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蓝色部分为本版更新内容
OMCL Network of the Council of Europe
欧洲理事会OMCL网络
GENERAL DOCUMENT
通用文件
PA/PH/OMCL (13) 82 2R
VALIDATION OF ANALYTICAL PROCEDURES
检验方法验证
Full document title and reference 文件全名和参考号 | Validation of Analytical Procedures分析方法验证 PA/PH/OMCL (13) 82 2R |
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| The present document was also accepted by EA as recommendation document to be used in the context of Quality Management System audits of OMCLs OMCL质量管理体系审计 |
Date of first adoption 首版采用日期 | |
Date of original entry into force 原生效日期 | |
Date of entry into force of revised document 修订版生效日期 | |
Previous titles/other references 原标题/其它参考号 | This document replaces document PA/PH/OMCL (05) 47 DEF Former titles/references: PA/PH/OMCL (99) 37 DEF 本文件替代文件PA/PH/OMCL (05) 47 DEF 原文题目/索引号：PA/PH/OMCL (99) 37 DEF |
Custodian Organisation 责任机构 | The present document was elaborated by OMCL Network/EDQM of the Council of Europe 目前文件由OMCL网络/欧洲议会EDQM |
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VALIDATION OF ANALYTICAL PROCEDURES
GUIDELINE FOR OMCLs
OMCL分析方法验证指南
INTRODUCTION 概述
The two ICH Guidelines on “Validation of Analytical Procedures: “Definition/ Terminology and Methodology” (Q2A and Q2B) constitute a discussion of the validation characteristics that should be considered during the validation of an analytical procedure (the guideline has also been adopted for veterinary products during VICH discussion). They are primarily addressed to pharmaceutical industry indicating which validation data need to be provided in an application file. These data should demonstrate that the proposed testing and acceptance criteria are sufficiently under control to guarantee reproducible quality of the products at release and adequate control during shelf-life (stability).
两个关于分析方法验证的ICH指南“分析方法的验证”和“定义/术语和方法学”（Q2A和Q2B）包括了一个分析方法验证中应该考虑的验证特性的讨论（该指南在VICH讨论中也被应用于兽药产品），它们告诉制药企业在提交申请文件时，需要提供哪些验证数据。这些数据应证明所提交的检验项目、方法、可接受标准是受控的，足以保证产品放行质量重现性及其生命周期（稳定性）内质量充分受控。
As the circumstances under which an OMCL works are different from those of a pharmaceutical company – in most cases no routine analysis, but often responses to be made in a short period of time -, the extent of analytical validation requested before performing an analysis needs to be reconsidered. On the other hand it has in all cases to be guaranteed that the result submitted is reliable. It should also be emphasised here, that adequate reference materials are an important factor in both the performance of the validation studies and the analysis it-self. The use of widely accepted reference preparations can in certain circumstances avoid the consideration of some validation characteristics, mainly in the field of biological products: this has then to be justified on a case by case basis.
由于OMCL的工作情况与制药公司并不一样---在大多情况下，并没有常规检验，但经常需要在很短时间内做出反应，在进行分析前所要求的方法验证的程度需要再进行考虑。另一方面，在所有情况下都需要保证所呈交的结果是可靠的。在此还需要强调的是，在验证研究和分析检测中对照物质均是重要的因素，采用被广泛认可的对照品在某些特定情况下可以避免考虑某些验证特征，这主要表现在生产产品方面，这些需要个案单独判断。
The scope of this document – specifically addressed to OMCLs - is to give guidance on the extent of validation needed, depending on various circumstances i.e. objective of the analysis (e.g. screening for non compliance), amount of validation data already available (e.g. in case of a method transfer), experience or historical data already available in the individual OMCL (e.g. recovery from a complex matrix; routine use of a standard titration even if different substances are titrated), etc. This document is equally applicable to products of synthetic and of biological origin. It does not address common laboratory practice: for instance specific use of the equipment, calibration etc.
