of the process
I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. 1. 绪论 本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。 This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications. 本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。这些建议适用于NDA，ANDA，BLA，PLA及其它们的补充中所涉及的原料药和制剂。 The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with the center with product jurisdiction to prevent the expenditure of resources on preparing a submission that may later be determined to be unacceptable. 这些原则同样适用于二类DMF所涉及的原料药和制剂。如果使用了其它方法，鼓励申请者事先和FDA药品评审中心的官员进行讨论，以免出现这种情况，那就是花了人力物力所准备起来的递交资料后来发现是不可用的。 The principles of methods validation described in this guidance apply to all types of analytical procedures. However, the specific recommendations in this guidance may not be applicable to certain unique analytical procedures for products such as biological, biotechnological, botanical, or radiopharmaceutical drugs. 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. 比如说，许多生物分析是建立在动物挑战模式，免疫原性评估或其它有着独特特性的免疫分析基础上的，在递交分析方法和分析方法验证资料时需考虑这些独特的性质。Furthermore, specific recommendations for biological and immunochemical tests that may be necessary for characterization and quality control of many drug substances and drug products are beyond the scope of this guidance document. 而且，许多原料药和制剂的界定和质量控制所需的生物和免疫化学检测并不在本指南的范围之内。 Although this guidance does not specifically address the submission of analytical procedures and validation data for raw materials, intermediates, excipients, container closure components, and other materials used in the production of drug
201507 FDA行业指南：分析方法验证（中英文）（下） VII. STATISTICAL ANALYSIS AND MODELS 统计学分析和模型 A. Statistics 统计学 Statistical analysis of validation data can be used to evaluate validation characteristics against predetermined acceptance criteria. All statistical procedures and parameters used in the analysis of the data should be based on sound principles and appropriate for the intended evaluation. Several statistical methods are useful for assessing validation characteristics, for example, an analysis of variance (ANOVA) to assess regression analysis R (correlation coefficient) and R squared (coefficient of determination) or linear regression to measure linearity. Many statistical methods used for assessing validation characteristics rely on population normality, and it is important to determine whether or not to reject this assumption. There are many techniques, such as histograms, normality tests, and probability plots that can be used to evaluate the observed distribution. It may be appropriate to transform the data to better fit the normal distribution or apply distribution-free (nonparametric) approaches when the observed data are
FDA清洗验证检查指南 I．引言 自FDA各种文件（包括化学原料药检查指南、生物技术检查指南）首次提出这个问题之后，清洗过程的验证已经引发了很多讨论。FDA的文件明确指出要求对清洗过程进行验证。 本指南讨论了各种可接受（或不可接受）的验证方法，从而使FDA的检查具有一致性。但必须清楚地认识到：与其他工艺验证一样，清洗验证方法也不止一种。所有过程验证的检查标准是：检查其科学数据能否证明系统稳定一致地达到预期目的，系统结果稳定地符合预先制定的标准。 本指南仅适用于设备化学残留物的清洗验证。 II．背景 对于FDA而言，使用设备前进行清洗不是什么新要求。1963年GMP法（133.4）规定“设备应处于清洁、有序的状态”。1978年的cGMP中规定了设备清洗的章节（211.67）。要求清洗设备的主要目的还是防止污染或混料。由于设备清洗维护不当或防尘管理不当，FDA检查官曾十分注意检查卫生状况。过去FDA总是更注意检查青霉素类与非青霉素类药物之间的交叉污染、药品与甾类物质或激素之间的交叉污染问题。在过去二十年间，因实际或潜在的青霉素交叉污染问题已从市场上撤回了大量的药品。 另一个事件使FDA对交叉污染问题日益重视，即1988年从市场上撤回了消胆胺成品制剂，原因是规程不当。生产该制剂的原料药受到了农业杀虫剂生产中少量中间体和降解物质的污染。造成交叉污染的主要原因使用了回收溶媒。而回收溶媒受到了污染，原因是对溶媒桶的重复使用缺少监控。贮存杀虫剂产生的回收溶媒桶又重复地用于贮存该药品生产中的回收溶媒。而工厂没有对这些溶媒桶进行有效的监控，没有对其中的溶媒进行有效的检验，也没有对桶的清洗规程进行验证。 被杀虫剂污染的部份化学原料药运到了另一地点的第二家工厂生产制剂，使该工厂的流化床干燥器中物料袋受到了杀虫剂的污染，料造成各批产品受到污染，而该工厂根本就没有生产杀虫剂。
