07fda行业指南分析方法验证中英文下Word格式文档下载.docx

1、所有用于数据分析的统计学程序和参数均应是基于合理的原则，并适合于既定评估。有几个统计学方法用于评估验证属性颇为有用，例如，变量分析（ANOVA）用于评估相关性分析R（相关因子）和R平方（判定系数或拟合优度）或线性回归用于测量线性。许多用于评估验证属性的统计学方法依赖于样本的正态性，决定是否拒绝该假设很重要。有许多技术，如柱状图、正态分布和概率图，可以用于评估所观察到的分布情况。如果观察到的数据是非正态分布的，则将数据转换成为更为正态分布或应用非正态分布（无参数）方法会更为恰当。在研发新的分析方法、评估现有分析方法、或评估测量系统性能时，应参考适当的文献或文件来获取关于统计学程序的信息，以及关于

2、分析数据诠释和处理的其它通用信息。数据分析应采用经过适当验证的软件，否则应单独确认其正确性。B. Models 模型Some analytical methods might use chemometric and/or multivariate models. When developing these models, the number of samples to provide adequate statistical power and range for model development and validation should be considered. Suitable

3、software should be used for data analysis. Model parameters should be deliberately varied to test model robustness.有些分析方法可能会使用化学计量学和/或多变量模型。如果研发的这些模型、样品数据可以提供足够的统计功效和范围用于建模，则应考虑进行验证。可以使用适当的软件进行数据分析。应该设计变化模型参数来测试模型的耐用性。VIII. LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES 分析方法的生命周期管理Once an analytical

4、 procedure （including compendial methods） is successfully validated （or verified） and implemented, the procedure should be followed during the life cycle of the product to continually assure that it remains fit for its intended purpose. Trend analysis on method performance should be performed at reg

5、ular intervals to evaluate the need to optimize the analytical procedure or to revalidate all or a part of the analytical procedure. If an analytical procedure can only meet the established system suitability requirements with repeated adjustments to the operating conditions stated in the analytical

6、 procedure, the analytical procedure should be reevaluated, revalidated, or amended, as appropriate.分析方法（包括药典方法）被成功验证（或确认）和实施后，在其产品的生命周期中应遵守该方法，以持续保证方法保持适合其既定用途。应定期对方法表现进行趋势分析，评估是否需要对分析方法进行优化，或对全面或部分分析方法进行再验证。如果一个分析方法只能通过不断调整分析方法里载明的运行参数来符合所建立的系统适用性要求，则应对该分析方法进行再评估、再验证，适当时进行修正。Over the life cycle of

7、 a product, new information and risk assessments （e.g., a better understanding of product CQAs or awareness of a new impurity） may warrant the development and validation of a new or alternative analytical method. New technologies may allow for greater understanding and/or confidence when ensuring pr

8、oduct quality. Applicants should periodically evaluate the appropriateness of a products analytical methods and consider new or alternative methods.在一个产品的整个生命周期中，新的资料和风险评估（例如，对产品CQA有更好的了解，或发现新的杂质）可能会保证一个新的或替代的分析方法的研发和验证。新技术可能会带来产品质量保证方面更多的了解和/或可信度。申报者应定期评估产品分析方法的适当性，考虑新的或可替代的方法。In anticipation of li

9、fe cycle changes in analytics, an appropriate number of retention samples should be maintained to allow for comparative studies. The number should be based on scientific principles and an assessment of risk. For complex products that are sensitive to manufacturing changes, reserve samples can be an

10、important tool to make these comparisons.预计在生命周期中会对分析方法进行变更，因此要保留适当数据量留样进行对比研究。样品数量应基于科学原理，以及风险评估。对生产工艺较为敏感的复杂产品，其留样可能是做对比研究的重要工具。The retention samples used in comparative studies should include samples that represent marketed product and, when possible, pivotal clinical trial material.用于对比研究的留样应包括代

11、表上市药品的样品，如可能，还应包括关键的临床试验物料。If a risk-based evaluation or other drivers lead to changes in an analytical procedure or replacement with a new method or if the procedure is transferred to a new testing site; revalidation, a new validation exercise, an analytical method comparability study, or a combina

12、tion of these exercises should be considered. In some cases, changes to the drug substance or drug product manufacturing process may also warrant analytical procedure revalidation. These additional studies are discussed below.如果基于风险的评估或其它原因导致对分析方法进行变更，或采取新的方法取代旧的方法，或分析方法转移至一个新的检测场所，则要考虑进行再验证、新的验证、分析

13、方法对比研究或联合进行这些工作。在有些情形下，对原料药或药品生产工艺的变更也会导致分析方法再验证。这些额外的研究讨论如下：A. Revalidation 再验证Principles described in the validation section （section VI） apply to revalidation. When a change is made to an analytical procedure （e.g., a change in a piece of equipment or reagent or because of a change in manufacturi

