美國FDA分析方法驗證指南中英文對照（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. 統計分析

A．基本原則

(比如：線性回歸分析，相對標準偏差)以說明方法的正確性。在開始分析方法驗證之前，應當就要確定用于驗證資料分析的統計方法。還應當要規定所要遵循的程序，包括所需采集的數據量和確定分析方法合適性的合格標準。

應當要在分析方法和控制章節中提供和討論分析方法驗證原始資料和所用的統計方法。所有用于數據分析的統計程序都應當是科學的，并適用于評估該數據群的。


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:對比研究

開展對比研究以評估中間精密度(如，不同設備，不同分析員，不同天等)。當一分析方法會在多個實驗室應用時，或要比較和評估兩個分析方法(比如，法定分析方法和替代分析方法)的精密度和準確度時，也會進行對比研究以評估實驗室間的差異(也就是，重現性)。在進行對比研究時，應當要盡可能地使用同一批號的均勻樣品。需對對比研究的結果進行統計分析和討論，并對偏差進行解釋。


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:統計

關于用于對比分析的統計技術資料，和用于分析數據處理和解析的其它基本資料，可參見相關的文獻(見參考文獻)。



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． 再驗證

當發起人對分析方法，原料藥(比如，合成路線)，或制劑(比如，組分)作了更改的話，則需要對分析方法進行重驗證。進行重驗證是為了確保該分析方法仍然保持其特性(比如，專屬性)，并論證說明該分析方法仍然能確保原料藥和制劑的同一性，濃度/劑量，質量，純度和功效，及制劑的生物利用度。重驗證的程序取決于該變更的性質。當使用了另一個法定分析程序的話(比如，用HPLC代替了滴定法)，則新的分析方法也需要驗證(見第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.

如果在每次使用時，都必須要對分析方法中所述的操作條件進行反復調整，才能使其符合系統適應性要求的話，則該分析方法需要適當進行重新評估，修正和重驗證。



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． 分析方法驗證資料：內容和數據處理

FDA實驗室的分析以論證說明某一分析方法是能被重現的。在這個過程中將會需要分析方法驗證資料(見X.A)和樣品(見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．分析方法驗證資料

分析方法驗證資料通常會包括申請中的相關章節。為了便于評審化學家進行評審，這些資料應當要和其在原來申請中一樣，包括內容和形式(archival copy)和其它副本。對于仿制藥申請和其相關的補充申請，需要提交一份分析方法驗證資料的存檔副本(archival copy)和另外兩份副本。對于新藥申請及其相關補充申請，需要提交一份分析方法驗證資料的存檔副本(archival copy)和另外三份副本。對于BLA和PLA，則不需要單獨遞交分析方法驗證資料。類似的資料應當擺在BLA和PLA申請中。

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.

分析方法驗證資料應當要包括：

1．所需遞交樣品的列表清單

(化學名和結構式)，包裝類型和大小，生產日期，樣品量。

2．分析方法

FDA實驗室分析人員根據這個描述進行操作。(見第VI章)

3．驗證資料

(見第VII章)。

4．結果

應當要提供申請者對所提供樣品所做分析的分析結果，或者提供其相應的分析報告單。需說明分析日期。

5．組分

需說明制劑的組分和組成。

6．質量標準

需提供原料藥和制劑的質量標準。

7．安全數據表

申請者應當要提供所有樣品，標準品和試劑的安全數據表(MSDS)(29CFR 1910.1200(g))。還要適當提供分析方法驗證中所列各分析方法所有的其它物料的安全數據表(MSDS)。如果是毒性物料或危險性物料，則在外包裝上要貼上MSDS，以便于安全處理。



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：樣品的選擇和運輸

NDA或ANDA申請者必須要根據藥品評審和研究中心(CDER)的要求遞交制劑，原料藥，非藥典對照品和空白，以使FDA實驗室可以評估申請者所用制劑和原料藥分析方法的適用性。(21CFR 314.50(e) 和314.94(a)(10))。對于BLA和PLA，需提交產品的代表性樣品，并提供所提交樣品批次的檢測結果。(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.

對于CDER產品，FDA實驗室會告訴申請者所需遞交樣品的量。一般來說，樣品量應當是實驗用量的兩倍。除了遞交原料藥和制劑樣品之外，申請者還應當要遞交內部對照品，非美國藥典對照品，雜質樣品，降解物和非常用試劑。應當要向每個指定的實驗室寄送一系列樣品。

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咨詢關于樣品和支持資料的遞交。

除非評審官另有說明，任一批次的樣品，最好是較早批次，都可以用于新藥申請及其補充申請。所遞交的制劑樣品必須是根據擬定的上市配方生產的。對于仿制藥申請及其相關的補充，應當要提交用于支持申請批準的制劑批次的樣品。如果樣品是來自于一申請中未提及的批次的話，則在ANDA中還應當要補充一份批記錄和分析報告單的復印件。對于不需要遞交申請和不需要審閱批記錄及相關資料的補充，可遞交任一商業批次的樣品。對于生物制品，應當要提交連續幾個生產批次的樣品。

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.

應當要以其原包裝提供制劑樣品。而像原料藥，雜質，賦形劑等，則應當要保存在不透明的惰性容器中。為了防止在運輸過程中泄露，樣品應當要裝在耐用的容器中。如果是美國國外的樣品，則應當要有適當的海關單據，以減少耽擱。

如果樣品需要特殊的儲存條件(比如，冷凍，惰性氣體保護)，則要事先和驗證實驗室聯系以安排直接遞送。如果是毒性樣品或危險性樣品，則在容器的顯著位置標明警示標志和預防措施。


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：各方職責

1.申請人

FDA可以向其發送提交樣品的要求。如果沒有提供這些信息的話，則會用NDA，ANDA，BLA或PLA申請中所寫地址和聯系人信息進行聯系。

NDA或ANDA資料一起編寫和遞交。對于BLA和PLA，則不需要遞交單獨的分析方法驗證資料。

一旦FDA實驗室要求申請人提交樣品的話，申請人應當要在10個工作日將樣品提供給FDA實驗室。除了樣品運送之外，所有關于在FDA實驗室進行驗證的交流工作都要當要讓CDER申請的化學評審官知道，如果是CBER申請，則要讓BLA/PLA委員會主席知道。

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.化學評審官

化學評審官負責審核分析方法驗證報告（包括鑒別，濃度/劑量，質量，純度和功效。對申請進行評審后，如要對分析方法作必要修改的話，則需要重新遞交分析方法驗證資料。化學評審官會和相關的FDA實驗室進行討論，確定需要對哪個分析方法進行驗證。化學評審官會將FDA實驗室對所做研究的意見轉給申請人。

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實驗室

FDA實驗室會和申請者聯系，告知樣品遞交程序和注意事項及郵寄地址。FDA實驗室會所遞交的分析方法對樣品進行檢測，以確定該分析方法是否適用于質量控制，并符合法規要求。在完成研究之后，FDA實驗室會將結果和意見轉給化學評審官。

4.檢查官

檢查官會對進行放行檢測和穩定性實驗的分析實驗室進行檢查，以確保所做的分析檢測能符合CGMP/GLP。