美国FDA分析方法验证指南中英文对照 美国FDA分析方法验证指南中英文对 照 I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. 1. 绪论 本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用 于支持原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。 This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications. 本指南旨在帮助申请者收集资料，递交样品并资料以支持分析方法。这些建议适 用于NDA，ANDA，BLA，PLA及其它们的补充中所涉及的原料药和制剂。 The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with
药品及生物制品的分析方法和方法验证指导原则 目录 1.介绍...................... (1) 2.背景..................... .. (2) 3.分析方法开发. ..................... . (3) 4.分析程序内容.............................................. ......... ..................................... .. 3 A.原则/范围 (4) B.仪器/设备............................................. . (4) C.操作参数.............................................. .. (4) D.试剂/标准............................................. . (4) E.样品制备.............................................. .. (4) F.标准对照品溶液的制备............................................ .. (5) G.步骤......... ....................................... (5) H.系统适应性..... (5) I.计算 (5) J.数据报告 (5) 5.参考标准和教材............................................ (6) 6分析方法验证用于新药，仿制药，生物制品和DMF (6) A.非药典分析方法............................................. (6) B.验证特征 (7) C.药典分析方法............................................. .. (8) 7.统计分析和模型 (8) A.统计 (8) B.模型 (8) 8.生命周期管理分析程序 (9) A.重新验证 (9) B.分析方法的可比性研究............................................ . (10) 1.另一种分析方法............................................... .. (10) 2.分析方法转移的研究 (11) C.报告上市后变更已批准的新药，仿制药，或生物制品 (11) 9.美国FDA方法验证............................................... . (12) 10.参考文献
1 II. 背景 (2) III. 分析方法的类型 (3) A. 法定分析方法 (3) B. 可选择分析方法 (3) 3 C. 稳定性指示分析 (3) IV. 对照品…………………………………………………………………………… 4 A. 对照品的类型 (4) B. 分析报告单 (4) C. 对照品的界定 (4) V. IND 中的分析方法验证 (6) VI. NDA, ANDA, BLA 和PLA 中分析方法验证的内容和格式 (6) A. 原则 (6) B. 取样 (7) C. 仪器和仪器参数 (7) D. 试剂 (7) E. 系统适应性实验 (7) F. 对照品的制备 (7) G. 样品的制备 (8) H. 分析方法 (8) L. 计算 (8) J. 结果报告 (8) VII. NDA，ANDA,BLA 和PLA 中的分析方法验证 (9) A．非法定分析方法 (9) 1．验证项目 (9) 2. 其它分析方法验证信息 (10) a. 耐用性 (11) b. 强降解实验 (11) c. 仪器输出/原始资料 (11) 3．各类检测的建议验证项目 (13) B．法定分析方法 (15) VIII. 统计分析………………………………………………………………………… 15 A. 总则 (15)
C. 统计 (16) IX. 再验证 (16) X. 分析方法验证技术包：内容和过程…………………………………………… 17 A. 分析方法验证技术包 (17) B. 样品的选择和运输 (18) C. 各方责任 (19) XI. 方法……………………………………………………………………………… 20 A. 高效液相色谱(HPLC) (20) B. 气相色谱(GC) (22) C. 分光光度法，光谱学，光谱法和相关的物理方法 (23) D. 毛细管电泳 (23) E. 旋光度 (24) F. 粒径相关的分析方法 (25) G. 溶出度 (26) H. 其它仪器分析方法 (27) 附件A：NDA，ANDA，BLA 和PLA 申请的内容 (28) 附件B：分析方法验证的问题和延误 (29) 参考文献…………………………………………………………………………………… 30 术语表……………………………………………………………………………………… 32 This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. 1. 绪论 本指南旨在为申请者提供建议，以帮助其提交分析方法，方法验证资料和样品用于支持 原料药和制剂的认定，剂量，质量，纯度和效力方面的文件。 This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications.
