【導(dǎo)讀】于理解FDA對(duì)DMF的要求和意圖非常有必要；因此，客戶務(wù)必依照規(guī)定提供盡可能詳細(xì)的內(nèi)容?！端幬锷贽k中質(zhì)量管理方面通用技術(shù)文件格式與內(nèi)容要求》；證等具體技術(shù)要求，請(qǐng)參照本公司專有的FDA相關(guān)技術(shù)標(biāo)準(zhǔn)文件，設(shè)施進(jìn)行現(xiàn)場(chǎng)檢查。DMF文件應(yīng)描述生產(chǎn)場(chǎng)地、設(shè)備能力、生產(chǎn)流程圖等。要設(shè)備的生產(chǎn)能力、用途和位置。通常不用描述設(shè)備的制造商和型號(hào)，除非特。別新或獨(dú)特的設(shè)備。相關(guān)法規(guī)要求對(duì)原料藥的物理和化學(xué)特征做出詳細(xì)描述。對(duì)于蛋白質(zhì)原料藥，參見(jiàn)：“CRC生物化學(xué)和分子生物學(xué)手冊(cè)”“酶。學(xué)方法”和有關(guān)描述蛋白質(zhì)特性的專論。

　　

【正文】 批產(chǎn)品（如：反應(yīng)條件超出一般范圍），應(yīng)該按使用分析標(biāo)準(zhǔn)參照品是否合格的程序來(lái)進(jìn)行檢驗(yàn)。 FDA recognizes that operating conditions (such as time and temperature) occasionally deviate from the NDA description. A protocol should be provided for the procedure which will be used to qualify the batch of intermediate or drug substance as meeting specifications when reaction conditions or operating parameters fall outside the typical/normal range (., excursions, or minor deviations). The protocol should describe the additional analytical testing which will be used in qualification of the batch. The testing should be more extensive than required by routine specifications and tests and may include, as appropriate, the use of nonregulatory analytical methods. For example, batches of new drug substance in this category (, when reaction conditions are outside the norm) should be examined by discerning analytical procedures such as those used for Reference Standard qualification. 對(duì)于母液的處理和二次回收應(yīng)當(dāng)制定控制程序并進(jìn)行描述。參見(jiàn) .。 雖然重復(fù)使用母液和二次回收是常見(jiàn)的并被 CGMP 接受 ，當(dāng)雜質(zhì)含量積累時(shí)，它并不完全被接受的。同時(shí)，廣泛的回收母液或反復(fù)回收是不鼓勵(lì)的（參見(jiàn)： CGMP第 IV 節(jié)和“關(guān)于大宗藥用化學(xué)物制造的現(xiàn)場(chǎng)檢查指南”）。 Inprocess control procedures should be established and described for the handling of mother liquors and recovery of second crops when this is done。 see section . While the reuse of mother liquors and recovery of second crops may be mon/normal practice and is acceptable from a CGMP viewpoint, it is not necessarily acceptable (., when impurity levels build up), and extensive recycling of mother liquors or repeated recoveries of additional crops is discouraged (refer to section IV (CGMP) and the Guideline for Inspection of 15 Bulk Pharmaceutical Chemical Manufacture in this regard.) 母液的回收程序應(yīng)該包括在批產(chǎn)品生產(chǎn)紀(jì)錄中。 新藥申請(qǐng) (NDA)中應(yīng)規(guī)定對(duì)不符合標(biāo)準(zhǔn)的原料藥的再加工程序，這一過(guò)程通常是通過(guò)從最終溶媒中進(jìn)行一次或多次再結(jié)晶來(lái)完成。不需要額外的分析檢驗(yàn)。 The recovery procedures should be included in batch production records. Provision should be made in the NDA for the typical and usual reprocess procedure for drug substance which fails to meet specifications, usually by one or more additional recrystallizations from the final solvent. Extraordinary analytical examination is not required in this case. 不符合既定標(biāo)準(zhǔn)的單一批產(chǎn)品可以通過(guò)適當(dāng)?shù)某绦騺?lái)純化， 然后按照新藥申請(qǐng)(NDA)中所描述的最終提純過(guò)程處理， 前提是，用于最終純化的材 料純度，與通常加工情況下的材料純度相同。 A single batch of drug substance which fails to meet specifications may be purified by an appropriate procedure and then processed by the same final purification procedure described in the NDA, provided that the purity of the reprocessed material being so treated in the final purification step is as good as the normal drug substance at this stage of processing. 一些可再利用的散裝原料藥（如：累積的未使用的分析樣品，未使用的批產(chǎn)品，由客戶退回的產(chǎn)品）可以用同樣的方法加工。 