美国FDA分析方法验证指南中英文对照（五）

VIII. STATISTICAL ANALYSIS

A. General

Methods validation includes an assessment of the adequacy of the analytical procedure. Statistical analysis (e.g., linear regression analysis, relative standard deviation) of methods validation data is often used to demonstrate the validity of the method. The statistical procedures for the analysis of the validation data should be determined prior to the start of any validation study. The procedure followed, including the amount of data to collect and the criteria used in determining the acceptability of the analytical procedure, should be specified.

The raw methods validation data and statistical procedures used to analyze the raw data should be provided and discussed in the sections on analytical procedures and controls. All statistical procedures used in the analysis of the data should be based on sound principles and be suitable for evaluating the dataset.

VIII. 统计分析

A．基本原则

(比如：线性回归分析，相对标准偏差)以说明方法的正确性。在开始分析方法验证之前，应当就要确定用于验证资料分析的统计方法。还应当要规定所要遵循的程序，包括所需采集的数据量和确定分析方法合适性的合格标准。

应当要在分析方法和控制章节中提供和讨论分析方法验证原始资料和所用的统计方法。所有用于数据分析的统计程序都应当是科学的，并适用于评估该数据群的。


B. Comparative Studies

Comparative studies are performed to evaluate intermediate precision (e.g., different equipment, analysts, days). Comparative studies are also used to evaluate between laboratory variability (i.e., reproducibility) when an analytical procedure is used in more than one laboratory or to compare and evaluate the precision and accuracy of two analytical procedures (e.g., regulatory analytical procedure and an alternative analytical procedure). When comparative studies are performed, homogeneous samples from the same batch should be used, if feasible. Comparative results should be statistically analyzed and discussed and any bias explained.

B:对比研究

开展对比研究以评估中间精密度(如，不同设备，不同分析员，不同天等)。当一分析方法会在多个实验室应用时，或要比较和评估两个分析方法(比如，法定分析方法和替代分析方法)的精密度和准确度时，也会进行对比研究以评估实验室间的差异(也就是，重现性)。在进行对比研究时，应当要尽可能地使用同一批号的均匀样品。需对对比研究的结果进行统计分析和讨论，并对偏差进行解释。


C. Statistics

For information on statistical techniques used in making comparisons, as well as other general information on the interpretation and treatment of analytical data, appropriate literature or texts should be consulted (see references) .

C:统计

关于用于对比分析的统计技术资料，和用于分析数据处理和解析的其它基本资料，可参见相关的文献(见参考文献)。



IX. REVALIDATION

When sponsors make changes in the analytical procedure, drug substance (e.g., route of synthesis), or drug product (e.g., composition), the changes may necessitate revalidation of the analytical procedures. Revalidation should be performed to ensure that the analytical procedure maintains its characteristics (e.g., specificity) and to demonstrate that the analytical procedure continues to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, and the bioavailability of the drug product. The degree of revalidation depends on the nature of the change. When a different regulatory analytical procedure is substituted (e.g., HPLC for titration), the new procedure should be validated (see section VII).

IX． 再验证

当发起人对分析方法，原料药(比如，合成路线)，或制剂(比如，组分)作了更改的话，则需要对分析方法进行重验证。进行重验证是为了确保该分析方法仍然保持其特性(比如，专属性)，并论证说明该分析方法仍然能确保原料药和制剂的同一性，浓度/剂量，质量，纯度和功效，及制剂的生物利用度。重验证的程序取决于该变更的性质。当使用了另一个法定分析程序的话(比如，用HPLC代替了滴定法)，则新的分析方法也需要验证(见第VII章)。

If during each use an analytical procedure can meet the established system suitability requirements only with repeated adjustments to the operating conditions stated in the analytical procedure, the analytical procedure should be reevaluated, amended, and revalidated, as appropriate.

FDA intends to provide guidance in the future on postapproval changes in analytical procedures.

如果在每次使用时，都必须要对分析方法中所述的操作条件进行反复调整，才能使其符合系统适应性要求的话，则该分析方法需要适当进行重新评估，修正和重验证。



X. METHODS VALIDATION PACKAGE: CONTENTS AND PROCESSING

Part of the methods validation process may include FDA laboratory analysis to demonstrate that an analytical procedure is reproducible by laboratory testing. A methods validation package (see X.A) and samples (see X.B) will be needed for this process.

X． 分析方法验证资料：内容和数据处理

FDA实验室的分析以论证说明某一分析方法是能被重现的。在这个过程中将会需要分析方法验证资料(见X.A)和样品(见X.B)。


A. Methods Validation Package

The methods validation package will usually include information copied from pertinent sections of the application. To aid the review chemist, these copies should retain the original pagination of the application sections. For ANDA and NDA products, the archival copy and extra copies of the methods validation packages should be submitted with the application. For ANDAs and related supplemental applications, one archival copy and two extra copies of the methods validation package should be submitted. For NDAs and related supplemental applications, one archival copy and three extra copies should be submitted. For BLAs and PLAs, a separate methods validation package need not be submitted. Information similar to that specified here should be included in the BLA or PLA submission.