本文件的范围—尤其对于OMCL来说—是提供验证所需进行的深度的指南，它取决于不同的环境，也就是分析的目的（例如，剔除不符合者），已有验证数据的数量（例如对一个方法进行转移的情况），在单个OMCL实验室已有的历史数据和经验（例如，一个复杂矩阵的回收率，即使是对不同物质同样适用的常规标准滴定法）等等。本文件同等适用于合成产品和生化产品。本文件未对一般化验室规范提出要求，例如仪器的特定使用、校正等。
This document is a note for guidance, which provides detailed recommendations of the extent of the validation exercise dependent on the category of the analytical procedure; it should be noted that other approaches are always possible. In all cases a short description and/or justification of the approach chosen, including the methods, should be described in the internal documentation of the analysis. Validation data of validated methods (compendial, marketing authorisation dossier) should be available. Modifications from the original validated method should be justified. The same definitions as in the ICH document apply.
本文件是对指南的一个注释，其中详细说明了验证的深度取决于分析方法的类别，需要注意的是总会有一些其它方法来实现相同目的。不管怎样，对所选择方法的论述，包括方法本身，应在内部分析文件中做一个简短的描述。已验证方法（药典、上市文件）的验证数据应该保存可查，对原始的经过验证的方法进行修订需要进行论证。ICH文件中的定义在此适用。
CATEGORIES OF ANALYSIS 分析的类别
This chapter defines the different analytical situations (categories) which might occur in an OMCL and the corresponding validation characteristics which should be considered. (As a reminder the table in the annex describes in general the validation characteristics to be considered, depending on the different types of analytical procedures).
本章定义了可能发生在一个OMCL里的不同分析情况（类别），以及需要考虑的相关的验证特性。（附件表中描述了根据不同分析程序类别需要考虑的验证特性供参考）
Formal validation studies , according to the ICH requirements, has to be performed for a new developed method or when for an existing method the validation data have to be completed.
正式验证研究：根据ICH指南，对于新建方法，或已有方法需要提交完整数据时必须实施
Method transfer check (verification of suitability ) has to be done to show that under actual conditions of use in the individual laboratories the method is adequate (fit for use). This might imply for instance the carrying out of the system suitability tests (e.g. resolution in a chromatographic method), the control of the reporting threshold, the control of the completeness of a reaction step (e.g. extraction, hydrolysis reaction) before the actual determination can be performed, the verification of the precision of the method etc. So for instance the system suitability tests described in a fully validated liquid chromatography method will in all cases have to be performed, as these tests are part of the analytical procedure. This is particular true for the category ‘Transfer of a method’.
方法转移检查（适用性验证）：方法转移检查必须要进行，以表明该方法在指定的实验室内在实际使用情况下，方法可以满足使用的要求。这可能表示，例如在实际检测进行前需要实施系统适用性（例如，色谱方法分辨率），报告阀值的控制，反应步骤的结束（例如萃取、水解反应），方法精密度确认等。所以，由于有些测试是分析方法的一部分，例如一个完整的验证过的液相色谱方法里描述的系统适用性，在任何情况下都需要进行确认。对于方法转移尤其如此。
In all cases, a short note, explaining the rational for the chosen approach -depending on the complexity of the analysis required-, will have to be provided in the internal documentation of the analysis. Deviation from this guideline should be justified.
所有情况下，在内部分析文件中均需要提供一个简短的注释，以解释所选择方法的合理性（取决于所需分析的复杂程度）。不符合本指南的情况需要进行判定。
The following categories of analysis are considered: 考虑的情况为以下三类
- Transfer of a method方法转移
- Screening 筛选
- Development of a new analytical procedure 建立新方法
1. Transfer of a Method 方法转移
In this category it is assumed that a certain amount or elements of validation data for this particular analysis is already available: so no or only a few validation characteristics need to be considered. In an ideal situation, this can also be done by comparison of the results of two laboratories performed on the same sample. “No formal validation required” indicates that the respective validation characteristics have already been considered by others. However a verification of suitability under conditions of use (=method transfer check) has to be done in all cases by the OMCL.
此类中，假定该方法已经有了一定数量或因素的验证数据：所以没有或仅有少量验证特性需要考虑。在理想的状态下，可以由两个化验室对同一个样品进行测定，对结果进行比较。“不需要正式的验证”表示前验证项目已经由其它人考虑过了。当然，任何情况下，OMCL都必须进行在实际使用情况下（=方法转移检查）的方法适用性验证。
1.1. Pharmacopoeial (compendial) method.药典方法
1.1.1 Active substance活性物质
The analytical procedures described in a monograph of a pharmacopoiea are considered to be validated. In this case it should be made sure that all reference materials needed are available and the required system suitability tests are performed. Nevertheless, it should also be considered that a pharmacopoeial monograph is only considered validated (related substances test) when it is applicable to the control of the listed impurities (specific source material, see Ph Eur).
