I. INTRODUCTION This guidance provides recommendations to applicants on submitting analytical procedures, validation data, and samples to support the documentation of the identity, strength, quality, purity, and potency of drug substances and drug products. 1. 緒論 本指南旨在為申請者提供建議，以幫助其提交分析方法，方法驗證資料和樣品用于支持原料藥和制劑的認定，劑量，質(zhì)量，純度和效力方面的文件。

　This guidance is intended to assist applicants in assembling information, submitting samples, and presenting data to support analytical methodologies. The recommendations apply to drug substances and drug products covered in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications. 本指南旨在幫助申請者收集資料，遞交樣品并資料以支持分析方法。這些建議適用于 NDA，ANDA，BLA，PLA 及其它們的補充中所涉及的原料藥和制劑。

　The principles also apply to drug substances and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is encouraged to discuss the matter in advance with the center with product

　jurisdiction to prevent the expenditure of resources on preparing a submission that may later be determined to be unacceptable. 這些原則同樣適用于二類 DMF 所涉及的原料藥和制劑。如果使用了其它方法，鼓勵申請者事先和 FDA 藥品評審中心的官員進行討論，以免出現(xiàn)這種情況，那就是花了人力物力所準備起來的遞交資料后來發(fā)現(xiàn)是不可用的。

　The principles of methods validation described in this guidance apply to all types of analytical procedures. However, the specific recommendations in this guidance may not be applicable to certain unique analytical procedures for products such as biological, biotechnological, botanical, or radiopharmaceutical drugs. 本指南中所述的分析方法驗證的原則適用于各種類型的分析方法。但是，本指南中特定的建議可能不適用于有些產(chǎn)品所用的特殊分析方法，如生物藥，生物技術(shù)藥，植物藥或放射性藥物等。

　For example, many bioassays are based on animal challenge models, 39 immunogenicity assessments, or other immunoassays that have unique features that should be considered when submitting analytical procedure and methods validation information. 比如說，許多生物分析是建立在動物挑戰(zhàn)模式，免疫原性評估或其它有著獨特特性的免疫分析基礎上的，在遞交分析方法和分析方法驗證資料時需考慮這些獨特的性質(zhì)。

　Furthermore, specific recommendations for biological and immunochemical tests that may be necessary for characterization and quality control of many drug substances and drug products are beyond the scope of this guidance document. 而且，許多原料藥和制劑的界定和質(zhì)量控制所需的生物和免疫化學檢測并不在本指南的范圍之內(nèi)。

　Although this guidance does not specifically address the submission of analytical procedures and validation data for raw materials, intermediates, excipients, container closure components, and other materials used in the production of drug

　substances and drug products, validated analytical procedures should be used to analyze these materials. 盡管本指南并不專門敘述原料，中間體，賦形劑，包裝材料及原料藥和制劑生產(chǎn)中所用的其它物料的分析方法及分析方法驗證資料的遞交，但是應該應用驗證過的分析方法來分析檢測這些物質(zhì)。

　For questions on appropriate validation approaches for analytical procedures or submission of information not addressed in this guidance, applicants should consult with the appropriate chemistry review staff at FDA. 對于本指南中未提及的關于分析方法驗證和資料提交方面的問題，請向 FDA 相關的化學評審人員咨詢。

　This guidance, when finalized, will replace the FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation (February 1987). 本指南，一旦定稿，將取代 FDA 于 1987 年 2 月份發(fā)布的工業(yè)指南：分析方法驗證所需提交的樣品和分析資料。

　II. BACKGROUND

　Each NDA and ANDA must include the analytical procedures necessary to ensure the identity, strength, quality, purity, and potency of the drug substance and drug product, including bioavailability of the drug product (21 CFR 314.50(d)(1) and 314.94(a)(9)(i)).

　II. 背景 每個 NDA 和 ANDA 都必需包括必要的分析方法以確保原料藥和制劑的認定，劑量，質(zhì)量，純度和效力，還包括制劑的生物利用度(21 CFR 314.50(d)(1) 和 314.94(a)(9)(i))。

　FDA 驗證文件現(xiàn)場備查，可以不與 DMF 一起交。

　Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.165(e) and 211.194(a)(2)). 必須要有資料來論證所用的分析方法是符合一定的準確度和可靠性標準的。

　Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. The methods validation process for analytical procedures begins with the planned and systematic collection by the applicant of the validation data to support the analytical procedures. 分析方法驗證是論證某一分析方法適用于其用途的過程。分析方法的驗證過程是從申請者有計劃地系統(tǒng)性收集驗證資料以支持分析方法開始的。

　The review chemist evaluates the analytical procedures and validation data submitted in the NDA or ANDA.

