【正文】 5年 11 月）。 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 (a)(7)). V． IND中的分析方法驗(yàn)證 對(duì)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。 These can include animalbased, cell culturebased, biochemical, or ligand/receptorbinding assays. While these tests may be needed for plete characterization of certain reference standards, specific remendations 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。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)。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(cè)和 /或其它檢測(cè)將是非常重要的。用于界定標(biāo)準(zhǔn)品的分析程序的詳細(xì)敘述。 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)。結(jié)構(gòu)確證資料應(yīng)當(dāng)要包括適當(dāng)?shù)姆治鰷y(cè)試，比如元素分析， IR， UV,NMR和 MS，及適用的官能團(tuán)分析。應(yīng)當(dāng)要應(yīng)用適當(dāng)?shù)臋z測(cè)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? Legible reproductions of the relevant spectra, chromatograms, thinlayer 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), highpressure 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。 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(jiǎn)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。 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 parison 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。 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(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。對(duì)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。 A working standard (., inhouse or secondary standard) is a standard that is qualified against and used instead of the reference standard. 工作對(duì)照品 (也就是內(nèi)部標(biāo)準(zhǔn)品或二級(jí)標(biāo)準(zhǔn)品 )是根據(jù)一級(jí)對(duì)照品標(biāo)定的，并用來代替一級(jí)對(duì)照品的。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(qǐng)者應(yīng)當(dāng)要向適當(dāng)?shù)幕瘜W(xué)評(píng)審人員咨詢。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。 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(cè)定其中的活性成分。 C. StabilityIndicating Assay A stabilityindicating 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(cè)出原料藥或制劑的某些性質(zhì)隨著時(shí)間的延長(zhǎng)而出現(xiàn)的變化的定量分析方法。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。為了確認(rèn)符合法規(guī)，需使用法定分析方法。 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 . 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 pendial items. For purposes of determining pliance 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(píng)估原料藥或制劑的特定性質(zhì)的。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。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。 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 inprocess, 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。 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 (a) and (c)(1)(vi)). The review mittee 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(hào)的檢測(cè)結(jié)果總結(jié) (21 CFR (a) and (c)(1)(vi))。 Data must be available to establish that the analytical procedures used in testing meet proper standards of accuracy and reliability (21 CFR (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 mittee. 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 (a)(2))。 FDA investigators inspect the analytical laboratory testing sites to ensure that the analytical procedures used for release and stability testing ply w