A．分析方法验证资料

分析方法验证资料通常会包括申请中的相关章节。为了便于评审化学家进行评审，这些资料应当要和其在原来申请中一样，包括内容和形式(archival copy)和其它副本。对于仿制药申请和其相关的补充申请，需要提交一份分析方法验证资料的存档副本(archival copy)和另外两份副本。对于新药申请及其相关补充申请，需要提交一份分析方法验证资料的存档副本(archival copy)和另外三份副本。对于BLA和PLA，则不需要单独递交分析方法验证资料。类似的资料应当摆在BLA和PLA申请中。

The methods validation package should include:

1. Tabular List of All Samples to Be Submitted

The list should include the lot number, identity (with chemical name and structure
where required for clarity), package type and size, date of manufacture, and quantity of the samples.

2. Analytical Procedures

A detailed description of each of the analytical procedures listed in the specifications should be submitted. The description should be sufficient to allow the FDA laboratory analysts to perform. the analytical procedure (see section VI).

3. Validation Data

Appropriate validation data to support the analytical procedures should be submitted. Individual values as well as summary tables should be provided. Representative instrument output and raw data and information regarding stress studies should be included (see section VII).

4. Results

The results obtained by the applicant for the submitted samples should be provided. Alternatively, COAs could be submitted. The dates of analysis should be stated.

5. Composition

The components and composition of the drug product should be provided.

6. Specifications

The specifications for the drug substance and the drug product should be included.

7. Material Safety Data Sheets

The applicant should include material safety data sheets (MSDSs) for all samples, standards, and reagents (29 CFR 1910.1200(g)). As appropriate, MSDSs should be provided for other materials used in the analytical procedures listed in the methods validation package. In the case of toxic or hazardous materials, MSDSs should be posted on the outside of the package to facilitate safe handling.

分析方法验证资料应当要包括：

1．所需递交样品的列表清单

(化学名和结构式)，包装类型和大小，生产日期，样品量。

2．分析方法

FDA实验室分析人员根据这个描述进行操作。(见第VI章)

3．验证资料

(见第VII章)。

4．结果

应当要提供申请者对所提供样品所做分析的分析结果，或者提供其相应的分析报告单。需说明分析日期。

5．组分

需说明制剂的组分和组成。

6．质量标准

需提供原料药和制剂的质量标准。

7．安全数据表

申请者应当要提供所有样品，标准品和试剂的安全数据表(MSDS)(29CFR 1910.1200(g))。还要适当提供分析方法验证中所列各分析方法所有的其它物料的安全数据表(MSDS)。如果是毒性物料或危险性物料，则在外包装上要贴上MSDS，以便于安全处理。



B. Selection and Shipment of Samples

On request from CDER, an NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks, so that the suitability of the applicant=s drug substance and drug product analytical procedures can be evaluated by FDA laboratories (21 CFR 314.50(e) and 314.94(a)(10)). For BLAs and PLAs, representative samples of the product must be submitted, and summaries of the results of tests performed on the lots represented by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi)).

B：样品的选择和运输

NDA或ANDA申请者必须要根据药品评审和研究中心(CDER)的要求递交制剂，原料药，非药典对照品和空白，以使FDA实验室可以评估申请者所用制剂和原料药分析方法的适用性。(21CFR 314.50(e) 和314.94(a)(10))。对于BLA和PLA，需提交产品的代表性样品，并提供所提交样品批次的检测结果。(21CFR601.2(a)和601.2(c)(1)(vi)).

For CDER products, the number of sets of samples that should be submitted for methods validation will be identified in the instructions forwarded to the applicant by the FDA laboratory. In general, the quantity of samples in each set should be double the amount needed to carry out the testing as performed by the applicant. Along with the drug substance and the drug product samples, the applicant should submit internal standards, non-USP reference standards, samples of impurities, degradation products, and unusual reagents. A set of samples will be shipped to each assigned laboratory.

对于CDER产品，FDA实验室会告诉申请者所需递交样品的量。一般来说，样品量应当是实验用量的两倍。除了递交原料药和制剂样品之外，申请者还应当要递交内部对照品，非美国药典对照品，杂质样品，降解物和非常用试剂。应当要向每个指定的实验室寄送一系列样品。

For biological products, CBER should be consulted on the submission of samples and supporting materials.

Unless specified differently by the reviewer, samples from any batch, preferably samples from an aged batch, may be selected for NDAs and NDA supplemental applications. The submitted drug product samples should be from a batch made with the proposed market formulation. For ANDAs and appropriate supplements, a sample of the finished product from a batch being used to support approval of the submission should be used. If a sample is selected from a batch not described in the application, an amendment containing a copy of the batch record and certificate of analysis should be provided to the ANDA. For supplements that do not require submission and review of an exhibit batch record and associated data, any commercial batch may be submitted. For biological products, samples from several consecutively manufactured batches should be submitted.