　審評化學家會對 NDA 或 ANDA 中的分析方法和驗證資料進行評審。

　On request from FDA, an NDA or ANDA applicant must submit samples of drug product, drug substance, noncompendial reference standards, and blanks so that 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)). 一旦 FDA 有要求，則 NDA 或 ANDA 的申請者必須提交制劑，原料藥，非藥典對照品和空白以使 FDA 實驗室能對申請者所用分析方法進行評審(21 CFR 314.50(e) and 314.94(a)(10))。

　The FDA laboratory analysis demonstrates that the analytical procedures are reproducible by laboratory testing. The review chemists and laboratory analysts

　determine the suitability of the analytical procedures for regulatory purposes. FDA 實驗室的分析會論證該分析方法在實驗室內(nèi)是可以重現(xiàn)的。審評化學家和實驗室分析家會從法規(guī)的角度確定該分析方法的適用性。

　FDA investigators inspect the analytical laboratory testing sites to ensure that the analytical procedures used for release and stability testing comply with current good manufacturing practices (CGMPs) (21 CFR part 211) or good laboratory practices (GLPs) (21 CFR part 58), as appropriate. FDA 檢查官會對分析實驗室進行檢查確保用于放行和穩(wěn)定性實驗的分析方法符合現(xiàn)行的 GMP（21CFR part 211) 和 GLP (21 CFR part 58)。

　Each BLA and PLA must include a full description of the manufacturing methods, including analytical procedures, that demonstrate that the manufactured product meets prescribed standards of safety, purity, and potency (21 CFR 601.2(a) and 601.2(c)(1)(iv)). 每個 BLA 和 PLA 都必須要有詳細的生產(chǎn)工藝描述，包括分析方法，以說明所生產(chǎn)的產(chǎn)品是符合規(guī)定睥安全，純充和效力標準的(21 CFR 601.2(a) and 601.2(c)(1)(iv))。

　Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 81211.194(a)(2)). For BLAs, PLAs, and their supplements, the analytical procedures and their validation are submitted as part of the license application or supplement and are evaluated by the review committee. 必須要有資料證明所用的分析方法是符合一定的準確度和可靠性要求的(21 CFR 81211.194(a)(2))。對于 BLA，PLA 及它們的補充，在所提交的許可證申請中應當要有分析方法和方法驗證這部分的資料，審評委員會會對這部分資料進行評審。

　Representative samples of the product must be submitted and summaries of 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)). The review committee chair may request analytical testing by CBER laboratory analysts to evaluate the applicant=s analytical procedures and verify the test results. 需 提 供 代 表 性 樣 品 及 該 樣 品 所 代 表 批 號 的 檢 測 結(jié) 果 總 結(jié) (21 CFR 601.2(a) and 601.2(c)(1)(vi))。評審委員會主席會要求 CBER 實驗室的分析人員進行分析實驗對申請者的分析方法進行評估，并確認其分析結(jié)果。

　All analytical procedures are of equal importance from a validation perspective. In general, validated analytical procedures should be used, irrespective of whether they are for in-process, release, acceptance, or stability testing. Each quantitative analytical procedure should be designed to minimize assay variation. 從驗證的角度來看，所有的分析方法有著同樣的重要性。一般來說，應當要應用已驗證過的分析方法，而不論其是被用于過程控制，放行，合格或穩(wěn)定性實驗。高等每個定量分析方法時都應當要減少其分析誤差。

　Analytical procedures and validation data are submitted in the sections of the application on analytical procedures and controls. Recommendations on information to be submitted are included in sections III through IX and XI of this guidance. Information on submission of the methods validation package to the NDA or ANDA and samples to the FDA laboratories is provided in section X. 分析方法和驗證資料應當擺在申請的分析方法和控制章節(jié)中提交。本指南的第 III 到 IX 章

