FDA行业指南:药品和生物制品分析方法验证(3)

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VIII. LIFE CYCLE MANAGEMENT OF ANALYTICAL PROCEDURES 分析方法的生命周期管理


Once an analytical 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 regular 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 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 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 product quality. Applicants should periodically evaluate the appropriateness of a product’s 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 life 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 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 combination 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 manufacturing 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 performance (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 analytical 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 comparability 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 determining equivalence of two test methods, appropriate literature or text should be consulted[19].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 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 theprocedure[20].After approval, for an NDA or ANDA, 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 procedure described in the approved application, must be documented in the next annual report[21].

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 procedure 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 modification 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 procedures requires FDA approval during application review or in a postapproval supplement[22].

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 use 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 to 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/杂质是因为新的方法灵敏度或选择性增加的结果,而不是工艺杂质变化的结果。


If the procedure has stability-indicating properties:

如果分析方法具有稳定性指示特性:

?   Appropriate samples should be included that allow a comparison of the ability ofthe new and original method to detect relevant product variants and degradation species.

?   应包括适当的样品,比较新的方法和原始方法检出相关产品变化和降解物的能力

?   The number of batches analyzed for comparison should provide sufficient statistical power.

?   对比时所分析的批次数应能提供足够的统计功效

?   Equivalence, non-inferiority, or superiority studies should be performed with appropriate statistical methods to demonstrate that the new or revised methods performance is comparable or better than the original method[23].

?   要采用适当的统计学方法来实施等同性、不低于或优越性研究,来证明新方法或修订过的方法的性能等同或优于原始方法

?   The statistical analyses performed to compare product testing should be identified.

?   要识别出用于比较产品检测结果的统计学分析方法

?   All bias or differences between analytical procedures seen with comparative results should be discussed with an explanation, as appropriate.

?   适当时,分析方法间所有观察到的偏差或差异以及对比结果均应进行讨论,并提出解释


2. Analytical Methods Transfer Studies 分析方法转移研究

Analytical method transfer is typically managed under a transfer protocol that details the parameters to be evaluated in addition to the predetermined acceptance criteria that will be applied to the results. Transfer studies usually involve two or more laboratories or sites (originating lab and receiving labs) executing the preapproved transfer protocol. A sufficient number of representative test articles (e.g., same lot(s) of drug substance or drug product) are used by the originating and receiving laboratories. The comparative studies are performed to evaluate accuracy and precision, especially with regard to assessment of inter laboratory variability. In cases where the transferred analytical procedure is also a stability-indicating method, forced degradation samples or samples containing pertinent product-related impurities should be analyzed at both sites. The USP General Chapter <1224>Transfer of Analytical Procedures provides additional guidance on this topic.

分析方法转移一般要使用转移方案进行管理,在方案中详细写明要评估的参数,以及适用于结果的预定可接受标准。转移研究通常包括两个或更多化验室或场所(转出化验室和接收化验室),由其实施预先批准的转移方案。转出化验室和接收化验室使用具有代表性的足够数量的测试物(例如,相同批号的原料药或制剂)。实施对比研究是为了评估准确度和精密度,特别是实验室之间的差异。如果所转移的分析方法也是稳定性指示性方法,则应在两个化验室均对强降解样品或含有所要检测的相关杂质的样品进行检测。USP通论<1224>“分析方法转移”提供了关于此问题的更多指南。


C. Reporting Postmarketing Changes to an Approved NDA, ANDA, or BLA 已批准的NDA、ANDA或BLA的上市后变更报告

Postmarketing changes to analytical procedures must be reported to the FDA in compliance with 21 CFR 314.70 or 21 CFR 601.12[24].Additional information on the appropriate reporting category for various kinds of postapproval changes for NDAs and ANDAs is provided in the FDA guidance for industry on Changes to an Approved NDA or ANDA and Changes to an Approved NDA or ANDA; Specifications – Use of Enforcement Discretion for CompendialChanges. Similar information on postapproval changes to BLAs regulated by CDER and CBERis provided in the FDA guidance Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products.

上市后对分析方法的变更必须根据 21 CFR 314.70 或 21 CFR 601.12向FDA报告。在FDA行业指南“已批准NDA或ANDA变更”和“已批准NDA或ANDA变更:质量标准---药典变更自行裁定实施”中给出了NDA和ANDA各种批准后变更的报告分类信息。由CDER和CBER管理的BLA上市后变更的类似信息已在FDA指南“特定生物技术和特定合成生物药品已批准申报的变更”中给出。


IX. FDA METHODS VERIFICATION /FDA方法确认

Part of the approval process for NDAs and ANDAs may include FDA laboratory assessment to determine whether the analytical procedures are acceptable for quality control and suitable for regulatory purposes[25].If a laboratory assessment will be conducted, the FDA laboratory will send you a request that will detail what samples and supplies to send to the FDA laboratory. These could include product samples, standards, critical reagents, material safety data sheets, and supplies. Laboratory results and comments will be forwarded from the FDA laboratory to the product quality reviewer.

有些NDA和ANDA的批准过程会包括FDA实验室评估决定一个分析方法是否被接受作为质量控制用,是否适合于法规目的。如果实施了化验室评估,则FDA实验室会向你发出一个要求,在其中详细说明要呈送给FDA实验室的样品和备用样品。其中可能包括产品样品、对照品、关键的试剂、物料安全数据、以及备用样品。实验室结果和建议会从FDA实验室送至产品质量审核人员那里。


For certain biological products, samples representative of the product for licensure along with summaries of results of tests performed on the lots represented by these samples should be submitted with the BLA[26].The FDA laboratory verifies the performance of the methods and the results you submit. During a pre-BLA meeting or after submission of the BLA, the FDA laboratory can send you a request to provide standards, controls, reagents, material safety data sheets, and supplies.

对于特定的生物药品,则要和BLA一起提交具有代表性的产品样品,以及对这些批次样品检验的结果汇总。FDA实验室会核实这些方法的性能以及你提交的结果。在BLA准备提交时的会议中,或在BLA提交之后,FDA实验室可能会发给你一个要求,要求提供对照品、受控样品、试剂、MSDS和备用样品。


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