美國FDA分析方法驗證指引中英文對照

1、美國FDA分析方法驗證指南中英文對照美國FDA分析方法驗證指南中英文對照八、I. INTRODUCTIONThis guida nee provides recomme ndati ons to applica nts on submitt ing an alytical procedures, validati on data, and samples to support the docume ntati on of the identity, strength, quality, purity, and potency of drug substances and drug produc

2、ts.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 guida nce is in ten ded to assist applica nts in assembli ng in formati on, submitt ing samples, and prese nti ng data to support an alytical methodologies. The recomme ndati ons apply to drug substa nces and drug products

3、 covered in new drug applicati ons (NDAs), abbreviated new drug applicati ons (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these即plicatio ns.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 prin ciples also apply

4、 to drug substa nces and drug products covered in Type II drug master files (DMFs). If a different approach is chosen, the applicant is en couraged to discuss the matter in adva nce with the cen ter with product jurisdict ion to preve nt the expe nditure of resources on prepari ng a submissi on that

5、 may later be determ ined to be un acceptable.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 prin ciples of methods validati on described in this guida nee applyto all types of an alytical procedures. However, the specific recomme ndati ons in

6、 this guida nee may not be applicable to certa in unique an alytical procedures for products such as biological, biotech no logical,bota ni cal, 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

7、ani mal challe nge models, 39 immunogeni city assessme nts, or other immuno assays that have unique features that should be con sidered whe n submitti ng an alytical procedureand methods validati on in formati on.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(chǔ)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

8、, specific recomme ndati ons for biological and immuno chemical tests that may be n ecessary for characterizati on and quality con trol of many drug substa nces and drug products are bey ond the scope of this guida nee docume nt.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 本指南的圍之。Although this guida nee does

9、not specifically address the submissi on of an alytical procedures and validatio n data for raw materials, in termediates, excipients, container closure components, and other materials used in the product ion of drug substa nces and drug products, validated an alytical procedures should be used to a

10、nalyze 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(yīng)該應(yīng)用驗證 過的分析方法來分析檢測這些物質(zhì)。For questi ons on appropriate validati on approaches for an alytical procedures or submissi on of in formati on not addressed in this guida nee, applica nts should con sult with the appropr

11、iate chemistry review staffat FDA.對于本指南中未提及的關(guān)于分析方法驗證和資料提交方面的問題，請向FDA相關(guān)的化學評審人員咨詢。This guida nee, whe n fin alized, will replace the FDA guida nee for in dustry onSubmitt ing Samples and An alytieal Data for Methods Validati on(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. BAC

12、KGROUNDEach NDA and ANDA must in elude the an alytieal procedures n eeessary toensure the identity, strength, quality, purity, and poteney of the drug substaneeand drug produet, in eludi ng bioavailability of the drugproduet (21 CFR 314.50(d) 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

13、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 an alytieal proeedures used in test ingmeet proper sta ndards of aeeuraey 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Metho

14、ds validati on is the proeess of dem on strat ing that an alytieal proeedures are suitable for their inten ded use. The methods validatio n proeess for an alytieal procedures beg ins with the pla nned and systematic collecti on by the applica nt of the validati on data to support thean alytical proc

15、edures.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 an alytical procedures and validati on 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 applica nt must submit samples of drug product, drug sub

16、sta nee, non compe ndial refere nee sta ndards, and bla nks so that the applica nts drug substa nee and drug product an alytical 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

17、314.94(a)(10)。The FDA laboratory an alysis dem on strates that the an alytical procedures are reproducible by laboratory testi ng. The review chemists and laboratory an alysts determ ine the suitability of the an alytical procedures for regulatory purposes.FDA實驗室的分析會論證該分析方法在實驗室是可以重現(xiàn)的。審評化學家和實 驗室分析家會從

18、法規(guī)的角度確定該分析方法的適用性。FDA inv estigators in spect the an alytical laboratory testi ng sites to en sure that the an alytical procedures used for release and stability test ing comply with curre nt good manu facturi ng practices (CGMPs) (21 CFR part 211) or good laboratory practices (GLPs) (21 CFR part 58)

19、, 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 manufacturingmethods, in clud ing an alytical procedures, that dem on strate that the manu factured product meets prescribed sta ndards of safety,

20、 purity, and pote ncy (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)oData must be available to establish that the an alytical procedures used in test ing meet proper sta ndards of accuracy and reliability (21 CFR 81

21、211.194(a )(2). For BLAs, PLAs, and their suppleme nts, the an alytical procedures and their validati on 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 CFR81211.194(a)(2)。對于BLA, PLA及它們的補充，在所提交的許可證申請中應(yīng) 當要有分析

22、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。Represe ntative samples of the product must be submitted and summariesof results of tests performed on the lots represe nted by the submitted sample must be provided (21 CFR 601.2(a) and 601.2(c)(1)(vi). Thereview committee chair may request an alytical testi ng by CB

23、ER laboratory an alysts to evaluate the applica nt=s an alytical 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) and601.2(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 an alytical procedures are of equal importa nee from a validati on perspective.

