美國FDA指南-中文版

1、?美國FDA認(rèn)證與申辦指南?權(quán)威資訊系列?合成原料藥 DMF 起草大綱?使用說明1、本大綱是為了幫助我公司客戶把握 DMF 的整體內(nèi)容而準(zhǔn)備 的，由于 DMF 內(nèi)容繁多， 從整體上了解內(nèi)容框架和組成局部， 對 于理解 FDA 對 DMF 的要求和意圖非常有必要；2、根據(jù) FDA 的要求，但凡本大綱提到的內(nèi)容，原料藥制造商均 應(yīng)該提供。因此，客戶務(wù)必依照規(guī)定提供盡可能詳細(xì)的內(nèi)容。3、本大綱的內(nèi)容和相關(guān)要求能夠確?？蛻裟壳暗倪\(yùn)作到達(dá) FDA 的 cGMP 標(biāo)準(zhǔn)，因此，準(zhǔn)備 DMF 的過程，也使客戶按照 FDA 的 要求進(jìn)行整改和提高的過程， 這些都為 FDA 未來的現(xiàn)場檢查打下 良好根底；4、但凡

2、本大綱中提到的非技術(shù)性具體內(nèi)容要求，請參照本公司專有的與此大綱配套的相關(guān)DFM指導(dǎo)性文件，包括?FD的物主文件指 南?、?關(guān)于在藥品遞交中遞交的有關(guān)原料藥生產(chǎn)的支持文件的指南? 、?藥物申辦中質(zhì)量管理方面通用技術(shù)文件格式與內(nèi)容要求?；5、但凡本大綱中提到的技術(shù)性具體內(nèi)容要求，如雜質(zhì)、穩(wěn)定性、驗(yàn) 證等具體技術(shù)要求，請參照本公司專有的 FDA 相關(guān)技術(shù)標(biāo)準(zhǔn)文件， 包括?原料藥認(rèn)證指南? 、?制劑認(rèn)證指南?、?化學(xué)藥物穩(wěn)定性指南? 、?化學(xué)藥物雜質(zhì)指南? 、?化學(xué)藥物化驗(yàn)與合格參數(shù)指南? 、?化學(xué)藥物 驗(yàn)證指南?等；合成原料藥 DMF 起草大綱?一、公司和生產(chǎn)場地的根本描述1、 第一類的DMF文件建

3、議由位于美國之外的人提供，以幫助FDA對他們的生產(chǎn) 設(shè)施進(jìn)行現(xiàn)場檢查。DMF文件應(yīng)描述生產(chǎn)場地、設(shè)備能力、生產(chǎn)流程圖等。A Type I DMF is recommended for a person outside of the United States to assistFDAin conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational l

4、ayout.2、學(xué)一類的DMF文件對美國國內(nèi)設(shè)施通常不需要，除非該設(shè)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 notregistered and not routinely inspected.3、場地的描述應(yīng)包括面積、實(shí)際地址以及說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面圖。 The description of the site should in

5、clude acreage, actual site address, and a mapshowing its location with respect to the nearest city. An aerial photograph and a diagram of the site maybe helpful.4、主要生產(chǎn)和加工區(qū)域的平面圖對于理解整個(gè)生產(chǎn)布局會(huì)有幫助。應(yīng)當(dāng)描述主 要設(shè)備的生產(chǎn)能力、用途和位置。 通常不用描述設(shè)備的制造商和型號(hào)，除非特 別新或獨(dú)特的設(shè)備。 A diagram of major production and processing areas is hel

6、pful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Makeand model would not normally be needed unless the equipment is new or unique.5、 公司主要的組成部門結(jié)構(gòu)圖，包括總公司和生產(chǎn)場地的關(guān)鍵生產(chǎn)、 質(zhì)量控制、 質(zhì)量保證崗位， A diagram of major corporate organiz

7、ational 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(xué)特征1、特性 Properties 相關(guān)法規(guī)要求對原料藥的物理和化學(xué)特征做出詳細(xì)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(xué)名、編碼等)、化學(xué)摘要效勞(CAS)編碼、性狀描述(如：外觀、顏色、物理狀態(tài))、

8、分子式和分子重量、結(jié)構(gòu)式(包括離 子狀態(tài)) 、立體化學(xué) (找出手性中心、 順式反式異性等) 、對映結(jié)構(gòu)體比率 (如： 外消旋物、規(guī)定的異構(gòu)體、對映異構(gòu)物和固態(tài)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(shù)、溶液 pH 值、解離常數(shù)、熔點(diǎn)或沸點(diǎn)、折射 率、比重。對于蛋白質(zhì)原料藥，參見：“ CRC生物化學(xué)和分子生物學(xué)手冊“酶學(xué)方法 和有關(guān)描述蛋白質(zhì)特性的專論。 The regulations require a full description of the physical and chemical characteristics of the drug substance. T

9、his 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 molecular weight; structural fo

10、rmula (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 profile (aqueous and nonaqueous as

11、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 related mono

12、graphs for how protein properties may be described.并非所有的遞交都要求上述信息， 額外的信息也可能需要， 特別是隨著生產(chǎn)工藝 的復(fù)雜性的增加。 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、結(jié)構(gòu) Structure對于結(jié)構(gòu)的說明 (如：相關(guān)數(shù)據(jù)和其解釋) 應(yīng)當(dāng)基于一個(gè)適宜的

