分析方法验证程序

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1、SOP标题SOP Title分析方法验证/确认Analytical Method Validation / VerificationSOP审核和批准 SOP Review and Approval职责Responsibility签名Signature日期Date打印名Printed Name职位Title起草人Created by 分析副主任Analytical Associate Director 复核Reviewed by分析主任Analytical Director批准人Approved by 副总经理Vice President批准人Approved byQA经理QA Manager1

2、.0 目的Purpose本规程的目的是为在XXX有限公司进行的验证研究制定一个程序，包括分析方法验证过程，分析方法的确认，文件记录，审计，原始数据归档以及验证/确认文件放行。2.0 范围Scope2.1 本标准操作程序适用于XXX有限公司产品研发部门GMP分析实验室，采用色谱技术对最终成品和API（如适用）进行的所有分析方法的验证/确认。2.2 本标准操作程序也可作为XXX有限公司产品研发部门分析研发实验室，采用其他分析技术进行其他任何方法验证/确认的参考。c. 3.0 职责Responsibility3.1 分析员Analyst3.1.1 负责准备验证方案Responsible for pr

3、eparation of validation protocol3.1.2 负责进行方法验证/确认Responsible for execution of method validation / method verification3.1.3 负责准备验证报告/确认报告Responsible for preparation of method validation report / method verification report3.2 主管小组/指定人员Group In-charge / Designee3.2.1 负责复核和审批验证方案Responsible for review &

4、 approval of validation protocol3.2.2 负责方法验证/确认活动的分配、监督以及验证/确认数据的复核Responsible for allotment & monitoring of method validation / verification activity and review of validation / verification data3.2.3 负责验证报告/确认报告的复核和审批Responsible for review & approval of validation report / verification report3.3 质量

5、保证Quality Assurance 3.3.1 负责验证报告/确认方案的复核和审批Responsible for review & approval of validation report / verification protocol3.3.2 负责验证报告/确认报告的复核和审批Responsible for review & approval of validation report / verification report3.4 注册Regulatory 3.4.1 负责验证/确认方案的复核Responsible for review of validation/verifica

6、tion protocol.4.0 简写和定义Abbreviations & Definitions序号S. No.简写Abbreviations定义Definitions4.1验证（全验证）Validation(Full Validation)分析规程的验证是，通过实验室研究，确定该规程的工作特性达到了预定分析用途要求的过程。Validation of an analytical procedure is the process by which it is established, by laboratory studies, that the performance characteri

7、stics of the procedure meets the requirement for the intended analytical application. 4.2准确度Accuracy分析规程的准确度是由该规程得到的测试结果与真实值的接近程度。The accuracy of an analytical procedure is the closeness of the test result obtained by that procedure to the true value.4.3精密度Precision分析规程的精密度是当该分析规程单独分析均质样品的多个样本时，若干检验

8、结果的一致程度。The precision of an analytical procedure is the degree of agreement among individual test results when the procedure is applied repeatedly to multiple samplings of a homogenous sample.4.4专属性Specificity专属性是指是当待分析物含有预期会有的其他组分（杂质，降解产物，基质成分等），准确可靠地评估待分析物的能力。The specificity is the ability to acce

9、ss unequivocally the analyte in the presence of components that may be expected to be present (impurities, degradation product, matrix component etc).4.5检测限Detection Limit指在规定的试验条件下，样品中可被检测到的待分析物的最小数量，但是无需定量。It is the lowest amount of analyte in a sample that can be detected, but not necessarily qua

10、ntitated, under stated experimental condition.4.6定量限Quantification Limit规定试验条件下，能够以可接受的精密度和精确度进行测定的样品中待分析物的最低量。It is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under stated experimental condition.4.7线性Linearity分析方法的线性度是通过直接或者明确给出的数学转换而间接地，得

11、出与特定范围内的样品中待分析物浓度呈比例关系的测试结果的能力。The linearity of an analytical procedure is its ability to elicit test results that are directly or by well-defined mathematical transformation, proportional to the concentration of the analyte in samples with in a given range i.e. linearity of the relationship of conc

12、entration and assay measurement.4.8范围Range分析规程的范围是分析物的较高浓度和较低浓度（含）之间的区间，已经证实在此区间内，使用该规程进行测定具有适当水平的精密度、准确度、和线性。The range of an analytical procedure is the interval between upper and lower level of analyte (including these levels) that have been demonstrated to be determined with a suitable level of p

13、recision, accuracy and linearity.4.9耐用性Robustness分析规程的耐用性是规程文件中列出的操作参数在微小、故意的变更中不受影响的能力的衡量单位，并在日常使用中提供了其适用性的指标。The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate variation in procedural parameter and provide an indication of its suitab