　和 XI 章給出了所需提供資料方面的建議。向 FDA 實驗室提供樣品和遞交 NDA 和 ANDA 中的分析方法驗證資料的信息見第 X 章。

　III. TYPES OF ANALYTICAL PROCEDURES

　A. Regulatory Analytical Procedure A regulatory analytical procedure is the analytical procedure used to evaluate a defined characteristic of the drug substance or drug product. The analytical procedures in the U.S. Pharmacopeia/National Formulary (USP/NF) are those legally recognized under section 501(b) of the Food, Drug, and Cosmetic Act (the Act) as the regulatory analytical procedures for compendial items. For purposes of determining compliance with the Act, the regulatory analytical procedure is used. III 分析方法的類型 A. 法定分析方法 法定分析方法是被用來評估原料藥或制劑的特定性質(zhì)的。USP/NF 中的分析方法是法定的用于藥典項目檢測的分析方法。為了確認符合法規(guī)，需使用法定分析方法。

　B. Alternative Analytical Procedure

　An alternative analytical procedure is an analytical procedure proposed by the applicant for use instead of the regulatory analytical procedure. A validated alternative analytical procedure should be submitted only if it is shown to perform equal to or better than the regulatory analytical procedure. B. 替代分析方法 替代分析方法是申請者提出用于代替法定分析方法的分析方法。只有當一替代分析方法相當于或優(yōu)于法定分析方法時，才可以應用驗證過的替代分析方法。

　If an alternative analytical procedure is submitted, the applicant should provide a rationale for its inclusion and identify its use (e.g., release, stability testing), validation data, and comparative data to the regulatory analytical procedure. 如果提交了替代分析方法，申請者還應當提供其理由，并標明其用途（如，放行，穩(wěn)定性實驗），驗證資料及其與法定分析方法的對比資料。

　C. Stability-Indicating Assay

　A stability-indicating assay is a validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product.

　C. 穩(wěn)定性指示分析 穩(wěn)定性指示分析是能檢測出原料藥或制劑的某些性質(zhì)隨著時間的延長而出現(xiàn)的變化的定量分析方法。

　A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities。

　穩(wěn)定性指示分析能不受降解產(chǎn)物，工藝雜質(zhì)，賦形劑或其它潛在雜質(zhì)的影響而準確測定其中的活性成分。

　If an applicant submits a non-stability-indicating analytical procedure for release testing, then an analytical procedure capable of qualitatively and quantitatively monitoring the impurities, including degradation products, should complement it. Assay analytical procedures for stability studies should be stability-indicating, unless scientifically justified.

　如果申請者遞交了用于放行檢測的非穩(wěn)定性指示分析方法，則應當要有能定性和定量地監(jiān)測雜質(zhì)，包括降解產(chǎn)物，的分析方法對其進行補充。穩(wěn)定性試驗中所用的含量分析方法應當要有穩(wěn)定性指示能力，除非有科學的理由能證明其合理性。

　IV. REFERENCE STANDARDS

　A. Types of Standards A reference standard (i.e., primary standard) may be obtained from the USP/NF or other official sources (e.g., CBER, 21 CFR 610.20). If there are questions on whether a source of a standard would be considered by FDA to be an official source, applicants should contact the appropriate chemistry review staff. When there is no official source, a reference standard should be of the highest possible purity and be fully characterized. IV 標準品 A．標準品的類型 可以從 USP/NF 處或其它官方(比如說，CBER，21CFR 610.20)獲得標準品 (也就是一級對照品)。如果不能確定一標準品的來源是否會被 FDA 認為是官方來源，申請者應當要向適當?shù)幕瘜W評審人員咨詢。如果沒有官方來源，則被用來作標準品的物質(zhì)應當要有盡可能高的純度，并得到充分界定。

　A working standard (i.e., in-house or secondary standard) is a standard that is qualified against and used instead of the reference standard. 工作對照品 (也就是內(nèi)部標準品或二級標準品)是根據(jù)一級對照品標定的，并用來代替一級對照品的。

　B. Certificate of Analysis

　A certificate of analysis (COA) for reference standards from non-official sources should be submitted in the section of the application on analytical procedures and controls. For standards from official sources, the user should ensure the suitability of the reference standard. The standard should be stored correctly and used within the established use interval. B．分析報告單 對于非官方標準品，在申請的分析方法和控制章節(jié)中應當要提供該標準品的分析報告單。對于從官方獲得的標準品，用戶應當要確保標準品的適用性。應當正確儲存標準品并在已確定的時間段內(nèi)使用該標準品。