FDA工艺验证指南新旧版透彻比较解读 【整理者提醒】 1-左侧文本为2011年1月最新修订版本，右侧文本为2008年11月草案版本。 2-蓝色文本为修订后文本或者新增加文本。 3-下划线文本是比旧版本增加的部分内容。 4-删除线文本表示该部分存在于旧版本中，在新版本中删除。 5-注释前面加【注释】2字注明。 6-Zhulikou431关于FDA2008年11月草案彻底解读版本可以在丁香园论坛搜索到，欢迎下载阅读、讨论。 7-不得用于商业用途，转载请注明丁香园信息。 8-增加了新旧版本的中文译文。 9-欢迎各位朋友提出宝贵建议，联系邮箱zhulikou431@https://www.doczj.com/doc/2b9096736.html,. Guidance for Industry Process Validation: General Principles and Practices Final Version January 2011 Draft 2008 I. INTRODUCTION I. INTRODUCTION 简介
This guidance outlines the general principles and approaches that FDA considers appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (APIs or drug substances), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use to validate manufacturing processes. 本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。本指南整合了一般的原则和方法，所有的生产企业都可以将这些原则和方法应用于生产工艺的验证。 This guidance outlines the general principles and approaches that FDA considers to be appropriate elements of process validation for the manufacture of human and animal drug and biological products, including active pharmaceutical ingredients (API or drug substance), collectively referred to in this guidance as drugs or products. This guidance incorporates principles and approaches that all manufacturers can use in validating a manufacturing process. 本指南概括了一般的原则与方法，这些原则与方法是FDA 认为进行工艺验证的恰当要素，这些工艺被用于生产人用药、动物用药以及生物制品，包括活性药物成分(API 或药用物质)，在本指南中以上统称为药品或产品。本指南整合了一般的原则和方法，所有的生产企业都可以将这些原则和方法应用于生产工艺的验证。 This guidance aligns process validation activities with a product lifecycle concept and with existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH) guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System.2 Although this guidance does not repeat the concepts and principles explained in those guidances, FDA encourages the use of modern pharmaceutical development concepts, quality risk man- agement, and quality systems at all stages of the manufacturing process lifecycle. 本指南将工艺验证活动与产品生命周期概念以及现有FDA 相关指南进行了协调；这些存在的FDA指南包括FDA/ICH指南，Q8(R2)药品研发指南、Q9质量风险管理指南和Q10制药质量体系指南。