14、ility during normal usage.4.10确认Verification对于药典测试方法确认过程是在实际使用条件下，评估对于特定的药物和/或药品，药典方法是否能够满足预期使用标1。The verification process for compendial test procedures is the assessment of whether the compendial procedure can be used for its intended purpose, under the actual conditions of use for a specified dru

15、g substance and/or drug product matrix. 4.11再验证（部分验证）Re-Validation(Partial Validation)一个分析程序重新验证的过程是重新建立分析方法，确保该分析方法在工艺、处方和方法改变的情况下，依然可以满足预期的分析应用的要求。 Re-validation of an analytical procedure is the process to re-establish the performance characteristics of the analytical procedure that can meet the

16、requirement for the intended analytical application, considering any change in process / formulation / method etc.4.12再确认Re-Verification对于药典测试方法重新确认的过程，是评估药典方法在工艺、处方和方法改变的情况下，药典测试方法依然能满足预期使用目标。Re-verification process for compendial test procedures is the re- assessment of whether the compendial proc

17、edure can be used for its intended purpose, considering any change in process / formulation / method etc.5.0 程序Procedure5.1 为了启动方法验证，相关人员或者指定人员应该起草验证方案。验证方案应该包含在验证过程中所有需要研究的参数和接受标准。相关主管或者指定人员应该对验证方案进行复核。To initiate method validation, a validation protocol should be filled by the concerned person / d

18、esignee. The validation protocol should contain all the parameters required to be studied during the validation along with acceptance criteria. Validation protocol should be checked by the concerned group head / designee. 备注：对于方法确认，不要求准备方案。Note: There is no requirement to prepare any protocol for me

19、thod verification activity.5.2 验证方案应该有QA给定的唯一编号。The validation protocol should have a unique number given to it by the quality assurance. 5.3 验证方案应该由宣泰主管或者指定人员批准后，接着由QA和注册（如适用）批准。The validation protocol should be approved at Sinotherapeutics by group-in-charge / designee followed by approval from a

20、representative of QA & Regulatory (if applicable).5.4 验证数据应该按照批准的验证方案在实验记录本（专门用于验证实验/观察）中记录。但是确认数据可以记录在方法研发记录本中，对于通用的药典测试方法不需要进行确认（如干燥失重、炽灼残渣、各种化学测试流程如酸度、简单的仪器测定如pH测定）。Validation data should be recorded in laboratory note book (dedicated for validation experiments/observations only) against each app

21、roved validation protocol. However, Verification data can be recorded in method development notebook. Verification is not required for basic compendial test procedures that are routinely performed (e.g. loss on drying, residue on ignition, various wet chemical procedures such as acid value, and simp

22、le instrumental determinations such as pH measurements). 5.5 在实验进行过程中或者实验完成后，来自方案的任何偏差应该被评估。任何来自方案的增补或变更应该在验证方案的合适章节中提到。During the execution of experimental work or after its completion, any deviation from the protocol should be justified. Any additions or changes from the protocol should be mention

23、ed under appropriate section in validation protocol.5.6 如果在之后的时间里，发现批准的方案中有一些小的差异或错误，如印刷或输入错误，主管或指定人员应该用“勘误表”说明并纠正这些错误。If at a later date minor discrepancies or errors are noticed in the approved validation protocol, such as typographical and transcriptional errors, an ERRATUM stating these errors,

24、along with the correction, should be prepared by the group in-charge/designee.5.7 在验证研究过程中，如果需要做额外的一些实验/参数，但它们不是主验证方案的一部分，就需要再产生一个补充方案（以及相应的编号），补充的实验将成为验证报告的一部分。During the course of validation studies, if any additional experiment / parameter needs to be done which is not part of the main validation

25、 protocol, an addendum protocol (and corresponding number) need to be taken, if that additional experiment will be part of validation report. 备注：补充验证方案可在最终的验证报告批准前的任何时间产生。最终的验证报告应包括来自于主验证方案和补充验证方案(如果有)的数据。Note: Addendum validation protocol can be taken any time before the approval of final validatio

26、n report. The final validation report should include the data generated against the main validation protocol and addendum protocol(s), if any.5.8 以下参数在验证活动中应该被考虑（但不限于这些）（方法验证/确认参数的选择，是基于个别技术/测试的特殊要求。但是，基于一些发现，可追加研究一些验证参数，这在任何情况下都适用）。Following parameters should be considered (but not limited to) duri