　C. Characterization of a Reference Standard

　Reference standards from USP/NF and other official sources do not require further characterization. A reference standard that is not obtained from an official source should be of the highest purity that can be obtained by reasonable effort, and it should be thoroughly characterized to ensure its identity, strength, quality, purity, and potency. C．標準品的界定 從 USP/NF 及其它官方來源獲得的標準品是不需要進一步界定的。非官方對照品要有盡可能高的純度，并進行充分地界定以確保其結(jié)構(gòu)，劑量，質(zhì)量，純度和效力。

　The qualitative and quantitative analytical procedures used to characterize a reference standard are expected to be different from, and more extensive than, those used to control the identity, strength, quality, purity, and potency of the drug substance or the drug product. Analytical procedures used to Draft — Not for Implementation characterize a reference standard should not rely solely on

　comparison testing to a previously designated reference standard. 用于界定標準品的定性和定量分析方法應當要不同于用于控制原料藥或制劑的結(jié)構(gòu)，劑量，質(zhì)量，純度和效力的分析方法，要比它們更深入。用于標準品界定的分析方法不應僅僅是和先前的指定標準品進行比較實驗。

　Generally, this characterization information should include:

　 A brief description of the manufacture of the reference standard, if the manufacturing process differs from that of the drug substance. Any additional purification procedures used in the preparation of the reference standard should be described. 一般來說，界定資料應當要包括：

　標準品的簡單工藝描述，如果其生產(chǎn)工藝是否于其相應的原料藥的話。應當要敘述制備標準品時所用的補充精制過程。

　Legible reproductions of the relevant spectra, chromatograms, thin-layer chromatogram (TLC) photographs or reproductions, and other appropriate instrumental recordings.

　Data establishing purity. The data should be obtained by using appropriate tests, such as TLC, gas chromatography (GC), high-pressure liquid chromatography (HPLC), phase solubility analysis, appropriate thermometric analytical procedures, and others as necessary. 相關光譜圖，色譜圖，TLC 照片及其它儀器輸出的清晰復印件。建立純度的資料。應當要應用適當?shù)臋z測方法來獲得這些資料，比如說 TLC，GC，HPLC，相溶解分析，適當?shù)臒岱治龇椒�及其它必要的分析方法�?/p>

　Appropriate chemical attribute information, such as structural formula, empirical formula, and molecular weight. Information to substantiate the proof of structure should include appropriate analytical tests, such as elemental analysis, infrared spectrophotometry (IR), ultraviolet spectrophotometry (UV), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS), as well as applicable functional group analysis. Detailed interpretation of the test data in support of the claimed structure should be provided. 適當?shù)幕瘜W性質(zhì)資料，比如結(jié)構(gòu)式，經(jīng)驗式和分子量等。結(jié)構(gòu)確證資料應當要包括適當?shù)姆治鰷y試，比如元素分析，IR，UV,NMR 和 MS，及適用的官能團分析。還應當要提供具體的結(jié)構(gòu)解析資料。

　A physical description of the material, including its color and physical form.

　Appropriate physical constants such as melting range, boiling range, refractive index, dissociation constants (pK values), and optical rotation.

　A detailed description of the analytical procedures used to characterize the reference standard. 物理性質(zhì)的描述，包括顏色和物理形態(tài)。

　適當?shù)奈锢沓��?shù)，比如說熔程，沸程，折射率，離解常數(shù)(pK 值)和旋光度。用于界定標準品的分析程序的詳細敘述。

　For biotechnological/biological product reference standards, the recommendations on characterization information above may apply and should be considered. However, additional and/or different tests would be important to assess physicochemical characteristics, structural characteristics, biological activity, and/or immunochemical activity. 至于生物技術(shù)/生物產(chǎn)品的標準品，應當要考慮上述建議，可能可以應用。然而，其它確定

　物理化學性質(zhì)，結(jié)構(gòu)特性，生物活性和/或免疫化學活性的補充檢測和/或其它檢測將是非常重要的。

　Physicochemical determinations may include isoform, electrophoretic, and liquid chromatographic patterns, as well as spectroscopic profiles. Structural characterization may include a determination of amino acid sequence, amino acid composition, peptide map, and carbohydrate structure. Biological and/or immunochemical activity should be assessed using the same analytical procedures used to determine product potency. 物理化學性質(zhì)包括異構(gòu)體，電泳和液相色譜行為及光譜性質(zhì)等。結(jié)構(gòu)界定可能包括氨基酸序列，氨基酸組成，縮氨酸圖和碳水結(jié)構(gòu)。確定生物和/或免疫化學活性的分析方法應當要和用來確定產(chǎn)品效力的分析方法一樣。

