美國FDA分析方法驗(yàn)證指南中英文對照（四）美國FDA分析方法驗(yàn)證指南中英文對照（/library/ShowArticle.asp?ArticleID=69）I. INTRODUCTIONThis 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(yàn)證資料和樣品用于支持原料藥和制劑的認(rèn)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(bǔ)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(lì)申請者事先和FDA藥品評審中心的官員進(jìn)行討論，以免出現(xiàn)這種情況，那就是花了人力物力所準(zhǔn)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(yàn)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(dòng)物挑戰(zhàn)模式，免疫原性評估或其它有著獨(dú)特特性的免疫分析基礎(chǔ)上的，在遞交分析方法和分析方法驗(yàn)證資料時(shí)需考慮這些獨(dú)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(xué)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(yàn)證資料的遞交，但是應(yīng)該應(yīng)用驗(yàn)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(guān)于分析方法驗(yàn)證和資料提交方面的問題，請向FDA相關(guān)的化學(xué)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(yàn)證所需提交的樣品和分析資料。II. BACKGROUNDEach 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(gè)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(rèn)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(yàn)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(zhǔn)確度和可靠性標(biāo)準(zhǔn)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(yàn)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(yàn)證過程是從申請者有計(jì)劃地系統(tǒng)性收集驗(yàn)證資料以支持分析方法開始的。Thereview chemist evaluates the analytical procedures and validation data submitted in the NDA or ANDA.審評化學(xué)家會(huì)對NDA或ANDA中的分析方法和驗(yàn)證資料進(jìn)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 applicants 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(shí)驗(yàn)室能對申請者所用分析方法進(jìn)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(shí)驗(yàn)室的分析會(huì)論證該分析方法在實(shí)驗(yàn)室內(nèi)是可以重現(xiàn)的。審評化學(xué)家和實(shí)驗(yàn)室分析家會(huì)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(huì)對分析實(shí)驗(yàn)室進(jìn)行檢查確保用于放行和穩(wěn)定性實(shí)驗(yàn)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(gè)BLA和PLA都必須要有詳細(xì)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(biāo)準(zhǔn)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(zhǔn)確度和可靠性要求的(21 CFR 81211.194(a)(2)。對于BLA，PLA及它們的補(bǔ)充，在所提交的許可證申請中應(yīng)當(dāng)要有分析方法和方法驗(yàn)證這部分的資料，審評委員會(huì)會(huì)對這部分資料進(jìn)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(huì)主席會(huì)要求CBER實(shí)驗(yàn)室的分析人員進(jìn)行分析實(shí)驗(yàn)對申請者的分析方法進(jìn)行評估，并確認(rèn)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(yàn)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(yīng)當(dāng)要應(yīng)用已驗(yàn)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(shí)驗(yàn)。高等每個(gè)定量分析方法時(shí)都應(yīng)當(dāng)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(yàn)證資料應(yīng)當(dāng)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(shí)驗(yàn)室提供樣品和遞交NDA和ANDA中的分析方法驗(yàn)證資料的信息見第X章。III. TYPES OF ANALYTICAL PROCEDURESA. Regulatory Analytical ProcedureA 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(xiàng)目檢測的分析方法。為了確認(rèn)符合法規(guī)，需使用法定分析方法。B. Alternative Analytical ProcedureAn 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(dāng)一替代分析方法相當(dāng)于或優(yōu)于法定分析方法時(shí)，才可以應(yīng)用驗(yàn)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(yīng)當(dāng)提供其理由，并標(biāo)明其用途（如，放行，穩(wěn)定性實(shí)驗(yàn)），驗(yàn)證資料及其與法定分析方法的對比資料。C. Stability-Indicating AssayA 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(shí)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(zhǔn)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(yīng)當(dāng)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(jìn)行補(bǔ)充。