27、ng validation activity / verification (Method validation parameters can be selected based on the specific requirements for particular technique / test. However, based on the observation, additional validation parameters can be studied, wherever applicable). 编号S. No.参数Parameters验证Validation确认Verifica

28、tion再验证Re-validation再确认Re-verification早期阶段验证Validation inEarly phase1准确度AccuracyYesYesYesYesYes2方法精密度Method PrecisionYesYes / NoYesYesYes3中间精密度Intermediate PrecisionYesNoNoNoNo4专属性/强制降解Specificity / Forced degradation*YesYesYes / NoYes / NoYes / No5线性/范围Linearity / RangeYesYes / NoNoNoYes6检测限Detecti

29、on Limit (DL)Yes / NoYes / NoNoNoYes / No7定量限Quantitation Limit (QL)Yes / NoYes / NoNoNoYes / No8耐用性Robustness*YesNoNoNoNo9分析溶液稳定性Stability in analytical solutionYesYesYesYesYes* 强制降解和耐用性数据可以借用任何适用的、已有的方法开发研究的数据。Forced degradation & Robustness data can be borrowed from method development studies, wh

30、erever applicable / if available.5.9 单个验证方案中的接受标准可参考附件-A中规定的接受标准，最终在批准的验证方案中的规定接受标准将会取代SOP中规定的接受标准。The acceptance criteria specified in appendix-A can be used as reference to define the acceptance criteria in the individual validation protocol. Finally, the acceptance criteria specified in approved

31、validation protocol will supersedes the acceptance criteria specified in this standard operating procedure.5.10 在实验工作和计算完成后，分析员应该准备验证/确认报告草案。On completion of the experimental work and calculations, a draft validation report / verification report should be prepared by analyst.5.11 主管/指定人员以及之后的QA，应该从准

32、确度和完整性角度审核验证/确认报告草案和方法验证研究的原始记录。The draft validation report / verification report and the raw data of the method validation studies should be reviewed for accuracy and adequacy by group-in-charge / designee, followed by quality assurance.5.12 如果有基于质量调查结果的纠正措施，应该在给予关注，并准备验证报告。Corrective actions, if a

33、ny, based on the quality assurance findings should be taken care of and a final validation report should be prepared. 5.13 分析部门主管/指定人员应该首先审批报告，然后由QA/指定人员审批。报告应该有QA分发的独立编号。The report should be approved by Head Analytical Research (or R&D) / Designee, followed by Quality Assurance / Designee. The vali

34、dation report should have a unique number, as given by Quality Assurance.5.14 归档最终报告的原件以及原始记录，销毁验证报告草案。The final original copy of the report along with the raw data should be archived. The draft report should not be retained.5.15 如果在最终报告签署后，要求产生额外的数据而不是更新原来已经存在的数据，应进行额外的实验工作，并准备一份原报告附录，放行额外产生的数据。If

35、at a later date additional data other than the already existing data is required to be generated, additional experimental work should be carried out and an addendum to the original validation report should be prepared and issued.5.16 如果报告批准后，发现一些小的差异和错误，如印刷或输入错误（不超过5个），应准备“勘误表”说明和纠正这些错误。如果印刷或输入错误超过5

36、个或者需要对一些现存数据的报告进行修正，那就需要准备和放行修订版本的报告或者补充报告。If at a later date minor discrepancies or errors are noticed in the approved report report, such as typographical and transcriptional errors (not more than five in number), an ERRATA stating these errors, along with the correction, should be prepared. If th

37、e typographical and transcriptional errors are more than five or there is any modification in the reporting of an existing data, a revised v report or addendum report should be prepared and issued. 5.17 原报告修订的原因应该清晰地在修订的报告中阐述。修订报告和原始记录应该交给QA审计。The reason for revision of the original report should be

38、 clearly stated in the introduction of the revised report. The revised validation report and the raw data should be submitted to quality assurance for audit. 5.18 批准的报告，以及原始记录、补充文件、勘误表和升级版本，都应该归档。All the approved reports along with raw data, addendum, erratum and version, wherever applicable, should

39、 be archived.5.19 如有需要，每份报告的复印件，应该同有关的生产厂家和注册部门分享。勘误表、补充文件和修订的报告以应该同原始验证报告的接受人员分享。A copy of each of the report should be shared with the concerned manufacturing location(s) and Regulatory, if required. The errata, addendum and revised v reports should be shared with the recipients of the original re

40、port, wherever applicable.5.20 分析方法的方案和报告应该保存至产品生命周期结束再加一年。Analytical method protocol and report(s) should be preserved up to a minimum period of Product life cycle + one year.6.0 附件Appendices附件编号Appendix No.附件名称Appendix NameF-ARD-002-A推荐的验证实验和相应的接受标准指导原则Recommended guideline for validation experime

