合成原料药DMF起草大纲.docx

1、合成原料药DMF起草大纲合成原料药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 manufactur

2、ing site, 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

3、该场地的鸟瞰图和平面图。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

4、 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. 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

5、量控制、质量保证岗位，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（

6、通用名、化学名、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 chara

7、cteristics 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

8、and molecular 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

9、profile (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 Biology, Methods in Enzymology, and r

10、elated monographs for how protein properties may be described.并非所有的递交都要求上述信息，额外的信息也可能需要，特别是随着生产工艺的复杂性的增加。The items above are not necessary or appropriate for all submissions. Additional information may be required, particularly as the state of the art progresses.2、结构 Structure对于结构的说明（如：相关数据和其解释）应当基于

11、一个合适的物理和化学检测结果。这包括以下内容：元素分析；质谱分析(MS)；核磁共振(NMR)；紫外(UV)和红外(IR)光谱学；分子量测定；立体化学和构象分析（如：光学和几何学异构体）；X光分析；降解分析（如：氨基酸排序和分析）；色析图谱；其它检验（如：功能团分析，衍生作用，络合形式等）The elucidation of structure (e.g., the data and its interpretation) should be based on appropriate physical and chemical test results. These may include th

12、e following: elemental analysis; mass spectrometry (MS); nuclear magneticresonance (NMR), ultraviolet (UV), and infrared (IR) spectroscopy; molecularweight determination; stereochemistry and configurational or conformationalanalysis (e.g., optical and geometric isomers); X-ray analysis; degradativea

13、nalysis (e.g., amino acid sequencing and/or analysis); chromatographicprofile; other tests (e.g., functional group analysis, derivatization, complexformation).同样，并非所有以上条目都是必须的或适用于所有情况，所列条目也不是完全的（工艺过程更加复杂和新原料药需要时，也许需要做出更多的分析）。实际数据及其解释的细节应当放在“参考标准”章节（参见II.F.2, 和 3）。Again, not all items are necessary o

14、r appropriate in all cases, and the listing should not be considered limiting (i.e., more analysis may be required as the state of the art progresses and the nature of the new drug substance demands). The actual data and the details of its interpretation should be placed in the section for Reference

15、 Standard (see II.F.2, and 3.).三、原料药的稳定性相关法规要求对原料药的稳定性做全面的描述。具体要求，参见“关于提交人类用药品和生物制品稳定性文件的指南”。The regulations require a full description of the stability of the drug substance. See the Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics for assistance in fulfilling t

16、his 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 provided. The analytical test

17、 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 specific identity test should be

18、 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/identification of impurities). Ass

19、urances or statements of quality from the supplier are acceptable for the profile, provided that the manufacturer establishes the reliability of the suppliers analyses through validation, initially and at appropriate intervals. These statements from suppliers should include specifications and result

20、s and should indicate the type of method2、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），

21、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 has been otherwise justified, e.g., b

22、ecause 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 example: a base (e.g., sodium hydroxide) used to neutralize excess acid in a synthetic reaction mixture would not normally req

23、uire extensive purity testing; in contrast, an optically active organic acid used in a resolution step (e.g., one enantiomer of dibenzoyltartaric acid) would require such additional testing.3、详细的合成信息递交者应当提供完整的合成信息，从起始原料到最终成品原料药。有关描述应当包括整个合成过程的流程图以及每一合成步骤的说明）。An applicant should provide complete info

24、rmation on the synthesis, from starting material(s) to the bulk new drug substance. The description should contain a diagrammatic flow chart of the whole synthesis and a written statement for each step of the synthesis.（1）合成流程图 Flow chart of the synthesis.合成的流程图应该包括以下内容 The flow chart typically shou

25、ld contain the following:(1) 反应物和产品的化学结构（如：起始原料、中间体，以及引入到结构中的分子） Chemical structures of reactants (i.e., starting materials andintermediates, and also molecules incorporated into the structure) andproducts;(2) ) 立体化学结构，如果有立体化学构形Stereochemical configurations, where applicable;(3) 中间体（未分离的或已分离的）Interm

26、ediates (either in situ or isolated);(4) 溶媒、催化剂和试剂 Solvents, catalysts, and reagents;反应所产生的产品与副产品混合比率(如：两个或更多异构体)应该显示在流程图上。重要的副产品和杂质，尤其是那些干扰分析过程或有毒性的，应当被分别表示出来（参见：第II.D.2.c. 和 II.F.3.） A ratio or mixture of products (e.g., two or more isomers) produced by a reaction should be shown in the flow chart

27、. Significant side products and impurities, particularly those that interfere with the analytical procedures or are toxic, should be illustrated separately (see sections II.D.2.c. and II.F.3.).（2）合成描述 Description of the synthesis每一个合成步骤的书面描述以及更详细的最后加工步骤的描述应该包括以下内容The written statement for each step

28、of the synthesis, with greater detailincluded toward the final steps of the process, should include the following:(1) 用于反应的典型设备 Typical equipment used for the reaction;(2) 反应物（本步骤所使用的起始原料或中间体，包括化学名称和数量）Reactants (starting material or intermediate used in the step, with chemical names and amounts);(3

29、) 溶媒、催化剂和试剂（注明化学名称和数量）Solvents, catalysts, and reagents (chemical names and amounts);(4) 反应条件（温度，pH值，时间，压力等）Conditions (temperature, pH, time, pressure, etc.);(5) 反应完成的检测，如果有的话。 Tests for completion of reaction, if employed;(6) 分离的程序 Workup and isolation procedures;(7) 原料药和中间体的纯化过程，如果有。 Purification

30、 procedures for drug substance and for intermediates, if employed;(8) 收率范围（初品和/或精品的重量和百分比） Yield ranges (crude and/or purified; weight and percent).应该提供原料药最后合成、分离和提纯的详细信息。(参见第II.D.2.c部分关于原料药提纯的内容)。The final step of the synthesis and the isolation of the crude new drug substance, as well as its purif

31、ication, should be provided in full detail. (See section II.D.2.c below regarding purification of the drug substance.)除了提供合成的书面描述，还包括经过确认的操作参数范围（参见第II节-E工艺控制）和第 IV节CGMP)以及预期收率，递交者同时要提供实际操作的书面实例（BPR），明确指出它是供审阅官参考。 这个例证不应该仅仅是批生产纪录的拷贝，它应该包括更详细的内容。Besides providing a written description of the synthesis

32、 which includes verified ranges for the operating parameters (refer to section II-E Process Controls and section IV CGMP) and for the expected yield, the applicant should provide a written example of actual practice, clearly identified as an example for the reviewers information. This example should not be merely a copy of batch records but should contain more detail.应该描述所采取的替代措施（如：替代起始原料、反应物、溶媒、条件、催化剂、分析和提纯过程）。应该提供每一不同合成方法所生产的原料的比较性分析数据Any alternate method or permissible variation that may be employed (e.g.,alternate starting materials, reactants, solvents, cond