美国fda认证与申办指南合成原料药dmf起草大纲(编辑修改稿)

美国fda认证与申办指南合成原料药dmf起草大纲(编辑修改稿)内容摘要：

solvent used, the quantity of solvent in relation to the amount of crude product, whether it is filtered while hot, whether a decolorizing agent is used, the rate of cooling and the final temperature, the use or reuse of any mother liquors, and if second crops are obtained)。 (4) 替代的提纯步骤（参见 ；参见 ） Alternative 9 purification procedures (see the last paragraph of section .。 see also section .)。 (5) 提纯产品的收率范围（重量和百分比） The yield range (weight and percent) of the purified product。 (6) 证明提纯过程增加纯度的有关证据，例如色析法的前后对比 Evidence demonstrating that the purification procedure improves the purity, such as beforeandafter chromatographic illustrations. 当提纯工艺被验证后，只需提供最初产品批次的检验相关信息。 This testing and information may be necessary only on initial production batches, once the purification process has been verified or validated. （ 4）合成的变化 Changes in the synthesis 相关合成的变化应该作为 DMF 的补充来提交。 为改变新药物递交 (NDA)中已经批准的有关原料药的合成方法，制剂递交者也需要提交一个批准的补充文件，这包括有关溶媒的改变。 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. 当合成的路线发生改 变时（如：反应和中间体与新药递交 (NDA)所批准的相关内容不同时），应该提供每一合成路线的比较分析数据（如：完整的纯度档案数据）。 下面我们将讨论有关变化旨在重新定义起始原料的情况。 When the route of synthesis is changed (., reactions and/or intermediates are different from those approved in the NDA), parative analytical data (., a plete purity profile) for the drug substance made by each route should be provided. A special case, where the proposed change is to redefine the starting material, is discussed below. 当用于原料药最终结晶的溶媒发生变化时，应该检查原料药有关晶形和溶剂化物的变化； 参见。 原料药必须符合有关晶形和溶剂化物的原定规格。 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。 refer to section . The new drug substance must meet its original specifications for crystalline form and/or solvation. 有关其它的反应和提纯的溶媒改变也需要一份补充递交，补充递交中应该提供该改变可以产生同等质量和纯度的产品（化合物或中间体）的证据，但无需考虑形态学问题。 Solvent changes for other reaction steps or purifications also require 10 a supplemental application. The application should contain evidence that the change affords material (pound or intermediate) of equivalent quality and purity, but morphology need not be considered. 如果递交者想缩短新药递交 (NDA)中批准的合成方法或者通过重新定义起始原料时，则需要提交一个补充文件 (21 CFR (b) (1))。 该起始原料是一种可从商业渠道获得的用于合成的化合物，该化合物必须是新药递交中（ NDA） 批准的中间体，而且，必须满足起始材料 b 和 c标准要求。 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. 在完成原料药的合成之前，该化合物至少在两个完整的合成阶段前使用。 依据所引用的参考文献（应该提供相关拷贝）的充分性，需要提供起始原料的纯度和特性等额外信息，这包括足够的文献资料（如提供的复印件）。 The pound should be used at least two full steps before the new drug substance if possible (., it should be prior to the final intermediate). Additional information on the characterization and purity profile of the starting material may be needed, depending on the adequacy of the literature references cited (copies should be provided). 对于学术期刊所引用的化合物，详尽的出版材料就够了（如：有关杂质检验的额外信息）。 在有关专利中所规定的化合物，需要提供其完整的特性和纯度档案。 应该描述用于检验每一批新起始原料的分析检测程序。 建立一个通用的检验方案通常就可以了。 For pounds cited in journal articles, an elaboration of the published material (., additional information about testing for impurities) may suffice. For pounds described in patents, both plete characterization and a full purity profile will usually be needed. Analytical test procedures used to qualify each new source/supplier of the new starting material should be described. A general testing protocol may be suitable. 递交者应该通过直接的比较（如：通过分析和使用）证明该化合物与用于临床 试验用的新原料药等效，同时应该证明该化合物的符合承诺的标准。 使用至少是试验性规模（如 :要大于实验室规模）。 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 应该提供用该材料所生产的前三批产品的完整检验结果。 该检验的广度和深度要和用于检测一个新的参考标准品的相同。 A mitment to submit results from thorough examination of the first three fullscale batches made with the material should be provided. The examination should be similar in scope and extent to the testing involved in qualifying a new reference standard. 对于依据联邦法典 21 CFR (c) (3)所做的改变类型，只要有对合成过程的充分描述文件，就可以。 这样的改变，无需 FDA的事先批准就可以执行。 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. 参照标准品 Reference Standard 原始递交的申报文件应该包括任何所使用的参照标准品的制备过程的描述， 包括对提纯步骤的描述，参见 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、生产过程的控制 中间体和生产过程的控制 Intermediates and Inprocess Controls 相关法规要求在合成过程中选择一些中间环节实施控制（检测项目与参数要求），以保证合成和提纯工序顺利进行，并保证检测后的中间体适合于以后的加工。 申请者可以根据对整个合成工艺的开发和确认的经验，自行确定对那些中间体或加工环节进行检测及进行那 些检测项目。 在早期的开发阶段，每一个步骤通常都进行了检验（至少是对反应的内容），每一个中间体至少都进行与纯度有关参数的测定，包括纯度的估计。 随着合成经验的积累，应选择关键的反应步骤和中间体进行监控。 在递交新药申请 (NDA)时，生产过程的控制点应该已经选定，相关控制参数和检验方法也已确立，以满足法律的要求。 The regulations require that controls (specifications a。