　These can include animal-based, cell culture-based, biochemical, or ligand/receptor-binding assays. While these tests may be needed for complete characterization of certain reference standards, specific recommendations for validation of biological and immunochemical tests are not contained in this guidance document. 這些分析方法可以包括基于動物的，細胞培養(yǎng)的，生物化學的或配位體/接受體螯合的分析方法。如果這些檢測需用于某些標準品的界定，生物和免疫化學檢測的分析方法驗證方面的特殊建議并不在本指南的范圍之內(nèi)。

　V. METHODS VALIDATION FOR INDs

　For an investigational new drug, sufficient information is required in each phase of an investigation to ensure proper identification, quality, purity, strength, and/or potency. The amount of information on analytical procedures and methods validation necessary will vary with the phase of the investigation (21 CFR 312.23(a)(7)). V．IND 中的分析方法驗證

　對于 IND 而言，每個階段的研究都需要有足夠的資料以確保合適的認定，質(zhì)量，純度，劑量和/或效力。所需的分析方法和方法驗證方面的資料會隨著研究的階段變化而變化(21 CFR 312.23(a)(7))。

　For general guidance on analytical procedures and methods validation information to be submitted for phase 1 studies, sponsors should refer to the FDA guidance for industry on Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well- Characterized, Therapeutic, Biotechnology-Derived Products (November 1995). 關于在第 1 階段研究所需提交的分析方法和方法驗證資料方面的指南，發(fā)起人可以參考 FDA的指南：藥品（包括結(jié)構(gòu)確定的，有療效的，生物技術(shù)產(chǎn)品）第 1 階段研究的 IND 申請的內(nèi)容和格式（1995 年 11 月）。

　General guidance regarding analytical procedures and methods validation information to be submitted for phase 2 or phase 3 studies will be provided in the FDA guidance for industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology-Derived Products, Chemistry, Manufacturing, and Controls Content and Format, when finalized (draft guidance published April 1999). 第 2 和第 3 階段研究所需提交的分析方法和方法驗證資料方面的指南，發(fā)起人將可以參考FDA 的指南：藥品（包括結(jié)構(gòu)確定的，有療效的，生物技術(shù)產(chǎn)品）第 1 階段研究的 IND 申請

　的 CMC 內(nèi)容和格式（草案，1999 年 4 月）。

　All analytical procedures should be fully developed and validation completed when the NDA, ANDA, BLA, or PLA is submitted. 在遞交 NDA，ANDA，BLA 或 PLA 時，所有的分析方法都應當要開發(fā)出來，并得到驗證。

　VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAs, 230ANDAs, BLAs, AND PLAs

　Any analytical procedure submitted in an NDA, ANDA, BLA, or PLA should be described in sufficient detail to allow a competent analyst to reproduce the necessary conditions and obtain results comparable to the applicant=s. Aspects of the analytical procedure that require special attention should be described. VI． NDA，ANDA，BLA 和 PLA 中分析方法的內(nèi)容和格式 NDA，ANDA，BLA 和 PLA 中所提交的任一分析方法都應當要有詳細的描述，以使合格的分析人員能重現(xiàn)出所需的實驗條件并獲得和申請者相當?shù)膶嶒灲Y(jié)果。應當要敘述分析方法中需要特殊注意的地方。

　If the analytical procedure used is in the current revision of the USP/NF or other FDA recognized standard references (e.g., AOAC International Book Of Methods) and the referenced analytical procedure is not modified, a statement indicating the analytical procedure and reference may be provided rather than a description of the method (21 CFR 211.194). 如果所用的分析方法是 USP/NF 或其它 FDA 認可參考文獻（如，<<AOAC 國際方法匯編>>）中且所參考的分析方法未經(jīng)過修改的話，則需提供該分析方法的參引，而不用提供該分析方法的描述（21 CFR 211.194）。

　A description of analytical procedures from any other published sources should be provided, because the referenced sources may not be readily accessible to the reviewer. 對于從其它公開發(fā)表的文獻上獲得的分析方法，應當要對其進行敘述，因為評審官可能并不能很方便的獲得這些文獻。

　分析方法描述中需要包括的典型內(nèi)容如下所示：

　A. Principle

　A statement of the principle of the analytical procedure should be included. For example, separation is based on isocratic reversed phase HPLC with detection by UV.