药典的专论中所述的分析方法被认为是经过验证的。这种情况下，需要确认所有的对照品都是有效的，需要进行系统适用性测试。无论如何，还需要考虑药典专论中检验方法（有关物质）的验证内容仅针对列出的杂质（已知来源物料，见欧洲药典）。
Identification:鉴别
no formal validation required; 不需要正式验证
Testing for Impurities:杂质检测
no formal validation required; 不需要正式验证
Assay:含量
no formal validation required.不需要正式验证
Note注: To fall under this category, the procedures must be described in detail, not for instance as in some cases for biologicals where there is only a general description of the method.
此类情况下，需要详细叙述检测方法，而不是象有些生物制品案例中仅有方法的概述
1.1.2 Medicinal product 药品
The pharmacopoeial monograph for a specific dosage form is a good basis for the analysis; however as in many cases there is no indication about the exact composition of the product (qualitative and quantitative composition of the excipients), it must at least be made sure that these do not interfere in the analysis of the active substance, unless addressed in the monograph.
药典中对特定剂型的专论是建立分析方法的一个很好基础，尽管如此，在许多情况下，并没有制剂产品中确切成分信息（赋形剂的定性和定量组成情况），除非专论中有说明，否则至少必须保证赋形剂对活性物质的分析不产生干扰。
- Identification:鉴别
no formal validation required;
不需要正式验证
- Testing for Impurities:杂质检测
specificity: no interference from excipients;
专属性：赋形剂无干扰
reporting threshold (at least the quant.limit)
报告阀值（最少需要定量限）
- Assay:含量
specificity,
专属性
accuracy: mainly recovery, minimum 1 determination.,
准确度：主含量回收率，最小一次测定
precision (repeatability): around the target test concentration (minimum 2 independent determinations)
精确度（重复性）：在目标浓度上下（最少2次独立测定）
linearity at three measuring points in the range around the target value.
目标值范围内三个检测点线性
1.2 Method of a manufacturer.生产商的检验方法
1.2.1: the analytical procedures have been fully validated by the company.
检验方法已由公司进行了全面验证
The same as under A.1.1. applies for both the active substance and the medicinal product:
与A.1.1项下相同：申请同时作为活性物质和药品
Identification:鉴别
no formal validation required;
不需要正式验证
Testing for Impurities:杂质检测
no formal validation required
不需要正式验证
Assay:含量
no formal validation required
不需要正式验证
1.2.2: old application file with no or insufficient validation data published.
老的申请文件中没有验证数据或验证数据不充分
This case should be notified to the authorities. For the validation characteristics to be considered please refer to 1.4, 1.5, 2.1 or 3.
此情况下应通知官方。需要考虑的验证特性参见 1.4，1.5，2.1或3。
1.3 Non compendial published method.非药典方法
The validation characteristics to be considered will always depend on the amount of validation data provided. If the method has been fully validated and data published in the literature, the same as under 1.1 applies (active substance and medicinal product). If not, the following has to be considered:
验证时需要考虑的特性总是依赖于提供验证数据的数量。如果方法已被充分验证，数据已文字化，与1.1项下应用（活性物质和药品）相同；如果不是，需要考虑下列情况
Identification:鉴别
no formal validation required不需要正式验证
Testing for Impurities:杂质检测
- specificity;
- 专属性
- reporting threshold (limit of quantitation);
- 报告阀值（定量限）
- precision/accuracy over the range.
- 指定范围的精密度/准确度
Assay:含量
- specificity: no interference from excipients
- 专属性：赋形剂无干扰
- accuracy: around the target concentration
- 准确度：目标浓度上下
- repeatability: around the target concentration (minimum 2 independent determinations)
- 重复性：目标浓度上下（最少2次独立测试）
- linearity at three measuring points in the range around the target value.
