【正文】 Sampling requirements are covered by CGMP regulations (see section IV). The sampling plan should be described, giving the basis for the plan。 參見“化學(xué)原料藥生產(chǎn)現(xiàn)場檢查指南”。 新藥申請 (NDA)中應(yīng)規(guī)定對不符合標(biāo)準(zhǔn)的原料藥的再加工程序，這一過程通常是通過從最終溶媒中進(jìn)行一次或多次再結(jié)晶來完成。如需要，可以使用非常規(guī)分析方法。檢測程序應(yīng)該能夠標(biāo)明，所需要的轉(zhuǎn)換（如：手性的引入或立體定向反應(yīng)）已經(jīng)按照預(yù)想的方式發(fā)生，并在預(yù)期的收率范圍內(nèi)，同時通過定量分析表明，不需要的材料（如：異構(gòu)體、副產(chǎn)品、起始原料）已經(jīng)限制在既定限度之內(nèi)。 (d) 確定收率 是限定在通常的操作范圍之內(nèi) determine that the yield is within the normal operating range. 在某些情況下，對中間體的控制是不可行的（如：它們處于溶液狀態(tài)或直接加工成下一個化合物）。應(yīng)當(dāng)證明控制參數(shù)和檢測方法對合成過程的控制是充分的。這樣的改變，無需 FDA的事先批準(zhǔn)就可以執(zhí)行。在有關(guān)專利中所規(guī)定的化合物，需要提供其完整的特性和純度檔案 。 原料藥必須符合有關(guān)晶形和溶劑化物的原定規(guī)格。 see also section .)。s information. This example should not be merely a copy of batch records but should contain more detail. 應(yīng)該描述所采取的替代措施（如：替代起始原料、反應(yīng)物、溶媒、條件、催化劑、分析和提純過程）。 (7) 原料藥和中間體的純化過程，如果有。 反應(yīng)所產(chǎn)生的產(chǎn)品與副產(chǎn)品混合比率 (如：兩個或更多異構(gòu)體 )應(yīng)該顯示在流程圖上。相反，用于關(guān)鍵環(huán)節(jié)的光學(xué)活性的有機(jī)酸（如：某種酸的 對映體），則需要這樣的額外檢測。在某些情況下，當(dāng)雜質(zhì)（如芳香化合物的異構(gòu)體）被混入原料藥時，應(yīng)提供純度檔案（如包括雜質(zhì)的定量與定性色譜圖）。實(shí)際數(shù)據(jù)及其解釋的細(xì)節(jié)應(yīng)當(dāng)放在“參考標(biāo)準(zhǔn)”章節(jié)（參見 , 和 3）。 mass spectrometry (MS)。 partition coefficients。 The regulations require a full description of the physical and chemical characteristics of the drug substance. This requirement may be satisfied by the submission of information such as the following: name (generic name, chemical name, code number)。 A Type I DMF is normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected. 場地的描述應(yīng)包括面積、實(shí)際地址以及表明該場地與最近的城市的距離的地圖。 本大綱的內(nèi)容和相關(guān)要求能夠確?？蛻裟壳暗倪\(yùn)作達(dá)到 FDA的 cGMP 標(biāo)準(zhǔn)，因此，準(zhǔn)備 DMF 的過程，也使客戶按照 FDA 的要求 進(jìn)行整改和提高的過程，這些都為 FDA 未來的現(xiàn)場檢查打下良好基礎(chǔ)； 凡是本大綱中提到的非技術(shù)性具體內(nèi)容要求，請參照本公司專有的與此大綱配套的相關(guān) DFM指導(dǎo)性文件，包括 《 FDA藥物主文件指南》、《 關(guān)于在藥品遞交中遞交的有關(guān)原料藥生產(chǎn)的支持文件的指南》、《藥物申辦中質(zhì)量管理方面通用技術(shù)文件格式與內(nèi)容要求》； 凡是本大綱中提到的技術(shù)性具體內(nèi)容要求，如雜質(zhì)、穩(wěn)定性、驗(yàn)證等具體技術(shù)要求，請參照本公司專有的 FDA 相關(guān)技術(shù)標(biāo)準(zhǔn)文件，包括 《原料藥認(rèn)證指南》、《制劑認(rèn)證指南》、《化學(xué)藥物穩(wěn)定性指南》、《化學(xué)藥物雜質(zhì)指南 》、《化學(xué)藥物化驗(yàn)與合格參數(shù)指南》、《化學(xué)藥物驗(yàn)證指南》等； 3 《合成原料藥 DMF 起草大綱》 一、公司和生產(chǎn)場地的基本描述 第一類的 DMF 文件建議由位于美國之外的人提供，以幫助 FDA 對他們的生產(chǎn)設(shè)施進(jìn)行現(xiàn)場檢查。 A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique. 公司主要的組成部門結(jié)構(gòu)圖， 包括總公司和生產(chǎn)場地的關(guān)鍵生產(chǎn)、質(zhì)量控制、質(zhì)量保證崗位， A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful. 4 二、原料藥的物理和化學(xué)特征 特性 Properties 相關(guān)法規(guī)要求對原料藥的物理和化學(xué)特征做出詳細(xì)描述。 stereochemistry (identifying chiral centers, cistrans isomerism, etc.)。 specific gravity. For drug substances that are proteins, see the CRC Handbook of Biochemistry and Molecular Biology, Methods in Enzymology, and related monographs for how protein properties may be described. 并非所有的遞交都要求上述信息，額外的信息也可能需要，特別是隨著生產(chǎn)工藝的復(fù)雜性的增加。 degradative analysis (., amino acid sequencing and/or analysis)。分析檢驗(yàn)方法應(yīng)當(dāng)簡要描述。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?(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。 (5) 反應(yīng)完成的檢測，如果有的話。 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。 (3) 詳細(xì)的分離和純化過程的記錄（如：對于重結(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。 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（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），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)）。 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完整的合成階段前使用。 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。在遞交新藥申請 (NDA)時，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。 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。 Some or all of the above kinds of process controls should be met at each point se