41、nts and corresponding acceptance criteria7.0 参考资料（如有）References 7.1 联邦食品,药品和化妆品法案章节501 Federal Food, Drug & Cosmetic act Section 5017.2 药品生产质量管理规范21CFR 211.194 (a), 21CFR 211.194 (a) (2)cGMP Practice Regulations 21CFR 211.194 (a), 21CFR 211.194 (a) (2) 7.3 国际药品注册协调会议: Q2 (R1)International Conference

42、 on Harmonization: Q2 (R1)7.4 美国药典普通章节 法规方法的验证USP General Chapter Validation of Compendial Procedures7.5 美国药典通则药典方法的确认USP General Chapter Verification of Compendial Procedures8.0 变更历史History of Changes版本编号 Version No.替换版本编号Superseded Version No.变更描述Change(s) Made00N/A不适用/新文件Not Applicable / New Docu

43、ment 推荐的验证实验指导原则和相应的接受标准Recommended guidelines for validation experiment and corresponding acceptance criteria含量/含量均匀度/混合均匀度方法验证指导原则Validation Guidelines for Assay / Content Uniformity / Blend Uniformity验证性能特征Validation performance Characteristics实验设计Experiment Design推荐的接受标准RecommendedAcceptance Cri

44、teria线性Linearity至少配制5份样品目标浓度附近（至少包括70-130%）的不同浓度水平的药物溶液（无基质成分）。Solution of drug substances (without matrix component) to be prepared at a minimum of 5 different concentration level of the target test concentration (covering the minimum range of 70% - 130%) of sample. 用线性溶液的响应（面积，峰高，吸收值等）对其含量（浓度），画出线

45、性曲线。报告相关系数，回归线%的截距和斜率。Plot the linearity curve from the response (area, height, absorbance etc) versus amount (concentration) of the linearity solutions. Report the correlation coefficient, % y-intercept & slope of regression line.备注Note:混合均匀度/含量均匀度可能会要求验证一个更宽的范围。Blend uniformity / content uniformit

46、y may require a wider range to validate.相关系数 0.99Correlation coefficient 0.99准确度Accuracy 配制含辅料和药物（纯度已知）的溶液，至少3个浓度水平（每个水平3份），覆盖的最小范围为样品目标测试浓度的70%-130%。计算回收率。Prepare a solution of placebo & drug substance (of known purity) at a minimum of three concentration level (each in triplicate), covering the mi

47、nimum range of 70%-130% of target test concentration and calculate the % recovery.备注Note: 混合均匀度/含量均匀度可能会要求验证一个更宽的范围。Blend uniformity / content uniformity may require a wider range to validate.每个浓度水平的每份样品的%回收率应在95 %- 105 %范围内% Recovery of individual sample at each level should be within 95 % to 105 %

48、.精密度Precision方法精密度（重复性）Method Precision (Repeatability)根据规定的流程，分别重复配制样品溶液6次（N=6），计算结果（%标示量）的%RSD 。Prepare sample solution six times (N=6) individually as per the defined procedure and calculate the % RSD from results (% against label claim)% RSD (N=6) 2 %中间精密度（耐用性）Intermediate Precision (Ruggedness)

49、根据规定的流程，在不同天，用不同的仪器，由不同的分析员，分别重复配制样品溶液6次（N=6），计算结果（%标示量）的%RSD 。Prepare sample solution six times (N=6) individually as per the defined procedure on another day using another instrument and performed by another analyst. Calculate the % RSD from results (% against label claim).% RSD (N=6) 2 % 总%RSD（方法

50、精密度和中间精密度）（N=12） 2 %The overall (method precision & intermediate precision) % RSD (N=12) 2 % 范围Range评估准确度、精密度和线性的结果，确定哪个浓度水平对于特定的方法而言，其线性、准确度和精密度是可接受的。Evaluate the results from accuracy, precision, linearity and determine the concentration levels at which the linearity, accuracy & precision are acce

51、ptable, for particular methodology. 备注Note:混合均匀度/含量均匀度可能会要求验证一个更宽的范围。Blend uniformity / content uniformity may require a wider range to validate.测试浓度的70%-130% 70%-130% of test concentration专属性Specificity评估稀释液、辅料和胶囊壳（如适用）的响应/发现。Evaluate the response / observation from diluent (blank), placebo and cap