Some types of bulk drug substance for salvage (., accumulated unused analytical samples, unused portions of lots, bulk returned from customers) may be processed in this fashion. 這些再加工的原料藥應(yīng)該接受如上面所描述的（如：對(duì)稍微背離正常加工條件下所生產(chǎn)出的原料藥）額外分析檢驗(yàn)。再加工操作和其原因應(yīng)該記錄。依照目前法規(guī)，在沒(méi)有額外提純 (經(jīng)過(guò)新藥申請(qǐng) (NDA)所描述的最終提純步驟的處理 )情況下， 為使不合格的批可再利用而進(jìn)行的混批是不能接受的。 Such reworked drug substance batches should be subjected to additional analytical examination, as indicated above (., for drug substance resulting from minor deviations of process conditions). The rework operation, and the reason for it, should be documented. The blending of batches or lots for the purpose of salvaging unsatisfactory batches, without subsequent additional purification by an appropriate procedure and processing by the final purification step described in the NDA, is not permitted under current guidelines. 如果在新藥申請(qǐng)（ NDA）中沒(méi)有提到，要經(jīng)常使用某一標(biāo)準(zhǔn)的（經(jīng)過(guò)驗(yàn)證的）再加工程序，對(duì)不合格原料藥進(jìn)行處理，那么，應(yīng)提供這方面的補(bǔ)充資料。 參見(jiàn)“化學(xué)原料藥生產(chǎn)現(xiàn)場(chǎng)檢查指南”。 If not part of the original NDA, a supplement should be submitted to the NDA when a standard (validated) reprocessing procedure for unsatisfactory bulk drug substance is to be 16 routinely employed。 refer to the Guide to Inspection of Bulk Pharmaceutical Chemical Manufacturing. 當(dāng)原料藥要從制劑中回收時(shí)， 應(yīng)當(dāng)參見(jiàn)“關(guān)于提交制劑產(chǎn)品生產(chǎn)和控制文件的指南”。這樣的操作需要提供補(bǔ)充資料。 When drug substance is to be recovered from dosage forms, reference should also be made to the Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products. This type of operation will require a supplement. 六、成品的控制 相關(guān)法律要求制定規(guī)格參數(shù)和分析方法（如：新原料藥的放行控制），以幫助確保原料藥的特性、濃度、質(zhì)量和純度達(dá)到要求并且每批均一致。應(yīng)該提交以下信息，以定義這些控制參數(shù)和檢驗(yàn)方法。 The regulations require specifications and analytical methods (., release controls for the new drug substance) to help assure that the proper identity, strength, quality, and purity of the drug substance have been attained and are consistent from batch to batch. The following information should be submitted to define these specifications and test methods: 抽樣 Sampling CGMP 條例 中有關(guān)于抽樣的描述（參見(jiàn)： IV）。應(yīng)該描述抽樣計(jì)劃，制定該計(jì)劃的依據(jù)；抽樣應(yīng)該滿足相關(guān)統(tǒng)計(jì)學(xué)的考慮。 Sampling requirements are covered by CGMP regulations (see section IV). The sampling plan should be described, giving the basis for the plan。 it should satisfy appropriate statistical considerations. 放行控制 Release Controls 對(duì)放行中可能使用的規(guī)格和檢驗(yàn)標(biāo)準(zhǔn)，舉例如下： Examples of specifications and tests that may be applicable are as follows: (1) 外觀 /描述 Appearance/description (2) 物理特性 （如：熔化范圍、旋光率、折射率、晶形、粒度） 對(duì)有手性中心或其它結(jié)構(gòu)要求的原料藥，相關(guān)的控制參數(shù)和檢驗(yàn)應(yīng)該能夠保證，所生產(chǎn)出原料藥具有治療活動(dòng)所需特征。參見(jiàn)第 III 部分。 Physical properties (., melting range, specific rotation, refractive index, crystalline form, particle size). For drug substances with chiral centers or other configurational requirements, the specifications and tests should assure that material (whether a single enantiomer or isomer, a racemate, or a known ratio of isomers) with the requisite properties for therapeutic activity has been produced. See section 17 III in this regard. 同樣，當(dāng)藥物的固態(tài)特性（參見(jiàn) ）， 如：多態(tài)現(xiàn)象或分子大小，會(huì)影響生理學(xué)或藥理學(xué)活性（如：藥物的生物效率），則相關(guān)控制參數(shù)和檢驗(yàn)應(yīng)該提供對(duì)這些特性的適當(dāng)?shù)南薅龋o(wú)論是單獨(dú)形式或混合物形式）。 Similarly, when the solidstate properties (see section .) of the new drug substa