CBER咨询关于样品和支持资料的递交。

除非评审官另有说明，任一批次的样品，最好是较早批次，都可以用于新药申请及其补充申请。所递交的制剂样品必须是根据拟定的上市配方生产的。对于仿制药申请及其相关的补充，应当要提交用于支持申请批准的制剂批次的样品。如果样品是来自于一申请中未提及的批次的话，则在ANDA中还应当要补充一份批记录和分析报告单的复印件。对于不需要递交申请和不需要审阅批记录及相关资料的补充，可递交任一商业批次的样品。对于生物制品，应当要提交连续几个生产批次的样品。

The drug product should be supplied in its original packaging. Bulk substances (e.g., drug substances, impurities, excipients) should be stored in opaque nonreactive containers. To prevent breakage during shipping, the samples should be adequately packaged in a sturdy container. Samples shipped from outside the United States should contain the appropriate customs forms to reduce delay in delivery.

If special storage precautions (e.g., freezing, use of an inert gas blanket) are required to protect sample integrity, arrangements should be made in advance with the validating laboratory for scheduled direct delivery. If a sample is toxic or potentially hazardous, the container should be prominently labeled with an appropriate warning and precautionary handling instructions.

应当要以其原包装提供制剂样品。而像原料药，杂质，赋形剂等，则应当要保存在不透明的惰性容器中。为了防止在运输过程中泄露，样品应当要装在耐用的容器中。如果是美国国外的样品，则应当要有适当的海关单据，以减少耽搁。

如果样品需要特殊的储存条件(比如，冷冻，惰性气体保护)，则要事先和验证实验室联系以安排直接递送。如果是毒性样品或危险性样品，则在容器的显著位置标明警示标志和预防措施。


C. Responsibilities of the Various Parties

1. Applicant

In the sections of the application on analytical procedures and controls, the applicant should provide a name, address, telephone number, and facsimile number so that samples can be requested. If this information is not provided, the contact person and address listed in the NDA, ANDA, BLA, or PLA submission will be used.

The methods validation packages should be compiled and submitted with the NDA or ANDA submission. For BLAs and PLAs, a separate methods validation package need not be submitted. When an FDA laboratory contacts the applicant for samples, the applicant should provide FDA laboratories with the samples within 10 working days. With the exception of sample delivery arrangements, all communications concerning validation at the FDA laboratories should be made through or with the knowledge of the review chemist for CDER applications, or the BLA/PLA committee chair for CBER applications.

C：各方职责

1.申请人

FDA可以向其发送提交样品的要求。如果没有提供这些信息的话，则会用NDA，ANDA，BLA或PLA申请中所写地址和联系人信息进行联系。

NDA或ANDA资料一起编写和递交。对于BLA和PLA，则不需要递交单独的分析方法验证资料。

一旦FDA实验室要求申请人提交样品的话，申请人应当要在10个工作日将样品提供给FDA实验室。除了样品运送之外，所有关于在FDA实验室进行验证的交流工作都要当要让CDER申请的化学评审官知道，如果是CBER申请，则要让BLA/PLA委员会主席知道。

2. Review Chemist

The review chemist will review the application to determine that the analytical procedures are adequate to ensure the identity, strength, quality, purity, and potency of the drug substance and/or drug product. Any changes in the methods resulting from the review of the application may require resubmission of the methods validation package. The review chemist, in coordination with the appropriate FDA laboratories, will decide which analytical procedures are to be validated. Comments from the FDA laboratories, if any, will be forwarded by the review chemist to the applicant on completion of the studies by the laboratories.

2.化学评审官

化学评审官负责审核分析方法验证报告（包括鉴别，浓度/剂量，质量，纯度和功效。对申请进行评审后，如要对分析方法作必要修改的话，则需要重新递交分析方法验证资料。化学评审官会和相关的FDA实验室进行讨论，确定需要对哪个分析方法进行验证。化学评审官会将FDA实验室对所做研究的意见转给申请人。

3. FDA Laboratory

An FDA laboratory will contact applicants with instructions on the submission of samples and the addresses to which samples should be mailed. The laboratory will test the samples according to the submitted analytical procedures to determine whether the analytical procedures are acceptable for quality control and suitable for regulatory purposes. Results and comments will be forwarded to the review chemist on completion of the studies.

4. Investigator

The investigator inspects the analytical laboratory testing sites where the release and stability testing are performed to ensure that the analytical procedures are performed in compliance with CGMP/GLP.

3.FDA实验室

FDA实验室会和申请者联系，告知样品递交程序和注意事项及邮寄地址。FDA实验室会所递交的分析方法对样品进行检测，以确定该分析方法是否适用于质量控制，并符合法规要求。在完成研究之后，FDA实验室会将结果和意见转给化学评审官。

4.检查官

检查官会对进行放行检测和稳定性实验的分析实验室进行检查，以确保所做的分析检测能符合CGMP/GLP。