- 目标值范围内三个检测点线性
1.4 Method of a first manufacturer to be used for a product of a 2nd manufacturer.第二个生产商采用第一个生产商的检验方法
1.4.1 Active substance:活性物质
Identification:鉴别
no formal validation required
不需要正式的验证
Testing for Impurities:杂质检测
specificity (impurity profile)
专属性（杂质概况）
(if the impurity profile is different, further validation data might be necessary
如果杂质概况不同，可能需要进一步验证的数据)
Assay:含量
- no formal validation required in case of a titration;
- 如果是滴定方法则不需要正式验证
- Stability indicating: see testing for impurities.
- 稳定性考察：参见杂质检测
1.4.2 Medicinal product:药品
A prerequisite is, that we have here comparable formulations (matrix):
一个前提条件是我们有可以比较的制剂（母体）
Identification:鉴别
no formal validation required
不需要正式验证
Testing for Impurities: 杂质检测
- Specificity (interference of excipients);
- 专属性（赋形剂干扰）
- reporting threshold (quantit. limit);
- 报告阀值（定量限）
- precision/accuracy over the range .
- 涵盖范围的精密度/准确度
Assay: 含量
- specificity: no interference from excipients
- 专属性：赋形剂无干扰
- accuracy: around the target concentration
- 准确度：目标浓度上下
- repeatability: around the target concentration (minimum 2 independent determinations)
- 重复性：目标浓度上下（最少2次独立检测）
- linearity at three measuring points in the range around the target value.
- 线性：目标值上下范围内三个检测点
If the matrixes are identical see 1.2.1. 如果矩阵相同，参见1.2.1.
1.5 Method for an active substance to be used for a medicinal product. 药用活性物质检测方法
The main factor to be considered here is the influence of the matrix on the analysis including interference from the excipients.
此处主要需要考虑的矩阵对分析影响包括赋形剂的干扰
Identification: 鉴别
no formal validation required
不需要正式验证
Testing for Impurities: 杂质检测
- specificity;
- 专属性
- reporting threshold (quantit. limit);
- 报告阀值（定量限）
- precision/accuracy over the range .
- 涵盖范围的精密度/准确度
Assay:含量
- specificity: no interference from impurities and excipients
- 专属性：杂质和赋形剂不产生干扰
- accuracy: around the target concentration
- 准确度：目标浓度上下
- repeatability: around the target concentration (minimum 2 independent determinations)
- 重复性：目标浓度上下（最少2次独立测试）
- linearity at three measuring points in the range around the target value.
- 线性：目标值上下范围内三个检测点
1.6 Methods validated to reduce, refine or replace animal use (3Rs) 方法验证用来减少、精简或替代兽用（3R）
In these cases the transfer will generally involve methods validated through collaborative trials, validated by the manufacturer for a particular product, or validated and published by another laboratory. The validation characteristics to be considered will always depend on the amount of validation data provided. If the method has been fully validated and data is published in the literature or available in the MA dossier, the same as under 1.1 applies (active substance and medicinal product). Elements highlighted under 1.2 to 1.4 may also be relevant in these situations. The OMCL should identify the key parameter(s) which should ensure the precision of the test procedure. Wherever possible the same protocols and reference material should be used in all labs. When a laboratory participated in a collaborative study to develop a method, data generated during the study can also be used in the validation package for regular lab use.
在这种情形下，转移通常涉及到通过综合试验来进行验证、由特定产品的生产商进行验证、或由另一个化验室验证或公布。要考虑的验证属性取决于所提供的验证数据的量。如果方法已经过了全面验证，数据在文献上发布，或在MA文档中可以获得，则适用1.1相同条款（活性物质和制剂）。在1.2至1.4下所强调的要素在这些情形下也相关。OMCL应识别关键参数，这些关键参数应能保证检验方法的精密度。应尽可能在所有化验室使用相同的方案和对照物质。如果一个化验室专注于综合性研究来建立一个方法，则在研究期间所产生的数据也可以在常规化验室的验证包中使用。
2. Screening 筛选
2.1. Screening for non-compliance 不符合检测筛选
Screening for non-compliance means that the target of the analysis is to detect potential noncompliance of the product with the specifications. This type of screening would be performed when a rapid analysis is requested and/or when no validation data of the method are at disposal. The procedure must in all cases be documented.