　B. Sampling

　The number of samples (e.g., vials, tablets) selected, how they are used (i.e., as individual or composite samples), and the number of replicate analyses per sample should be described. A．基本方法 HPLC 進行分離的，檢測器為 UV 檢測器。

　B．取樣 需要敘述的有：所選樣品的數(shù)目（比如，瓶，片等），它們是如何使用的（也就是，單獨的或是混合樣品），每個樣品分析的重復次數(shù)。

　C. Equipment and Equipment Parameters

　A listing of all equipment (e.g., instrument type, detector, column type, dimensions) should be included, as well as a list of equipment parameters (e.g., flow rate, temperatures, run time, wavelength settings). A drawing representing the experimental configuration (e.g., illustrating positions for a spray pattern analytical procedure) should be provided, when appropriate.

　C．儀器和儀器參數(shù) 需要敘述的有：儀器列表（比如，儀器類型，檢測器，柱子類型，尺寸等）和儀器參數(shù)（比如，流速，溫度，運行時間和設定波長等）。如果必要的話，還要提供實驗結(jié)構(gòu)示意圖（比如，闡述噴灑式分析方法的位置）。

　D. Reagents

　A list of reagents and their grades (e.g., USP/NF, American Chemical Society (ACS) Analytical Reagent) should be included. If in-house or modified commercial reagents are used, directions for their preparation should be included. Unstable or potentially hazardous reagents should be identified, and storage conditions, directions for safe use, and usable shelf life for these reagents should be specified. D．試劑 需要敘述的有：試劑列表及其相應的規(guī)格（比如：USP/NF，美國化學社（ACS）分析試劑）。如果使用的是自制試劑或更改過的商業(yè)試劑，則應當要有其制備方法。對于不穩(wěn)定的或有潛在危險的試劑，應標明其儲存條件，安全使用說明和使用周期。

　E. System Suitability Testing

　System suitability test parameters and acceptance criteria are based on the concept that the equipment, electronics, analytical operations, and samples to be analyzed constitute an integrated system. System suitability testing ensures that the system is working properly at the time of analysis. Appropriate system suitability criteria should be defined and included in the analytical procedure. E．系統(tǒng)適應性實驗 系統(tǒng)適應性實驗參數(shù)和合格標準是建立基礎是：儀器，電子元件，分析操作和待測樣品是個不可分割的整體。系統(tǒng)適應性實驗確保系統(tǒng)在樣品分析的時候能很好地運行。在分析方法中應當要包括適當?shù)南到y(tǒng)適應性合格標準。

　All chromatographic analytical procedures should include system suitability testing and criteria. Parameters typically used in system suitability evaluations are defined and discussed in the CDER reviewer guidance on Validation of Chromatographic Methods (November 1994). 所有的色譜分析方法都應當要有系統(tǒng)適應性實驗及相應的合格標準。CDER 評審官指南<<色譜分析方法的驗證>>（1994 年 11 月）對用于評估系統(tǒng)適應性的典型參數(shù)進行了定義和討論。

　System suitability testing is recommended as a component of any analytical procedure, not just those that involve chromatographic techniques. Regardless of the type of analytical procedure, testing should be used to confirm that the system will function correctly independent of the environmental conditions. For example, titration analytical procedures should always include the evaluation of a blank (commonly referred to as a blank titration). 建議系統(tǒng)適應性實驗應成為所有分析方法的一部分，而不僅僅是色譜分析方法。無論是哪類分析方法，都要采用實驗來證實該系統(tǒng)能不受環(huán)境條件的影響而正確地運行。比如說，滴定法一般來說需要進行空白實驗。

　F. Preparation of Standards Procedures for the preparation of all standard solutions (e.g., stock, working standard solutions, internal standards) should be included. F．標準品的制備 要有所有標準品溶液（比如，儲備液，工作對照品溶液，內(nèi)部對照品溶液）的配制方法。