52、sule shell (if applicable).备注Note: 跟主峰共洗脱的杂质（如果已知并存在），可能会干扰到主峰，从而影响到含量值，可以通过杂质加入法（不少于质量标准中规定的水平）证明其专属性。Co-eluting impurities (if known & available), which can be interfere with main peak that may impact the assay value, can be spiked (not less than specification level) to demonstrate the specificity

53、. 如果含量和杂质的色谱方法相似，总杂质不超过1.0%，那么不要求做该专属性实验。If chromatographic method is similar to that of impurity method and total impurities are limited to NMT 1.0%, this experiment is not required to perform.所有来源的干扰均不能不超过1%。% Interference from all these sources should not be more than 1%.主峰和杂质峰之间必须达到充分的分离（如果采用色谱方

54、法），或者跟主峰共洗脱峰的量/含量响应不应超过1%。The resolution between main analyte peak and impurity peak should be adequate (in case of chromatographic method) or the amount of any co-eluting peak / assay response should not be more than 1%.如果用色谱方法，用色谱软件测定峰纯度，报告得到的结果（纯度角，纯度阈和纯度图）。In case of chromatographic method, dete

55、rmined the peak purity with the help of chromatographic software and report the observations (purity angle, purity threshold & purity plot).专属性（继续）Specificity(Continued)强制降解实验（只适用于色谱方法），将药物、药物制剂（辅料加药物）、辅料、空白样品等暴露。每个强制降解条件（如适用）最剧烈的推荐条件如下所列：1. 1M HCl，80C，24小时2. 1M NaOH，80C，24小时3. 3% v/v 双氧水，80C，24小时4.

56、 光照破坏（120万勒克斯小时的冷白荧光灯照射和200瓦小时/平方米的紫外荧光灯照射）5. 25C 5/90% 5%，24小时6. 105C，24小时，或者80C，24小时，或者60C，真空，24小时Forced degradation study to be performed (only for chromatographic methods) using exposure on drug substances, drug product (placebo spiked with drug substances), placebo & blank sample. The maximum r

57、ecommended degradation condition followed is given below, under each degradation condition (if applicable)1. 1M Hydrochloric acid /80C/24 hours2. 1M sodium hydroxide /80C/24 hours3. 3% v/v hydrogen peroxide solution /80C/24 hours4. Light exposure (1.2 million lux hours & 200 watt hours per meter2)5.

58、 90% 5% relative humidity at 25C 5C for 24 hours6. 105C / 24 hours or 80C / 24 hours or 60 with vacuum / 24 hours期望的降解目标是在5%-20%之间。超出这些降解条件范围，也是可以接受的。The target degradation preferred to be 5% to 20%. Degradation condition outside these range are acceptable.使用色谱软件测定样品溶液中主峰的纯度，报告得到的结果（纯度角，纯度阈，和纯度图）。De

59、termine the peak purity of the main analyte peak in sample solution with the help of chromatographic software and report the observations (purity angle, purity threshold & purity plot).耐用性Robustness必须考虑对下列推荐的色谱参数（在方法仪器性能的基础上）的变异（不限于这些）进行实验，1. 最低比例的溶剂（等度/多溶剂流动相）变化 5 %（相对）2. 流动相缓冲盐/流动相（仅针对HPLC）pH值变化 0

60、.13. 色谱柱温度变化 5C4. 流速变化 10% 5. 检测波长变化 5 nm6. 更换色谱柱（首选使用不同批号的）Recommended variation (but not limited to) for the following chromatographic parameters (based on method instrument capability) should be considered to perform.1. Variation of 5 % (relative) of lowest percent solvent (isocratic / multi solv

61、ent mobile phase)2. Variation of 0.1 pH unit in mobile phase buffer / mobile phase (HPLC only)3. Variation of 5C in column oven temperature 4. Variation of 10% flow rate 5. Variation of 5 nm in detection wavelength6. Variation in column (preferred to use different lots)备注Note: 专属性实验中用到的加了已知杂质的样品溶液，被

62、推荐用于耐用性研究。Spiked sample prepared under specify experiment is recommended to use under robustness study. 每个条件（色谱的）的系统适用性接受标准须满足。System suitability criteria should met at each condition (Chromatographic).跟目标参数（紫外）相比，量/含量不应超过2%。The amount / assay should not be more than 2% at target parameters (UV).如果使用色谱方法，并有要求，使用色谱软件测定峰的纯度，报告得到的结果（纯度角，纯度阈，和纯度图）。In case of chromatographic method, determined the peak purity with the help of chromatographic software and report the observations (purity angle, purity threshold & purity plot), if required.分析溶液稳定性Stability in analytica