1、美国FDA认证与申办指南权威资讯系列合成原料药DMF起草大纲2使用说明：1、 本大纲是为了帮助我公司客户把握 DMF 的整体内容而准备的，由于 DMF 内容繁多，从整体上了解内容框架和组成部分，对于理解 FDA 对 DMF 的要求和意图非常有必要；2、 根据 FDA 的要求，凡是本大纲提到的内容，原料药制造商均应该提供。因此，客户务必依照规定提供尽可能详细的内容。3、 本大纲的内容和相关要求能够确保客户目前的运作达到 FDA的 cGMP 标准，因此，准备 DMF 的过程，也使客户按照 FDA的要求进行整改和提高的过程，这些都为 FDA 未来的现场检查打下良好基础；4、凡是本大纲中提到的非技术性
2、具体内容要求，请参照本公司专有的与此大纲配套的相关DFM指导性文件，包括FDA药物主文件指南 、 关于在药品递交中递交的有关原料药生产的支持文件的指南 、药物申办中质量管理方面通用技术文件格式与内容要求；5、凡是本大纲中提到的技术性具体内容要求，如杂质、稳定性、验证等具体技术要求，请参照本公司专有的 FDA 相关技术标准文件，包括原料药认证指南 、 制剂认证指南 、 化学药物稳定性指南 、化学药物杂质指南 、 化学药物化验与合格参数指南 、 化学药物验证指南等；3 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
3、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, equipment capabilities, and operational layout.2、第一类的 DMF 文件
4、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面图。The description of the site should include acreage, actu
5、al 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 major production and processing areas is helpful for understandi
6、ng 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、质量保证岗位，A diagram of major corporate organizational elements, wit
7、h key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.4二、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）、
8、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 characteristics of the drug substance. This requirement may be satis
9、fied 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 molecular weight; structural formula (including ionic state
10、 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 profile (aqueous and nonaqueous as applicable); partition coeff
11、icients; 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 related monographs for how protein properties may be describ
12、ed.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
13、)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 the following: elemental analysis; mass spectrometry (MS); n
14、uclear magneticresonance (NMR), ultraviolet (UV), and infrared (IR) spectroscopy; molecular5weight determination; stereochemistry and configurational or conformationalanalysis (e.g., optical and geometric isomers); X-ray analysis; degradativeanalysis (e.g., amino acid sequencing and/or analysis); ch
15、romatographicprofile; 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 or appropriate in all cases, and the listing should not b
16、e 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 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
17、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 this requirement.四、原料药的生产1、起始材料的控制程序 Control procedures
18、 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 methods should be briefly described. The source of th
19、e 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 performed, as well as an assay, with limits for impur
20、ities. 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 6quantitation/identification of impurities). Assurances or statements of quality from the supplier ar
21、e 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 results and should indicate the type of method2、试剂、溶媒和辅料控制
22、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），则需要这样的额外检测。These chemicals should also be listed. The
23、 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., because of hazard). The extent of additional testing p
24、erformed 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 require extensive purity testing; in contrast, an optica
25、lly 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 information on the synthesis, from starting material(s) t
26、o 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 should contain the following:(1) 反应物和产品的化学结构（如：起始原料、中间体，以
27、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) and7products;(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）Intermediates (either in situ or isolated);(4) 溶媒、催化剂和试剂 S
28、olvents, 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. Significant side products and impurities, particu
29、larly 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 of the synthesis, with greater detailincluded towar
30、d 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) 溶媒、催化剂和试剂（注明化学名称和数量） Solvents, catalysts, and rea
31、gents (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 procedures for drug substance and for intermediat
32、es, 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 purification, should be provided in full detail. (See s
33、ection 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-E8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 which includes verified ranges for the operat
34、ing 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 sho
35、uld 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, conditions, catalysts,isolation, and/or purification procedures) should be repor
36、ted. Comparativeanalytical data for the material produced by each variant synthetic methodshould be provided.（3）原料药的纯化 Purification of the drug substance应该详细描述原料的提纯情况和其从最终反应混合物中分离的情况。其中应该包括以下内容：The description of the purification of the crude new drug substance and its isolation from the final react
37、ion step mixture should be given in detail, and should include:(1) 原料药的收率范围 The yield ranges of the crude product;(2) 任何用于判断原料产品纯度的检验。（参见下面第6条） Any tests performed on the crude product to determine its purity (see item 6, below);(3) 详细的分离和纯化过程的记录（如：对于重结晶过程：所使用的溶媒，与原料产品相关的溶媒的数量，溶媒在热时候是否被过滤，是否使用了脱色剂，冷
38、却温度与和最终温度，母液的使用和再使用，溶媒是否进行了二次回收。 A detailed description of the isolation and purification procedures (e.g., for recrystallization: the 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
39、 cooling and the final temperature, the use or re-use of any mother liquors, and if second crops are obtained);(4) 替代的提纯步骤（参见II.D.2.b.中的最后一段；参见II.G）Alternative purification procedures (see the last paragraph of section II.D.2.b.; see also section II.G.);9(5) 提纯产品的收率范围（重量和百分比） The yield range (weight
40、 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 before-and-after 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
41、 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
42、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 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
43、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 drug substance made by each route should be provided. A special case, where the propo
44、sed 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 the new drug substance, the new drug substance should be examined for changes in cryst
45、alline 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）的证据，但无需考虑形态学问题。Solvent changes for other reaction steps or purifications also require a
46、supplemental application. The application should contain evidence that the10change affords material (compound or intermediate) of equivalent quality andpurity, 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 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
47、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 synthetic method by redefining the starting material, in order to employ a compound later in the synthesis that ha
48、s 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 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 compound should be used
49、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 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 compounds cited in journal articles, an elaboration of the published material (i.e., additional informat