24、 In gen eral, validated an alytical procedures should be used, irrespective of whether they are for in-process, release, acceptanee, or stability testing. Each quantitative an alytical procedure should be desig ned to mini mize assay variati on.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(yīng)當要應(yīng) 用已驗證過的分析方法，而不論其是被用于過

25、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(yīng)當要減少其分析誤差。An alytical procedures and validati on data are submitted in the sect ions of the applicati on on an alytical procedures and con trols. Recomme ndatio ns on information to be submitted are included in sections III through IX and XI of this guida nee. In format

26、io n on submissi on of the methods validati on package to the NDA or ANDA and samples to the FDA laboratories is provided in sect ion X.分析方法和驗證資料應(yīng)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 PROCEDURESA. Regulatory An alytical Pr

27、ocedure A regulatory an alytical procedure is theanalytical procedure used to evaluate a defined characteristicof the drug substa nee or drug product. The an alytical procedures in the U.S.Pharmacopeia/Natio nal Formulary (USP/NF) are those legally recog ni zed un der section 501(b) of the Food, Dru

28、g, and Cosmetic Act (the Act) as the regulatory an alytical procedures for compe ndial items.For purposes of determ ining complia nee with the Act, the regulatory an alytical 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. Alter nati

29、ve An alytical ProcedureAn alter native an alytical procedure is an an alytical procedure proposed by the applica nt for use in stead of the regulatory an alytical procedure. A validated alter native an alytical procedure should be submitted on ly if it is shown to perform equal to or better than th

30、e 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(yīng)用驗證過的替代分析方法。If an alter native an alytical procedure is submitted, the applica nt should provide a rati on ale for its in clusi on and ide ntify its use (e.g.,release, stability testing), validation d

31、ata, and comparative data to the regulatory an alytical procedure.如果提交了替代分析方法，申請者還應(yīng)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-I ndicati ng AssayA stability-indicating assay is a validated quantitative analytical procedure that can detect the cha nges with time in the pert inent proper

32、ties of the drug substa nce 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-i ndicati ng assay accurately measures the active in gredie nts, without in terfere nce from degradati on products, process impurities, excipie nts, or other potential impurities 。穩(wěn)定性指示分析能

33、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 applica nt submits a non-stability-i ndicati ng an alytical procedure for release test ing, the n an an alytical procedure capable of qualitatively and quantitatively monitoring the impurities, including degradation products, should complement it. Assay a

34、nalytical procedures for stability studies should be stabilityin dicati ng, uni ess scie ntifically 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(yīng)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 STANDARDSA. Types of Stan dards A refere nee sta ndard (i.e., primar

35、y sta ndard) may be obta in ed from the USP/NF or other official sources (e.g., CBER,21 CFR 610.20). If there are questi ons on whether a source of a sta ndard would be con sidered by FDA to be an official source, applica nts should con tact the appropriate chemistry review staff. When there is no o

36、fficial source, a refere nee sta ndard 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(yīng)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(yīng)當要有盡可能高的純度，并得到充分界定。A worki ng sta ndard (i.e., i n-house

37、or sec on dary sta ndard) is a sta ndard that is qualified aga inst and used in stead of the refere nee sta ndard.工作對照品(也就是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 An alysisA certificate of an alysis (COA) for refere nee sta ndards from non-o fficial sources should be submitted in the s

38、ect ion of the applicati on onan alytical procedures and con trols. For sta ndards from official sources, the user should en sure the suitability of the refere nee sta ndard.The sta ndard should be stored correctly and used with in the established use in terval.B份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(yīng)當要提供該標準品

39、的分 析報告單。對于從官方獲得的標準品，用戶應(yīng)當要確保標準品的適用性。應(yīng)當正 確儲存標準品并在已確定的時間段使用該標準品。C. Characterizati on of a Refere nee Sta ndardRefere nee sta ndards from USP/NF and other official sources do not require further characterizatio n. A refere nee sta ndard that is not obtained from an official source should be of the highe

40、st purity that can be obta ined by reas on able effort, and it should be thoroughly characterized to en sure 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 qua ntitative an alytical procedur

41、es used to characterize a refere nee sta ndard are expected to be differe nt from, and more exte nsive tha n, those used to con trol the ide ntity, stre ngth, quality, purity, and pote ncy of the drug substa nee or the drug product. An alytical procedures used to Draft Not forImpleme ntati on charac