不符合筛选是指分析的目的是检测出产品潜在的与质量标准不符合的项目。当需要一个快速分析方法和/或当方法的验证数据得不到时，会采用筛选。任何情况下均需要记录所用的程序。
Minimum validation required: 最小验证要求
Identification: 鉴别
specificity 专属性
Testing for Impurities: 杂质检测
- specificity;
- 专属性
- reporting threshold (quantit. limit);
- 报告阀值（定量限）
- precision over the range .
- 涵盖范围的精密度
Assay: 含量
- specificity: no interference from excipients and impurities;
- 专属性：赋形剂和杂质无干扰
- precision: around the target test concentration, (minimum 2 independent determinations)
- 专属性：目标检测浓度上下（最少2次独立测试）
If non-compliance is detected or suspected, the extent of validation has to be expanded. The follow-up of possible OOS situation has to be regulated by a standard operation procedure.
如果检出不合格或存疑，需要补充验证，可能的OOS情况需要按标准操作规程进行跟踪。
2.2. Analysis of an unknown product 未知产品的分析
In this case there is a lack of information on the product which has to be tested with respect to its label claim (presence or absence of certain substances) or to clarify other aspects asked by the Inspectorate. 如果没有需要检测的产品关于其标签申明的相关信息（特定物质是否存在），或由审计方询问的其它方面申明内容
Testing to be considered: identification, assay and perhaps purity testing. The first important step is to identify the major components of the product.
检测时要考虑：鉴别、含量以及可能需要纯度检测，第一个重要步骤是鉴别产品中的主成份
Identification: Specificity 鉴别：专属性
Assay: 含量
- specificity: no interference from the matrix
- 专属性：主峰不受干扰
- accuracy: around the target test concentration, mainly recovery (performed on 2 independent determinations)
- 纯度：在目标检测浓度左右，主成份回收率（需进行2次独立检测）
- precision: around the target test concentration, (performed on 2 independent determinations)
- 精密度：目标检测浓度左右（需进行二次独立检测）
2.3.Screening for contaminants / Analytical procedures for trace analysis污染物/痕量分析方法筛选
Mainly the situations as under 1 (transfer of a method) can be encountered; the most important validation characteristics which need to be considered are of course specificity, detection limit and quantitation limit.
主要会在第1种情况下（方法转移）时碰到，最重要的验证特点是当然需要考虑专属性、检测限和定量限。
3. Development of a new analytical procedure 新检测方法的开发
This is mainly the case where a product is tested in routine testing conditions and/or where an in-house analytical procedure is used. The analytical procedures should be validated according to the ICH guideline.
主要是当产品在一般常规检测情况和/或采用自主开发的检测方法时。检测方法需要按照ICH指南进行验证。
When tests involve animals, the advice provided by Ph.Eur., ECVAM and EMA on the reduction of animals used in validation of new procedures/test methods should be used, wherever available.
如果检测中涉及到动物，应尽可能采用欧洲药典、ECVAM和EMA关于减少在新程序/检验方法验证中使用动物的建议。
In addition validation of the new assay should not require (re)validation of an established in vivo test, even if the original test is not validated according to current validation procedures.
另外，新的含量方法的验证不应要求对已建立的体内测试进行（再）验证，即使原始检验方法并未根据现行验证程序进行验证。
Use should also be made of any data already available from own/other lab(s) and/ or the literature.
还应尽可能使用自己/其它化验室和/或文献中已有的可获得数据。
APPENDIX I TABLE 附表
Type of analytical procedure 分析方法类别 | | TESTING FOR IMPURITIES 杂质检测 | ASSAY含量 - dissolution溶出度 (measurement only仅测量) - content/potency成分/效价分析 | |
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- signifies that this characteristic is not normally evaluated表示该项通常不需要评价
+ signifies that this characteristic is normally evaluated表示该项通常需要评价
(1) In cases where reproducibility (see glossary in the ICH guideline) has been performed, intermediate precision is not needed. 如果重复性（见ICH指南术语）已验证，不需要验证中间精密度。
(2) Lack of specificity of one analytical procedure could be compensated by other supporting analytical procedure(s).一个检验方法如果缺乏专属性，可以由另一个支持性分析方法来进行补充。
(3) May be needed in some cases. 在有些个案中可能需要。
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