尽管本指南没有重复上述指南解释的概念和This guidance aligns process validation activities with the product lifecycle concept and with existing FDA guidance.2 2 See the FDA/International Conference on Harmonisation (ICH) guidances for industry: Q8 Pharmaceutical Development, Q9 Quality Risk Management, and when finalized, Q10 Pharmaceutical Quality System (a notice of availability for the May 2007 ICH draft guidance, Q10 Pharmaceutical Quality System, published in the Federal Register on July 13, 2007 (72 FR 38604)). We update guidance documents periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page at https://www.doczj.com/doc/2b9096736.html,/cder/guidance/index.htm, the CBER guidance page at
（中英对照）美国FDA 分析方法验证指南
目 录 1.绪论 (4) II.背景 (5) III.分析方法的类型 (7) A. 法定分析方法 (7) B. 替代分析方法 (7) C. 稳定性指示分析 (8) IV 标准品 (8) A．标准品的类型 (8) B．分析报告单 (9) C．标准品的界定 (9) V．IND中的分析方法验证 (11) VI．NDA，ANDA，BLA和PLA中分析方法的内容和格式 (12) A．基本方法 (12) B．取样 (12) C．仪器和仪器参数 (12) D．试剂 (13) E．系统适应性实验 (13) F．标准品的制备 (14) H．操作过程 (14) J．计算 (14) K.结果报告 (14) VII.NDA，ANDA，BLA和PLA中的分析方法验证 (16) A．非药典分析方法 (16) 1)验证项目 (16) 2)其它分析方法验证信息 (17) a.耐用性 (18) b.强降解实验 (19) c.仪器输出/原始资料 (19)
3)各类检测的推荐验证项目 (21) B.药典分析方法 (24) VIII.统计分析 (25) A．基本原则 (25) B.对比研究 (25) C.统计 (25) IX．再验证 (26) X．分析方法验证资料：内容和数据处理 (27) A．分析方法验证资料 (27) B.样品的选择和运输 (29) C.各方职责 (30) XI．方法学 (32) A.高效液相色谱(HPLC) (32) B.气相色谱(GC) (35) C.分光光度法，光谱法和相关的物理方法 (37) D.毛细管电泳(CE) (37) E.旋光度 (39) F.粒径分析相关的分析方法 (40) G.溶出度 (41) H.其它仪器分析方法 (43) 附录A NDA, ANDA, BLA 和PLA申请的内容 (44) 附录B 析方法验证的问题和延误 (45) 参考文献 (46) 术语表 (48)
第三篇检验方法和清洁验证、无菌保证 第一章检验方法验证 第一节概述 一、引言 药品的生产过程中，原料、中间体、成品均需进行检验，检验结果既是过程受控的依据， 也是评价产品质量的重要依据，检验结果应具有准确可靠。而检验方法的验证为检验结果的 准确及可靠提供了有力保障。 国内外在检验方法的验证方面已有了许多法规、规定。如美国食品药品管理局 (Food and Drug Administration，简称FDA)1994 年11 月公布了《色谱方法的验证》(Validation of Chromatographic Methods)；1987 年2 月公布新品注册相关的《送样及上报检验方法验证资料 指南》)(Guidance for Submitting Samples and Analytical Data for Methods Validation)；人用药品 注册技术要求国际互认协会(the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use，简称 ICH)1995 年3 月颁布了 《分析方法的验证》》(Text on Validation of Analytical Procedures)，规定了需进行验证的方法的 种类和应考察的项目，还对分析方法、专属性、准确度、精密度、重现性作出明确定义，从 而统一了各国药典和法规对这些术语的解释；作为对《分析方法的验证》的补充、扩展，ICH