42、terize a reference standard should not rely solely on comparison testing to a previously desig nated refere nce sta ndard.用于界定標準品的定性和定量分析方法應(yīng)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 疋的分析方法不應(yīng)僅僅是和先前的指定標準品進行比較實驗。Gen erally, this characterizati on in formatio n should in clude:A brief descript

43、i on of the manu facture of the refere nce sta ndard, ifthe manu facturi ng process differs from that of the drug substa nee. Any additi onal purificati on procedures used in the preparati on of the refere nee sta ndard should be described.一般來說，界定資料應(yīng)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(yīng)的原料藥的話。應(yīng)當要 敘述制備標準品時所用

44、的補充精制過程。Legible reproducti ons of the releva nt spectra, chromatograms, thi n-layer chromatogram (TLC) photographs or reproduct ions, and other appropriate in strume ntal recordi ngs. Data establish ing purity. The data should be obta ined by using appropriate tests, such as TLC, gas chromatography

45、(GC), high-pressure liquid chromatography (HPLC), phase solubility an alysis, appropriate thermometric an alytical procedures, and others as n ecessary.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)當要應(yīng)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捌渌匾姆治龇椒āppropriate chemical attribute in formatio n, suc

46、h as structural formula, empirical formula, and molecular weight. I nformatio n to substa ntiate the proof of structure should in clude appropriate an alytical tests,such as eleme ntal an alysis, in frared spectrophotometry (IR), ultraviolet spectrophotometry (UV), nu clear mag netic res onance spec

47、troscopy (NMR), andmass spectrometry (MS), as well as applicable functional group analysis. Detailedin terpretati on of the test data in support ofthe 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(yīng)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(yīng)當要提供具體的結(jié)構(gòu)解析資料。A physical descripti

48、on of the material, including its color and physical form. Appropriate physical con sta nts such as melt ing ran ge, boili ng ran ge, refractive index, dissociation constants (pK values), and optical rotation. A detailed description of the an alytical procedures used to characterize the refere nee s

49、ta ndard.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 biotech no logical/biological product refere nee sta ndards, therecomme ndati ons on characterizati on in formati on above may apply and should be con sidered. However, additi onal an d/or differe nt tests would be i

50、mporta nt to assess physicochemical characteristics, structural characteristics, biological activity, an d/or immunochemical activity.至于生物技術(shù)/生物產(chǎn)品的標準品，應(yīng)當要考慮上述建 議，可能可以應(yīng)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 determi natio ns may in elude isoform, electrophoretic, and liqu

51、id chromatographic patter ns, as well as spectroscopic profiles. Structural characterizati on may in clude a determ in atio n of amino acid seque nee, amino acid compositi on, peptide map, and carbohydrate structure. Biological an d/or immuno chemical activity should be assessed using the same an al

52、ytical procedures used to determ ine product pote ncy.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(yīng)當要和用來確定產(chǎn)品效力的分析方法一樣。These can in clude ani mal-based, cell culture-based, biochemical, or liga nd/receptor-b inding assays. While these tests may be n eeded for complete

53、characterizati on of certa in refere nee sta ndards, specific recomme ndati ons for validati on of biological and immuno chemical tests arenot contained in this guida nee docume nt.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圍之。V. METHODS VALIDATION FO

54、R INDsFor an inv estigati onal new drug, sufficie nt in formati on is required in each phase of an investigation to ensure proper identification, quality, purity, strength, and/or pote ncy. The amount of in formati on on an alytical procedures and methods validati on n ecessary will vary withthe pha

55、se 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 gen eral guida nee on an alytical procedures and methods validati oninformation to be submitted for phase 1 studies, sponsors should refer t

56、o the FDA guida nee for in dustry on Content and Format of Inv estigati onal New Drug Applicatio ns (INDs) for Phase 1 Studies of Drugs, I nclud ing Well- Characterized, Therapeutic, Biotech no logy-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

57、)第1 階段研究的IND申請的容和格式(1995年11月)。Gen eral guida nee regard ing an alytical procedures and methods validati onin formatio n to be submitted for phase 2 or phase 3 studies will beprovided in the FDA guida nee for in dustry INDs for Phase 2 and 3 Studies of Drugs, In cludi ng Specified Therapeutic Biotech

58、 no logy-Derived Products, Chemistry, Manu facturi ng, and Con trols Content and Format, whe n fin alized (draft guida nee 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容和格式（草案，1999年4月）。All an alytical procedures should be fully developed and validati on 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(yīng)當要開發(fā)出來，并 得到驗證。VI. CONTENT AND FORMAT