【正文】 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 ）， 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論是單獨(dú)形式或混合物形式）。 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。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。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。這樣的操作需要提供補(bǔ)充資料。 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。 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）中沒有提到，要經(jīng)常使用某一標(biāo)準(zhǔn)的（經(jīng)過驗(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。再加工操作和其原因應(yīng)該記錄。 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。不需要額外的分析檢驗(yàn)。 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。同時(shí)，廣泛的回收母液或反復(fù)回收是不鼓勵(lì)的（參見： 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”）。參見 .。例如 ,對(duì)超出正常條件的 新原料藥批產(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進(jìn)行檢驗(yàn)。這樣的檢驗(yàn)應(yīng)該比日常要求的控制參數(shù)和檢驗(yàn)范圍更廣。應(yīng)當(dāng)制定一個(gè)方案，規(guī)定當(dāng)反應(yīng)條件或操作控制參數(shù)超出通常的范圍時(shí)（如：偏離或較小的背離），應(yīng)當(dāng)采用什么樣的程序，來使該批中間體或原料藥合格。當(dāng)采用替代的提純方法時(shí)，獲得的產(chǎn)品應(yīng)象第一次一樣，接受最 后 加 工 操 作 與 檢 驗(yàn) 。The specifications should be adequate to assure that the molecular architecture necessary for the final product, as well as the requisite degree of purity, have been attained. Test procedures should thus show that the desired transformation (such as introduction of chirality, or a stereospecific reaction) has occurred in the manner expected and within the normal yield range expected, and show by quantitative determination(s) that undesired materials (., isomers, byproducts, starting materials) are within established limits. 最終中間體 （參見術(shù)語表） Final intermediate (see Glossary.) 關(guān)于最終中間體的規(guī)格和檢驗(yàn)應(yīng)該與原料藥的規(guī)格和檢驗(yàn)同樣廣泛和嚴(yán)格，因?yàn)檫@是最終反應(yīng)前的最后監(jiān)控純度和雜質(zhì)的機(jī)會(huì)。當(dāng)關(guān)鍵中間體接近成為最終中間體時(shí)，對(duì)其進(jìn)行的檢測(cè)程度和純度要求也應(yīng)該增加 Any pivotal intermediate should be described in adequate detail (., be well characterized) and be subject to rigorous examination procedures as part of the specifications and tests, including thorough chromatographic examination so as to avoid overlooking impurities arising from alternative syntheses. Such rigorous examination need not be routine but may be needed in special circumstances such as when the supplier or synthesis is changed. The degree of testing and the level of purity required for a pivotal intermediate should increase as its position in the synthesis scheme approaches the final intermediate. 核心中間體 （參見術(shù)語表） Key intermediate(s) (See Glossary.) 對(duì)核心中間體，應(yīng)制定充足的規(guī)格，以保證能生產(chǎn)出所需的分子結(jié)構(gòu)和純度的最終產(chǎn)品。 Some or all of the above kinds of process controls should be met at each point selected for inprocess control testing. Pivotal, key, and final intermediates (see Glossary, and below) would ordinarily require at least the inprocess controls listed above. To eliminate the need for heroic final cleanups, it is expected that the degree of purity of intermediates will increase progressively, from the first intermediate on to the drug substance itself. 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)。關(guān)鍵、核心和最后的中間體（參見：術(shù)語表）通常至少應(yīng)當(dāng)符合以上所列過程控制的要求。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）。 (c) 確定中間體的純度和雜質(zhì) determine purity/impurity of the intermediate。 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).