于1996 年11 月颁了《分析方法的验证：方法学》 (Validation of Analytical Procedures．Methodology)；美国药典第24 版 <1225>规定了《药典方法的验证)) (Validation of Compendial Methods)；中国药典 2000 版附录ⅩⅨA 规定了《药品质量标准分析方法验证》。 这些法规、规定从不同方面对检验方法的验证作了规定，它们是实施检验方法验证的重要依 据。本章将着重讨论检验方法验证的基本内容，并以示例形式介绍验证的基本实践，以使本 章的内容具有可操作性。 方法验证有以下几个先决条件，在进行方法验证以前，必须逐条进行检查［1］。 (1) 仪器已经过校正且在有效期内。 (2) 人员人员应经过充分的培训，熟悉方法及所使用的仪器。 (3) 参照品参照品的来源一般有 3 个：购自法定机构(如中国生物制品检定所)的法定参 照品；购自可靠的供应商，如Sigma，Merck 等；自备参照品，其纯度和性能可自行检测或 由法定检验机构检测。 (4) 材料所用材料，包括试剂、实验用容器等，均应符合试验要求，不给实验带来污 染、误差。如进行高效液相色谱分析时，所用试剂应为色谱级；检查铁盐时使用的盐酸不得 含有铁盐等。 (5) 稳定性应在开始进行方法验证前考察试验溶液和试剂的稳定性，确保在检验周期 内试验溶液和试剂是稳定的。使用自动进样器，一般是预先配制好一系列样品溶液置进样器 中，依次进样。这时要确保进样周期内样品溶液是稳定的。
目录表 I. 导言 (1) II. 背景 (2) III. 分析方法的类型 (3) A. 法定分析方法 (3) B. 可选择分析方法 (3) 3 C. 稳定性指示分析 (3) IV. 对照品 (4) A. 对照品的类型 (4) B. 分析报告单 (4) C. 对照品的界定 (4) V. IND中的分析方法验证 (6) VI. NDA, ANDA, BLA 和PLA中分析方法验证的内容和格式 (6) A. 原则 (6) B. 取样 (7) C. 仪器和仪器参数 (7) D. 试剂 (7) E. 系统适应性实验 (7) F. 对照品的制备 (7) G. 样品的制备 (8) H. 分析方法 (8) L. 计算 (8) J. 结果报告 (8) VII. NDA，ANDA,BLA和PLA中的分析方法验证 (9) A． 非法定分析方法 (9) 1．验证项目 (9) 2. 其它分析方法验证信息 (10) a. 耐用性 (11)
b. 强降解实验 (11) c. 仪器输出/原始资料 (11) 3．各类检测的建议验证项目 (13) B． 法定分析方法 (15) VIII. 统计分析 (15) A. 总则 (15) B. 比较研究 (16) C. 统计 (16) IX. 再验证 (16) X. 分析方法验证技术包：内容和过程 (17) A. 分析方法验证技术包 (17) B. 样品的选择和运输 (18) C. 各方责任 (19) XI. 方法 (20) A. 高效液相色谱(HPLC) (20) B. 气相色谱(GC) (22) C. 分光光度法，光谱学，光谱法和相关的物理方法 (23) D. 毛细管电泳 (23) E. 旋光度 (24) F. 粒径相关的分析方法 (25) G. 溶出度 (26) H. 其它仪器分析方法 (27) 附件 A：NDA，ANDA，BLA和PLA申请的内容 (28) 附件 B：分析方法验证的问题和延误 (29) 参考文献 (30) 术语表 (32) I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical
色谱方法验证审评指南 色谱方法通常用于原料、药物、药物制剂和生物体液中化合物的定性和定量。涉及的成分包括手性的或非手性的药物、过程杂质、残留溶媒、附加剂如防腐剂、分解产物、从容器和密闭包装或制造过程中带入的可提取和可过滤的杂质、植物药中的农药和代谢物等。 试验方法的目的是得到可信赖的和准确的数据，无论是用于验收、出厂、稳定性或药物动力学研究。得到的数据用于药品开发或批准后的定性和定量，试验包括原料的验收、药物和药物制剂的出厂、过程检验(In- process testing)的质量保证和失效期的建立。 方法的验证是由药品的开发者或使用者来检验其方法是否达到预期的可靠性、准确度和精密度的过程。得到的数据成为方法的验证资料的一部分交给CDER.。 