【正文】 lf. 關(guān)鍵中間體 （見術(shù)語表） Pivotal intermediate(s) (See Glossary.) 應(yīng)該用足夠的細(xì)節(jié)（如詳細(xì)描述其特征）描述任何關(guān)鍵中間體，并作為 控制參數(shù)與檢驗(yàn)的一個(gè)部分，對(duì)其進(jìn)行嚴(yán)格的檢查，其中還包括通過層析法，以避免忽略由替代合成方法產(chǎn)生的雜質(zhì)。如有可能，檢測(cè)也可僅限于對(duì)合成過程的監(jiān)控 （如：反應(yīng)是否完成）。 This whole operation is part of the process validation of the synthesis. The basis for selecting control points and intermediates should be explained, and the adequacy of the specifications and tests to control the synthetic process demonstrated. The ranges for the operating parameters in the written description of the synthesis should be chosen in light of the controls (specifications and tests). Generally, broad operating ranges will require stricter controls. (See also section . (recovery and rework) below.) With additional experience subsequent to NDA approval, the choice and nature of inprocess control procedures may require modification. Changes in inprocess control procedures will require additional validation (see section IV). 設(shè)計(jì)控制為得是： Controls may be designed to (a) 證明已獲得了想要生產(chǎn)的產(chǎn)品 demonstrate that the desired product has been obtained。應(yīng)當(dāng)依據(jù)相關(guān)控制點(diǎn)（控制參數(shù)和檢測(cè)方法）來提供控制參數(shù)范圍的書面描述。在遞交新藥申請(qǐng) (NDA)時(shí)，生產(chǎn)過程的控制點(diǎn)應(yīng)該已經(jīng)選定，相關(guān)控制參數(shù)和檢驗(yàn)方法也已確立，以滿足法律的要求。 For changes of the type permitted by 21 CFR (c) (3), an adequate synthesis description on file would facilitate a conclusion that changes in site of manufacture of the new drug substance do not require prior FDA approval for implementation. 參照標(biāo)準(zhǔn)品 Reference Standard 原始遞交的申報(bào)文件應(yīng)該包括任何所使用的參照標(biāo)準(zhǔn)品的制備過程的描述， 包括對(duì)提純步驟的描述，參見 original application should include a full description of the preparation of any reference standard substance used, including the description of the purification steps. See also section . . 五、生產(chǎn)過程的控制 中間體和生產(chǎn)過程的控制 Intermediates and Inprocess Controls 相關(guān)法規(guī)要求在合成過程中選擇一些中間環(huán)節(jié)實(shí)施控制（檢測(cè)項(xiàng)目與參數(shù)要求），以保證合成和提純工序順利進(jìn)行，并保證檢測(cè)后的中間體適合于以后的加工。 The applicant should demonstrate by direct parison (., both by analyses and by a use test) that the pound is equivalent to the material used to make the new drug substance employed in the clinical trials, and that the acceptance tests and specifications for the pound are adequate. The use test should be at least on a pilot scale (., larger than bench scale). 11 應(yīng)該提供用該材料所生產(chǎn)的前三批產(chǎn)品的完整檢驗(yàn)結(jié)果。應(yīng)該描述用于檢驗(yàn)每一批新起始原料的分析檢測(cè)程序。 An approved supplement is required (21 CFR (b) (1)) if an applicant wants to shorten the synthesis approved in the NDA or develop a new synthetic method by redefining the starting material, in order to employ a pound later in the synthesis that has bee mercially available. This pound must have been an intermediate in the approved NDA synthesis, and must meet both the b and c criteria for starting material. 在完成原料藥的合成之前，該化合物至少在兩個(gè)完整的合成階段前使用。 When there is a change in the solvent used for the final crystallization of the new drug substance, the new drug substance should be examined for changes in crystalline form and/or solvation。 