　G. Preparation of Samples

　Sample preparation for individual tests should be clearly described. Specific details should be provided for unusual sample preparations (e.g., solid-phase extraction, derivatization). G.操作過程 應當要按操作步驟對操作過程進行逐步敘述。敘述應當要適當包括如下信息：平衡時間，樣品進樣順序和系統(tǒng)適應性或啟動參數(shù)。需標明不常見的危險。

　I. Calculations

　Representative calculations, with a tabulation defining all symbols and numerical factors, and specific instructions for the calculation of degradation products and impurities should be included. Any mathematical transformations or formulas used in data analysis should be described in detail. These may include logarithmic transformations used to obtain a linear relationship from exponential data, or the use of multiple order regression analyses. I．計算 應當要提供代表性計算公式，并要列表說明所有符號和數(shù)字系數(shù)，及計算降解產(chǎn)物和雜質(zhì)的特殊使用說明。所有用于數(shù)據(jù)分析的數(shù)學轉(zhuǎn)換或公式應詳細描述。這些包括對數(shù)轉(zhuǎn)換以獲得指數(shù)數(shù)據(jù)的線性關系，或多元回歸分析的使用。

　J.Reporting of Results J.結(jié)果報告 1. General

　The format used to report results (e.g., percent label claim, weight/weight, weight/volume, parts per million (ppm)) including the specific number of significant figures to be reported should be provided. 1．通則 應該規(guī)定關鍵計算步驟中的數(shù)字單位（例如，‘標簽’標示量的百分比，W/W，W/L，ppm 等）

　2. Impurities Analytical Procedures

　The name and location/identifier (e.g., retention time (RT), relative retention time (RRT)) of impurities and the type of impurity (e.g., process, degradant, excipient degradant) should be included in the analytical procedures for impurities in the drug substance and drug product. The detection limit (DL) or quantitation limit (QL) should be stated, as appropriate. The DL or QL can be set using the drug substance"s detection response.

　2．雜質(zhì)分析規(guī)程 在有關原料藥和產(chǎn)品的雜質(zhì)檢測規(guī)程中，應當包括雜質(zhì)的名稱和檢測位/標志（例如，保留時間 RT，相對保留時間 RRT），以及雜質(zhì)的種類（比如工藝降解產(chǎn)物，賦形劑降解產(chǎn)物），如有可能，還應當指明檢測限 DL 或定量限 QL。也可以在原料藥檢測中設置 DL 和 QL。

　Reporting of organic impurities should cover (1) specified identified impurities by name, (2) specified unidentified impurities by location/identifier, (3) any unspecified impurities, and (4) total impurities. The total organic impurities for the drug product or drug substance is the sum of all impurities equal to or greater than their individual QL. See recommendations regarding appropriate QLs in FDA impurities guidances (see references). Inorganic impurities and residual solvents should also be addressed.

　有機雜質(zhì)的報告中，應當包括：1、有記載的已經(jīng)過確認的雜質(zhì)的名稱；2、有記載但未經(jīng)過確認雜質(zhì)的（檢測）位/標志；3、所有的沒有記載的雜質(zhì)，以及；4、總雜質(zhì)。總有機雜質(zhì)是指所有達到或超過其自身定量限度的雜質(zhì)的總量。在這里可以參考 FDA 雜質(zhì)指南文章中有關判定定量限度的內(nèi)容（看后面的參考）。無機雜質(zhì)和溶劑的殘留，也應該被提到。

　For the drug product, drug substance process impurities may be excluded from reporting if an acceptable rationale is provided in the sections on analytical procedures and controls. Drug product impurities from the drug product manufacturing process, packaging, and labeling should be addressed.

　對于產(chǎn)品以及原料藥的工藝雜質(zhì)也可以不包括在報告中，除非分析規(guī)程和控制環(huán)節(jié)中描敘了一個可以被接受的原則，那么，在產(chǎn)品制造和包裝過程中（包括貼簽）產(chǎn)生的雜質(zhì)就要被提到。

　The above reporting information may not be strictly applicable to all products (e.g., biological, biotechnological, botanical, radiopharmaceutical drugs), but any significant process and product-related impurities should be determined and reported.