方法的验证对于完成机构满足档案要求不是一次性的，开发者和使用者都应验证其方法的耐用度或耐久性（ruggedness or robustness.），其他的分析者、用其它相当的仪器，在其它的日期或地点，在药品生产期限(有效期)全过程，方法都应能够重现。如果产生数据的方法是可靠的，那么所得到的验收、出厂、稳定性或药物动力学的数据就是可信赖的。验证的过程和方法的设计应在开发过程中重要的数据产生之前，如果方法改变了，还应该再验证。 . 色谱类型 色谱是一种技术，通过该技术，样品中的组分载入液相或气相中，通过在固定相上由吸附—解吸附来完成。 A. 高效液相色谱 (HPLC) HPLC分离是基于在样品在流动相液体和固定相之间的不同分配。一般地说HPLC大体分为以下几种(未考虑其重要性顺序) 1. 手性液相色谱 2. 离子交换色谱 3. 离子对/亲和色谱 4. 正相色谱 5. 反相色谱 6. 分子排阻色谱 1. 手性液相色谱 分离光学异构体可在手性固定相上，用衍生化试剂或在非手性固定相上用流动相添加剂形成非对对映体来实现。用作杂质试验方法时，如果光学异构体杂质在光学异构体药物之前洗脱，要增加灵敏度。 2. 离子交换色谱 分离基于荷电功能团，样品负离子(X - )为阴离子，样品正离子((X + )为阳离子，一般用pH程序洗脱。 3. 离子对/亲和色谱 分离基于与目标样品的专一的化学相互作用。更普遍的反相型用缓冲液和加入的对离子(与被分离的样品荷相反电荷)分离。分离受pH、离子强度、温度、浓度和共存的有机溶剂类型的影响。亲和色谱，一般用于大分子，使用配合体（共价结合在固体基质上的生物活性分子)，与其同类的抗原(分析介质)反应，生成可逆转的复合物，通过改变缓冲条件洗脱。 4. 正相色谱 正相色谱为用有机溶剂为流动相和极性的固定相。此时较小极性的组分比较大极性组分更快地洗脱。 5. 反相色谱 报给CDER的最通常的实验方法是反相HPLC方法，最通常用紫外检测器。 反相色谱，一种键合相的色谱技术，用水作基本溶剂，选择性也受溶剂强度、柱温和pH的影响，一般来说较大极性比较小极性组分洗脱更快。
分析方法验证指南 1、目的 本文件的目的是为分析方法验证的数据收集提供基本指南。该指南参考了USP，EEC（BP/EP）和ICH 中的分析方法验证指南，能够满足公司的产品的分析方法验证工作。 2、范围本文件中提供的定义和程序是为了促使公司质量方针的基本原则符合所有关于方法验证 的法 规要求。本指南适用于API、原料、中间体的检测和放行的分析方法，并为新药物的应用收集支持性的数据。本指南是为了规范验证为公司的产品提供一个通用和分析方法验证方案。现有的方法中的小变化不需要全面验证，如：对柱子的固定相的生产厂家变化，样品准备的变化（搅拌和超声，震摇和超声）。在实际分析中，方法验证需要提供更多的信息或细节，需要制定的特殊的方案。这个指南不包括微生物分析方法的验证。 3、参考文件 USP<1225>，法定方法的验证 ICH 指南Q2A&Q2B，分析方法验证程序。 公司关于有效数字修约原则 4、定义降解物：降解物是由于一个物质经一段时间的化学变化（经过诸如光照、温度、pH、水分，经与容器发生反应）产生，也叫降解产物或分解产物。大剂量原料药：原料药在产品中的最大剂量大于2g/天。定量限（LOQ）：指试样中的被分析物能够被定量测定的最低值，其测定结果应具有一定的准确度和精密度。线性：在设计的测定范围内，检测结果与供试品中被分析物的浓度直接呈线性关系的程度。通常相关系数（R）在回归线上有一定的斜率（m）。小剂量原料药：原料药的在产品中的最大剂量小于或等于2g/天。 测量精密度（ICH-重复性）：多次测定同一样品时的重现性（%RSD）。在HPLC 或GC 中也叫进样精密度。方法精密度：同一样品或标准品（若有时）准备多份供试品在测定含量时的重现性（%RSD）。回收精密度：测定同一标准时对准确度和线性的评估。也叫水平精密度。报告限度（RL）：低于某一数值的时候报告中就不体现。报告限度一般大于或等于定量限。再现性 （ICH-中间精密度）：在不同检测条件下对样品检测结果的重现性。（不同的实验室、分析人员、仪器、试剂、分析时间、日期等） 5、指南A、总则因为在对产品的物理性质的评估时，分析方法会因测定的准确性和精密性而有所不同，故验证的可接受标准也不同于一般的检测方法。一个可接受的标准可能需要根据方法的特性和检测的指标