穩(wěn)定性試驗(yàn)中所用的含量分析方法應(yīng)當(dāng)要有穩(wěn)定性指示能力，除非有科學(xué)的理由能證明其合理性。IV. REFERENCE STANDARDSA. Types of StandardsA 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(biāo)準(zhǔn)品A標(biāo)準(zhǔn)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(biāo)準(zhǔn)品 (也就是一級對照品)。如果不能確定一標(biāo)準(zhǔn)品的來源是否會(huì)被FDA認(rèn)為是官方來源，申請者應(yīng)當(dāng)要向適當(dāng)?shù)幕瘜W(xué)評審人員咨詢。如果沒有官方來源，則被用來作標(biāo)準(zhǔn)品的物質(zhì)應(yīng)當(dāng)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(biāo)準(zhǔn)品或二級標(biāo)準(zhǔn)品)是根據(jù)一級對照品標(biāo)定的，并用來代替一級對照品的。B. Certificate of AnalysisA 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(bào)告單對于非官方標(biāo)準(zhǔn)品，在申請的分析方法和控制章節(jié)中應(yīng)當(dāng)要提供該標(biāo)準(zhǔn)品的分析報(bào)告單。對于從官方獲得的標(biāo)準(zhǔn)品，用戶應(yīng)當(dāng)要確保標(biāo)準(zhǔn)品的適用性。應(yīng)當(dāng)正確儲(chǔ)存標(biāo)準(zhǔn)品并在已確定的時(shí)間段內(nèi)使用該標(biāo)準(zhǔn)品。C. Characterization of a Reference StandardReference 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(biāo)準(zhǔn)品的界定從USP/NF及其它官方來源獲得的標(biāo)準(zhǔn)品是不需要進(jìn)一步界定的。非官方對照品要有盡可能高的純度，并進(jìn)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(biāo)準(zhǔn)品的定性和定量分析方法應(yīng)當(dāng)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(biāo)準(zhǔn)品界定的分析方法不應(yīng)僅僅是和先前的指定標(biāo)準(zhǔn)品進(jìn)行比較實(shí)驗(yàn)。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(yīng)當(dāng)要包括：標(biāo)準(zhǔn)品的簡單工藝描述，如果其生產(chǎn)工藝是否于其相應(yīng)的原料藥的話。應(yīng)當(dāng)要敘述制備標(biāo)準(zhǔn)品時(shí)所用的補(bǔ)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(guān)光譜圖，色譜圖，TLC照片及其它儀器輸出的清晰復(fù)印件。建立純度的資料。應(yīng)當(dāng)要應(yīng)用適當(dāng)?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(dāng)?shù)臒岱治龇椒捌渌匾姆治龇椒āppropriate 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(dāng)?shù)幕瘜W(xué)性質(zhì)資料，比如結(jié)構(gòu)式，經(jīng)驗(yàn)式和分子量等。結(jié)構(gòu)確證資料應(yīng)當(dāng)要包括適當(dāng)?shù)姆治鰷y試，比如元素分析，IR，UV,NMR和MS，及適用的官能團(tuán)分析。還應(yīng)當(dāng)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(dāng)?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(biāo)準(zhǔn)品的分析程序的詳細(xì)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(biāo)準(zhǔn)品，應(yīng)當(dāng)要考慮上述建議，可能可以應(yīng)用。然而，其它確定物理化學(xué)性質(zhì)，結(jié)構(gòu)特性，生物活性和/或免疫化學(xué)活性的補(bǔ)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(xué)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(xué)活性的分析方法應(yīng)當(dāng)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(dòng)物的，細(xì)胞培養(yǎng)的，生物化學(xué)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(biāo)準(zhǔn)品的界定，生物和免疫化學(xué)檢測的分析方法驗(yàn)證方面的特殊建議并不在本指南的范圍之內(nèi)。V. METHODS VALIDATION FOR INDsFor 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).VIND中的分析方法驗(yàn)證對于IND而言，每個(gè)階段的研究都需要有足夠的資料以確保合適的認(rèn)定，質(zhì)量，純度，劑量和/或效力。所需的分析方法和方法驗(yàn)證方面的資料會(huì)隨著研究的階段變化而變化(21CFR312.23(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(guān)于在第1階段研究所需提交的分析方法和方法驗(yàn)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(yàn)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(shí)，所有的分析方法都應(yīng)當(dāng)要開發(fā)出來，并得到驗(yàn)證。VI. CONTENT AND FORMAT OF ANALYTICAL PROCEDURES FOR NDAs, 230ANDAs, BLAs, AND PLAsAny 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.VINDA，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(yīng)當(dāng)要有詳細(xì)的描述，以使合格的分析人員能重現(xiàn)出所需的實(shí)驗(yàn)條件并獲得