　并不是所有產(chǎn)品（比如，生物制劑、生物工藝制劑、植物制劑、放射制劑）的報告都必須嚴格按照以上談到的內(nèi)容來寫，但是所有關鍵的工序以及產(chǎn)品相關的雜質(zhì)都要有檢測和報告。

　VII. METHODS VALIDATION FOR NDAs, ANDAs, BLAs, AND PLAs

　A. Noncompendial Analytical Procedures

　In an NDA, ANDA, BLA, or PLA, data must be submitted to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR 211.194(a)(2)). Methods validation is the process of demonstrating that analytical procedures are suitable for their intended use. At the time of submission, the NDA, ANDA,

　BLA, or PLA should contain methods validation information to support the adequacy of the analytical procedures. VII．NDA，ANDA，BLA 和 PLA 中的分析方法驗證 A．非藥典分析方法 在 NDA，ANDA，BLA 或 PLA 中，應當要遞交資料以說明檢測中所用的分析方法是滿足適當?shù)臏蚀_度和可靠性要求(21 CFR 211.194(a)92))。分析方法驗證是個論述分析方法是適用于其擬定用途的過程。在遞交資料時，NDA，ANDA，BLA 或 PLA 中應當要包含分析方法驗證資料以支持分析方法的準確度。

　The International Conference on Harmonisation (ICH) guidance Q2A Text on Validation of Analytical Procedures (March 1995) and Q2B Validation of Analytical Procedures: Methodology (November 1996) provide recommendations on validation of analytical procedures. Analytical procedures outside the scope of the ICH guidances should still be validated. ICH 指導原則 Q2A：分析方法驗證（1995 年 3 月）和 Q2B：分析方法驗證：方法學（1996 年11 月）給出了分析方法驗證的建議。對于超出 ICH 指導原則范圍的分析方法也是需要驗證的。

　1. Validation Characteristics Applicants should submit information on the validation characteristics of their proposed analytical procedures (see ICH Q2A and ICH Q2B). Although not all of the validation characteristics are needed for all types of tests (see section VII.A.3),

　typical validation characteristics are: 1.驗證項目 申請者應當要送交其所擬定分析方法的驗證項目方面的信息（見 ICH Q2A 和 ICH Q2B）。盡管不是對于所有類型的分析方法都需要進行所有的驗證項目（見第 VII.A.3 章），但還是有典型的驗證項目，如：

　Accuracy

　Precision (repeatability and intermediate precision)

　Specificity

　Detection limit

　Quantitation limit

　Linearity

　Range

　Robustnes 準確度 精密度（重復性和中間精密度）

　專屬性 檢測限 定量限 線性 范圍 耐用性 2. Other Methods Validation Information

　Methods validation information should also include:

　Data to demonstrate the stability of all analytical sample preparations through the time required to complete the analysis. 2.其它驗證資料 分析方法驗證資料還應當要包括：

　說明所有分析制備樣品在完成分析所需的時間內(nèi)的穩(wěn)定性的資料。

　Legible reproductions of representative instrument output or recordings (e.g., chromatograms) and raw data output (e.g., integrated areas), as appropriate. Instrument output for placebo, standard, and sample should also be provided (see section VII.A.2.c). 清晰可讀的儀器代表性輸出和記錄資料（如色譜圖）和原始資料輸出（積分面積）。安慰劑，對照品和樣品的儀器輸出也都是需要提供的（見第 VII.A.2.c 章）。

　Representative calculations using submitted raw data, to show how the impurities in drug substance are calculated. Information from stress studies (see section VII.A.2.b). Impurities labeled with their names and location identifiers (e.g., RRT for chromatographic data) for the impurity analytical procedure. 代表性計算公式，以表明原料藥中的雜質(zhì)是如何計算的。(見 VII.A.2.b 章）。對于雜質(zhì)分析方法，要標明雜質(zhì)的名稱和位置標識符（如，色譜中的相對保留時間 RRT）。

　For drug substances:

　 A discussion of the possible formation and control of polymorphic and enantiomeric substances.

　Identification and characterization of each organic impurity, as appropriate. This

　information may not be needed for all products (e.g., botanicals). Other impurities (e.g., inorganics, residual solvents) should be addressed and quantitated. 對于原料藥：

　1. 討論可能會形成的異構(gòu)體并討論異構(gòu)體的控制。

　對每個有機雜質(zhì)進行適當?shù)臉俗R和界定。不是所有的產(chǎn)品（如，植物藥）都需要這些資料的。對于其它雜質(zhì)（如無機雜質(zhì)，殘留溶劑），應當要進行說明并定量分析。

　Recommendations on submitting information on i...

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