《合成原料药DMF起草大纲》

1、合成原料药DMF起草大纲 一、公司和生产场地的基本描述 1、第一类的DMF文件建议由位于美国之外的人提供，以帮助FDA对他们的生产设施进行现场检查。DMF文件应描述生产场地、设备能力、生产流程图等。A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site,

2、equipment capabilities, and operational layout. 2、第一类的DMF文件对美国国内设施通常不需要，除非该设施没有登记并定期接受检查。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. 3、场地的描述应包括面积、实际地址以及表明该场地与最近的城市的距离的地图。提供该场地的鸟瞰图和平

3、面图。The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful. 4、主要生产和加工区域的平面图对于理解整个生产布局会有帮助。应当描述主要设备的生产能力、用途和位置。 通常不用描述设备的制造商和型号，除非特别新或独特的设备。A diagram of majo

4、r 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. 5、公司主要的组成部门结构图， 包括总公司和生产场地的关键生产、质量控制、质量保证

5、岗位，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.二、原料药的物理和化学特征 1、特性 Properties 相关法规要求对原料药的物理和化学特征做出详细描述。该要求可以通过提供下述信息来满足： 名称（通用名、化学

6、名、编码等）、化学摘要服务(CAS)编码、性状描述（如：外观、颜色、物理状态）、分子式和分子重量、结构式（包括离子状态）、立体化学（找出手性中心、顺式反式异性等）、对映结构体比率（如：外消旋物、规定的异构体、对映异构物和固态形式的混合物）、溶解度概况（水溶性的或非水溶性的）、分配系数、溶液pH值、解离常数、熔点或沸点、折射率、比重。对于蛋白质原料药，参见：“CRC生物化学和分子生物学手册” “酶学方法”和有关描述蛋白质特性的专论。The regulations require a full description of the physical and chemical characteris

7、tics 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); Chemical Abstracts Service (CAS) number if available; description (e.g., appearance, color, physical state); molecular formula and mo

8、lecular weight; structural formula (including ionic state if applicable); stereochemistry (identifying chiral centers, cis-trans isomerism, etc.); enantiomer or solid-state form ratios (e.g., for racemates, and for defined admixtures of isomers or enantiomers or solid-state forms); solubility profil

9、e (aqueous and nonaqueous as applicable); partition coefficients; solution pH; dissociation constant(s); melting or boiling point; refractive index; specific gravity. For drug substances that are proteins, see the "CRC Handbook of Biochemistry and Molecular BiologyDrugs and Biologics" for

10、assistance in fulfilling this requirement.四、原料药的生产 1、起始材料的控制程序 Control procedures for starting materials 应当列出起始原料。应该提供其承诺的标准和用来判定其特性、质量和纯度的检验方法。分析检验方法应当简要描述。起始原料的来源通常无需说明，但有时会要。Starting materials should be listed. Acceptance specifications and tests defining identity, quality, and purity should be p

11、rovided. The analytical test methods should be briefly described. The source of the starting material need not be identified, but may be requested. 对起始材料应该进行鉴别和含量测定分析。在某些情况下，当杂质（如芳香化合物的异构体）被混入原料药时，应提供纯度档案（如包括杂质的定量与定性色谱图）。通过定期与不定期的核查与验证来评估原料供应商提供的产品质量是稳定的，供应商提供的质量保障声明应该包括相关的规格和结果,并应该注明用于检测的分析方法。A spe

12、cific identity test should be performed, as well as an assay, with limits for impurities. In those cases where impurities (e.g., positional isomers of aromatic compounds) could be carried through to the drug substance, a purity profile should be provided (e.g., chromatography with quantitation/ident

13、ification of impurities). Assurances or statements of quality from the supplier are acceptable for the profile, provided that the manufacturer establishes the reliability of the supplier#39;s analyses through validation, initially and at appropriate intervals. These statements from suppliers should

14、include specifications and results and should indicate the type of method 2、试剂、溶媒和辅料控制 Reagents, solvents, and auxiliary materials controls 应列出合成原料、溶媒的内容。标明以上原料、溶媒的规格和检验方法，并应该提供相关的质量声明。递交者应当注明具体的检验方法（除非忽略这种检验可被认为是正当的）。无论是原料供应商还是递交者，进行额外检验时，应该依据该化学成分在合成中的作用进行。例如，对于用来中和合成反应混合物中多余的酸用得碱时(如氢氧化钠)，通常不需要进行的

15、纯度检测。相反，用于关键环节的光学活性的有机酸（如：某种酸的对映体），则需要这样的额外检测。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 ha

16、s been otherwise justified, e.g., 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 examp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 synt

17、hesis 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 314.70(b) (1) (iv) to change the method of synthesis approved in the NDA for the drug substance, including a change in sol

18、vents. 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 (i.e., reactions and/or intermediates are different from those approved in the NDA), comparative analytical data (i.e., a complete purity profile) for the

19、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II.G。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 t

20、he new drug substance, the new drug substance should be examined for changes in crystalline form and/or solvation; refer to section II.G. 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

21、据，但无需考虑形态学问题。Solvent changes for other reaction steps or purifications also require a supplemental application. The application should contain evidence that the change affords material (compound 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(ND

22、A)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 314.70(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 314.70(b) (1) if an applicant wants to shorten the synthesis approved in the NDA or develop a new synthet

23、ic method by redefining the starting material, in order to employ a compound later in the synthesis that has become commercially available. This compound must have been an intermediate in the approved NDA synthesis, and must meet both the "b" and "c" criteria for starting materia

24、l. 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 compound should be used at least two full steps before the new drug substance if possible (i.e., it should be prior to the final intermediate). Additional information on the characterization and pu