CIPAC 方法验证指南 1. 范围 本指南适用于农药制剂的化学分析方法，也可以用于原药的化学分析方法验证；不适用于残留物和痕量分析方法。 2. 方法验证 2.1 线性 线性范围至少要包括目标浓度的±20%。至少要配制三个浓度，每个浓度重复检测。在给出曲线的同时，要报告斜率、截距和相关系数。 曲线要能够清楚地显示出响应值和目标物浓度的相互关系，结果不能有明显非线性特征，也就是说在目标值±20%的范围内相关系数r 应该大于0.99。 2.2 精确性 至少要进行5次重复测试，计算RSD （%）。 可以用Q 检验法或者格鲁布斯（Grubbs ）方法来确定可疑值的取舍。但是如果在测试过程中舍弃过数据，那么一定要进行说明为什么要舍弃这些数据。 符合下列条件的精确性结果是可以接受的： RSD < RSDr RSDr = 2 (1-0.5lgC) x 0.67 其中：C 是用小数表示的样品含量 2.3 准确性 准确性的验证至少要准备4个样品进行测试。实验室制备的样品中含量已知。实验结果可以通过t 方法或其它统计方法进行评估。 t 方法评估步骤如下： ● 计算平均回收率和标准偏差 ● 这个相对偏差和此方法预计的相对标准偏差用F 检验法进行判断，结果应显示实验 所得的相对偏差和预计相对标准偏差没有显著差异。 ● F 检验做完合格后，再做t 检验。按照如下公式计算t 值 t = n s u x 其中：x = 样品测试的平均值
u = 理论值 n = 样品数量 s = 标准偏差 ● 根据自由度（n-1）和置信区间（一般是95%）查t 值表。计算所得的t 值应小于查表所得的t 值。 ● t 方法也可以用来确定平均回收率的置信范围 u = x ± t ??? ? ??n s 计算：平均回收率 = 检测值的平均值*100/理论含量%
FDA药品及生物制品的分析方法和方法验证指导原则草案 前言 本指导原则草案，定稿后，将代表美国食品和药物管理局（FDA）目前关于这个话题目前的想法。它不会创造或赋予或任何人的任何权利，不约束FDA 或公众。您可以使用另一种方法，如果该方法符合适用的法律和法规的要求。如果你想讨论一个替代方法，请与FDA工作人员负责实施本指南。如果你不能确定适当的FDA 工作人员，请拨打本指南的标题页上所列的电话号码。 介绍： 该修订指南草案将取代行业2000 年的指导分析方法和方法验证草案，并最终确定后，也将取代1987 年美国FDA 行业指南《提交的样品和分析数据的方法验证》。该草案提供了有关申请人如何提交分析程序和方法验证数据来支持说明原料药和制剂具有强度、质量、纯度和效用的文件。它会帮你收集信息和现有数据来支持你的分析方法。该指导原则适用于原料药和制剂产品涵盖新药申请（NDA），简化新药申请（仿制药），生物制品许可申请（BLA），以及这些申请的补充申请。在这个修订草案指导原则也适用于原料药和制剂产品涵盖二类药物主文件（DMFs）。 该修订指南草案补充了国际协调会议（ICH）Q2（R1）指导原则《分析程序的验证：开发和验证的分析方法Q2（R1）和方法的文本。 该修订指南草案不涉及研究性新药申请（IND）方法验证，但研究者在准备研究性新药申请时应考虑该指导原则中的建议。研究性新药申请需要在研究的每个阶段有足够的信息，以确保正确鉴别性，质量，纯度，强度和/或效力。对分析方法和方法验证的信息量将随研究中不同阶段而变化。有关分析程序和需提交的阶段方法验证资料方面的指导意见的研究中，申请者可以参考FDA 的指导原则《Ⅰ期研究药物的IND 的内容和格式，包括性状、疗效和生物技术衍生产品》。 一般考虑在第三阶段的研究进行之前，分析方法和分析方法验证（例如，生物测定）是在FDA 行业指导原则《人类药物和生物制剂、化学、制造、控制信息会议》。 该修订指南草案不涉及生物和免疫化学检测的表征和许多原料药和制剂产 品质量控制的具体方法验证的建议。例如，一些基于动物模型的生物测定，并且免疫原性评估或其它免疫测定具有独特的特征，应开发和验证过程中予以考虑。 此外，需要对现有的分析方法再验证时可能需要在制造过程中产品的生命周期的变化予以考虑。有关适当的验证方法的分析程序或者提交本指南中未提及的信息的问题，您应该向用FDA 产品质量评审人员咨询。 如果您选择了与本指导草案中不同的方式，我们建议您在提交申请前与相应的FDA 产品质量评审人员讨论。 FDA 的指南文件，包括本指导原则，不具有法律强制性的责任。相反，指南描述的是FDA 对某个主题目前的想法，并应仅作为建议，除非有明确的法律或法规要求的引用。使用“应该”这个词在FDA 指南意味着什么建议或推荐，但不是必需的。 II. BACKGROUND背景 每个NDA 和ANDA 都必需包括必要的分析程序，以确保原料药和制剂的鉴别，强度，质量，纯度和效果.每个BLA 必须包括完整的制造方法描述，包括能够确保产品身份、质量、安全、纯度和有效的分析程序。数据必须能够用于建立满足精度和可靠性标准的分析方法并适合与拟定目的.对于BLAs 及补充补充，分析方法和方法验证是许可证申请或补充申请必须提交的一部分，并通过美国FDA质量评审小组进行评估。 分析方法和验证资料应当按照ICH M2 eCTD 的相应部分提交。 当一个分析程序作为NDA，ANDA 或者BLA 的一部分被批准时，它就变成了FDA 获批药品