14、ng process or formulation）, revalidation of all or part of the analytical procedure should be considered. Analytical method revalidation may also be warranted because of manufacturing process changes, such as an alteration in the drug substance manufacturing process that could impact method performa

15、nce （e.g., route of synthesis, fermentation） or introduction of a new drug product formulation.在验证部分（第VI部分）所述原则适用于再验证。如果对一个分析方法进行了变更（例如，对设备有变更，或试剂的变更，或因为生产工艺或配方有变更），则可能要考虑对分析方法进行全部或部分再验证。在和平工艺变更时可能也需要对分析方法进行再验证，例如可能影响分析方法性能的原料药生产工艺变更（例如，合成路线、发酵）或引入新的制剂配方。You should revalidate to ensure that the anal

16、ytical procedure maintains its critical performance characteristics （e.g., specificity, precision, accuracy）. The degree of revalidation depends on the nature of the change.你要进行再验证以保证分析方法维持其关键性能指标（例如，专属性、精密度、准确性）。再验证的程度取决于变更的性质。B. Analytical Method Comparability Studies 分析方法对比研究Analytical method com

17、parability study requests are typically generated when you propose to substitute an FDA-approved analytical procedure with an alternative analytical procedure or when an analytical method is transferred from one laboratory to the other. For information on statistical procedures to use for determinin

18、g equivalence of two test methods, appropriate literature or text should be consulted19.These scenarios are discussed below.分析方法对比研究要求一般是在你提议采用一个替代分析方法取代一个FDA批准的分析方法时，或将一个分析方法从一个实验室转移至另一个实验室时产生的。用于决定两个分析方法的等同性的统计学方法信息，需要引用适当的文献或文件。这些情况讨论如下：1. Alternative Analytical Procedures 可替代的分析方法An alternative

19、analytical procedure is an analytical procedure that you use in place of the FDAapproved analytical procedure. For an NDA or ANDA, you should include any proposed alternate analytical procedures in the application. You must include a description of theprocedure20.After approval, for an NDA or ANDA,

20、or for a procedure approved in a BLA butnot included in an FDA regulation, the addition, revision, or deletion of an alternative analyticalprocedure that provides the same or increased assurance of the identity, strength, quality, purity, or potency of the material being tested as the analytical pro

21、cedure described in the approved application, must be documented in the next annual report21.替代性分析方法是你用来代替FDA已经批准的分析方法的一种分析方法。对于一个NDA或ANDA，你要将所有拟定的替代分析方法包括在申报资料中。你必须包括方法描述。在批准后，对于一个NDA或ANDA，或在BLA里批准但未包括在FDA法规里的分析方法，凡增加、修改或删除替代分析方法均要在下一次年报中记载。For biological products, in rare cases an analytical proce

22、dure may be included in an FDA regulation. If the analytical method required is described by a regulation, however, and you wantto use an alternate method, you must submit the alternate method for review and approval according to 21 CFR 610.9（a）. You must present evidence “demonstrating that the mod

23、ification will provide assurances of the safety, purity, potency, and effectiveness of the biological product equal to or greater than the assurances provided by the method or process specified in the general standards or additional standards for the biological product.” Modification of such procedu

24、res requires FDA approval during application review or in a postapproval supplement22.对于生物制品，FDA法规里可能很少包括分析方法。如果所需的分析方法在法规里进行了描述，但你想使用一个方法来替代，你必须根据21 CFR 610.9（a）提交替代方法供审核和批准。你必须提交证据“证明方法修订能确保生物制品的安全、纯度、效价和有效性等同或优于生物制品通用标准或附加标准中给出的方法或程序”。对这样程序的修订需要在申报资料评估过程中或在批准后增补中获得FDA批准。You should identify the us

25、e of the alternative analytical procedure （e.g., release, stability testing） and provide a rationale for its inclusion, validation data, and comparative data to the FDA-approved analytical procedure. You should perform an analytical method comparability study that demonstrates at a minimum that:你要分辨

26、可替代性分析方法的使用（例如，放行检测、稳定性测试），提供其内容的合理性论证、验证数据和与FDA批准的分析方法的对比数据。你要进行分析方法对比研究，至少证明： The new method coupled with any additional control measures is equivalent orsuperior to the original method for the intended purpose. 新的方法配备了另外的控制手段，在其既定用途上等同或超过原始方法 The new analytical procedure is not more susceptible t

27、o matrix effects than theoriginal procedure. 新的分析方法比原始方法更不易受到基质的影响If new process-related or product-related variants or any new impurities are discovered with the new procedure, testing on retention samples from historical batches should be performed to demonstrate that the variants/impurities detected by the new method are a result of an increase in the sensitivity or selectivity of the new procedure and not a result of a change to process-related impurities.如果采用新的检验方法能发同新的与工艺杂质或产品变化产生的杂质或所有新的杂质，则应对历史批准的留样进行检查，证实新方法检出的变化/杂质