1、合成原料藥DMF起草大綱 一、公司和生產場地的基本描述 1、第一類的DMF文件建議由位于美國之外的人提供，以幫助FDA對他們的生產設施進行現場檢查。DMF文件應描述生產場地、設備能力、生產流程圖等。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、第一類的DMF文件對美國國內設施通常不需要，除非該設施沒有登記并定期接受檢查。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、場地的描述應包括面積、實際地址以及表明該場地與最近的城市的距離的地圖。提供該場地的鳥瞰圖和平

3、面圖。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、主要生產和加工區域的平面圖對于理解整個生產布局會有幫助。應當描述主要設備的生產能力、用途和位置。 通常不用描述設備的制造商和型號，除非特別新或獨特的設備。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、公司主要的組成部門結構圖， 包括總公司和生產場地的關鍵生產、質量控制、質量保證

5、崗位，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、原料藥的物理和化學特征 1、特性 Properties 相關法規要求對原料藥的物理和化學特征做出詳細描述。該要求可以通過提供下述信息來滿足： 名稱（通用名、化學

6、名、編碼等）、化學摘要服務(CAS)編碼、性狀描述（如：外觀、顏色、物理狀態）、分子式和分子重量、結構式（包括離子狀態）、立體化學（找出手性中心、順式反式異性等）、對映結構體比率（如：外消旋物、規定的異構體、對映異構物和固態形式的混合物）、溶解度概況（水溶性的或非水溶性的）、分配系數、溶液pH值、解離常數、熔點或沸點、折射率、比重。對于蛋白質原料藥，參見：“CRC生物化學和分子生物學手冊” “酶學方法”和有關描述蛋白質特性的專論。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、原料藥的生產 1、起始材料的控制程序 Control procedures for starting materials 應當列出起始原料。應該提供其承諾的標準和用來判定其特性、質量和純度的檢驗方法。分析檢驗方法應當簡要描述。起始原料的來源通常無需說明，但有時會要。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. 對起始材料應該進行鑒別和含量測定分析。在某些情況下，當雜質（如芳香化合物的異構體）被混入原料藥時，應提供純度檔案（如包括雜質的定量與定性色譜圖）。通過定期與不定期的核查與驗證來評估原料供應商提供的產品質量是穩定的，供應商提供的質量保障聲明應該包括相關的規格和結果,并應該注明用于檢測的分析方法。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、試劑、溶媒和輔料控制 Reagents, solvents, and auxiliary materials controls 應列出合成原料、溶媒的內容。標明以上原料、溶媒的規格和檢驗方法，并應該提供相關的質量聲明。遞交者應當注明具體的檢驗方法（除非忽略這種檢驗可被認為是正當的）。無論是原料供應商還是遞交者，進行額外檢驗時，應該依據該化學成分在合成中的作用進行。例如，對于用來中和合成反應混合物中多余的酸用得堿時(如氫氧化鈉)，通常不需要進行的

15、純度檢測。相反，用于關鍵環節的光學活性的有機酸（如：某種酸的對映體），則需要這樣的額外檢測。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新藥物遞交(NDA)中已經批準的有關原料藥的合成方法，制劑遞交者也需要提交一個批準的補充文件，這包括有關溶媒的改變。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. 當合成的路線發生改變時（如：反應和中間體與新藥遞交(NDA)所批準的相關內容不同時），應該提供每一合成路線的比較分析數據（如：完整的純度檔案數據）。下面我們將討論有關變化旨在重新定義起始原料的情況。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. 當用于原料藥最終結晶的溶媒發生變化時，應該檢查原料藥有關晶形和溶劑化物的變化； 參見II.G。原料藥必須符合有關晶形和溶劑化物的原定規格。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. 有關其它的反應和提純的溶媒改變也需要一份補充遞交，補充遞交中應該提供該改變可以產生同等質量和純度的產品（化合物或中間體）的證

21、據，但無需考慮形態學問題。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. 如果遞交者想縮短新藥遞交(ND

22、A)中批準的合成方法或者通過重新定義起始原料時，則需要提交一個補充文件(21 CFR 314.70(b) (1)。該起始原料是一種可從商業渠道獲得的用于合成的化合物，該化合物必須是新藥遞交中（NDA）批準的中間體，而且，必須滿足起始材料"b" 和 "c"標準要求。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. 在完成原料藥的合成之前，該化合物至少在兩個完整的合成階段前使用。依據所引用的參考文獻（應該提供相關拷貝）的充分性，需要提供起始原料的純度和特性等額外信息，這包括足夠的文獻資料（如提供的復印件）。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