Proposed changes in the synthesis should be submitted to the application as a supplement for an approved NDA or as an amendment to an IND, a DMF, or a pending NDA. An approved supplement is required [21 CFR (b) (1) (iv)] to change the method of synthesis approved in the NDA for the drug substance, including a change in solvents. 當(dāng)合成的路線發(fā)生改 變時(shí)（如：反應(yīng)和中間體與新藥遞交 (NDA)所批準(zhǔn)的相關(guān)內(nèi)容不同時(shí)），應(yīng)該提供每一合成路線的比較分析數(shù)據(jù)（如：完整的純度檔案數(shù)據(jù)）。 (5) 提純產(chǎn)品的收率范圍（重量和百分比） The yield range (weight and percent) of the purified product。 (3) 詳細(xì)的分離和純化過程的記錄（如：對(duì)于重結(jié)晶過程：所使用的溶媒，與原料產(chǎn)品相關(guān)的溶媒的數(shù)量，溶媒在熱時(shí)候是否被過濾，是否使用了脫色劑，冷卻溫度與和最終溫度，母液的使用和再使用，溶媒是否進(jìn)行了二次回收。應(yīng)該提供每一不同合成方法所生產(chǎn)的原料的比較性分析數(shù)據(jù)Any alternate method or permissible variation that may be employed (., alternate starting materials, reactants, solvents, conditions, catalysts, isolation, and/or purification procedures) should be reported. Comparative analytical data for the material produced by each variant synthetic method should be provided. （ 3）原料藥的純化 Purification of the drug substance 應(yīng)該詳細(xì)描述原料的提純情況和其從最終反應(yīng)混合物中分離的情況。 The final step of the synthesis and the isolation of the crude new drug substance, as well as its purification, should be provided in full detail. (See section below regarding purification of the drug 8 substance.) 除了提供合成的書面描述，還包括經(jīng)過確認(rèn)的操作參數(shù)范圍（參見第 II 節(jié) E 工藝控制）和第 IV 節(jié) [CGMP])以及預(yù)期收率，遞交者同時(shí)要提供實(shí)際操作的書面實(shí)例（ BPR），明確指出它是供審閱官參考。 Purification procedures for drug substance and for intermediates, if employed。 (5) 反應(yīng)完成的檢測(cè)，如果有的話。重要的副產(chǎn)品和雜質(zhì)，尤其是那些干擾分析過程或有毒性的，應(yīng)當(dāng)被分別表示出來（參見：第 . 和 .） A ratio or mixture of products (., two or more isomers) produced by a reaction should be shown in the flow chart. Significant side products and impurities, particularly those that interfere with the analytical procedures or are toxic, should be illustrated separately (see sections . and .). （ 2）合成描述 Description of the synthesis 每一個(gè)合成步驟的書面描述以及更詳細(xì)的最后加工步驟的描述應(yīng)該包括以下內(nèi)容 The written statement for each step of the synthesis, with greater detail included toward the final steps of the process, should include the following: (1) 用于反應(yīng)的典型設(shè)備 Typical equipment used for the reaction。 (2) ) 立體化學(xué)結(jié)構(gòu)，如果有立體化學(xué)構(gòu)形 Stereochemical configurations, where applicable。 These chemicals should also be listed. The specifications and test methods for each such material should be stated, and/or a statement of quality provided. The applicant should describe the specific identity test performed (unless omitting such a test has been otherwise justified, ., because of hazard). The extent of additional testing performed – whether by the supplier or by the applicant should be based on the role of the chemical in the synthesis. For example: a base (., sodium hydroxide) used to neutralize excess acid in a synthetic reaction mixture would not normally require extensive purity testing。遞交者應(yīng)當(dāng)注明具體的檢驗(yàn)方法（除非忽略這種檢驗(yàn)可被認(rèn)為是正當(dāng)?shù)模?。通過定期與不定期的核查與驗(yàn)證來評(píng)估原料供應(yīng)商提供的產(chǎn)品質(zhì)量是穩(wěn)定的 ，供應(yīng)商提供的質(zhì)量保障聲明應(yīng)該包括相關(guān)的規(guī)格和結(jié)果 ,并應(yīng)該注明用于檢 6 測(cè)的分析方法。分析檢驗(yàn)方法應(yīng)當(dāng)簡(jiǎn)要描述。 Again, not