13、物理和化學(xué)檢測 結(jié)果。這包括以下內(nèi)容：元素分析；質(zhì)譜分析(MS);核磁共振(NMR);紫外(UV)和紅外 (IR) 光譜學(xué)；分子量測定；立體化學(xué)和構(gòu)象分析(如：光學(xué)和幾何學(xué)異構(gòu) 體)；X光分析；降解分析(如:氨基酸排序和分析)；色析圖譜；其它檢驗(yàn)(如: 功能團(tuán)分析，衍生作用，絡(luò)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

14、e following: elemental analysis; mass spectrometry (MS); nuclear magnetic resonance (NMR), ultraviolet (UV), and infrared (IR) spectroscopy; molecular weight determination; stereochemistry and configurational or conformational analysis (e.g., optical and geometric isomers); X-ray analysis; degradati

15、ve analysis (e.g., amino acid sequencing and/or analysis); chromatographic profile; other tests (e.g., functional group analysis, derivatization, complex formation).同樣，并非所有以上條目都是必須的或適用于所有情況， 所列條目也不是完全的 (工藝過程更加復(fù)雜和新原料藥需要時(shí)， 也許需要做出更多的分析) 。實(shí)際數(shù)據(jù) 及其解釋的細(xì)節(jié)應(yīng)當(dāng)放在“參考標(biāo)準(zhǔn)章節(jié)(參見II.F.2, 和3 )。Again, notall items are ne

16、cessary or 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

17、Reference Standard (see II.F.2, and 3.).三、原料藥的穩(wěn)定性相關(guān)法規(guī)要求對原料藥的穩(wěn)定性做全面的描述。 具體要求， 參見“關(guān)于提交人類 用藥品和生物制品穩(wěn)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 a

18、ssistance in fulfilling this requirement.四、原料藥的生產(chǎn)1、起始材料的控制程序 Control procedures for starting materials應(yīng)當(dāng)列出起始原料。 應(yīng)該提供其承諾的標(biāo)準(zhǔn)和用來判定其特性、 質(zhì)量和純度的檢 驗(yàn)方法。分析檢驗(yàn)方法應(yīng)當(dāng)簡要描述。 起始原料的來源通常無需說明， 但有時(shí)會(huì) 要。 Starting materials should be listed. Acceptance specifications and tests defining identity, quality, and purity should

19、be provided. 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(yīng)該進(jìn)行鑒別和含量測定分析。 在某些情況下， 當(dāng)雜質(zhì)(如芳香化合 物的異構(gòu)體)被混入原料藥時(shí)， 應(yīng)提供純度檔案 (如包括雜質(zhì)的定量與定性色譜 圖)。通過定期與不定期的核查與驗(yàn)證來評估原料供給商提供的產(chǎn)品質(zhì)量是穩(wěn)定 的，供給商提供的質(zhì)量保障聲明應(yīng)該包括相關(guān)的規(guī)格和結(jié)果 , 并應(yīng)該注明用于檢

20、 測的分析方法。 A specific 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 quan

21、titation/identification 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's analyses through validation, initially and at appropriate intervals. These statements from su

22、ppliers should include specifications and results and should indicate the type of method2、試劑、溶媒和輔料控制Reagents, solvents, and auxiliary materials controls應(yīng)列出合成原料、溶媒的內(nèi)容。標(biāo)明以上原料、溶媒的規(guī)格和檢驗(yàn)方法，并應(yīng)該 提供相關(guān)的質(zhì)量聲明。 遞交者應(yīng)當(dāng)注明具體的檢驗(yàn)方法 (除非忽略這種檢驗(yàn)可被 認(rèn)為是正當(dāng)?shù)?。無論是原料供給商還是遞交者，進(jìn)行額外檢驗(yàn)時(shí)，應(yīng)該依據(jù)該 化學(xué)成分在合成中的作用進(jìn)行。 例如，對于用來中和合成反響混合物中多余的酸 用

23、得堿時(shí) ( 如氫氧化鈉 ) ，通常不需要進(jìn)行的純度檢測。 相反，用于關(guān)鍵環(huán)節(jié)的光 學(xué)活性的有機(jī)酸(如：某種酸的對映體)，那么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 (unl

24、ess omitting such a test has been otherwise justified, e.g., because of hazard). The extent of additi onal testi ng performed -whether by the supplier or by the applica nt -should be based on the role of the chemical in the synthesis. For example: a base (e.g., sodium hydroxide) used to neutralize e

25、xcess acid in a synthetic reaction mixture would not normally require 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、詳細(xì)的合成信息 遞交者應(yīng)當(dāng)提供完整的合成信息， 從起始原料到最終成品原料藥。 有關(guān)描述

26、應(yīng)當(dāng) 包括整個(gè)合成過程的流程圖以及每一合成步驟的說明)。 An applicant should provide complete information 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) 合成流程圖 F

27、low chart of the synthesis.合成的流程圖應(yīng)該包括以下內(nèi)容 The flow chart typically should contain the following:(1) 反響物和產(chǎn)品的化學(xué)結(jié)構(gòu)(如：起始原料、中間體，以及引入到結(jié)構(gòu)中的 分子) Chemical structures of reactants (i.e., starting materials and intermediates, and also molecules incorporated into the structure) and products;(2) ) 立體化學(xué)結(jié)構(gòu)，如果有立體化學(xué)

28、構(gòu)形Stereochemical configurations, where applicable;(3) 中間體(未別離的或已別離的) Intermediates (either in situ or isolated);(4) 溶媒、催化劑和試劑 Solvents, catalysts, and reagents;反響所產(chǎn)生的產(chǎn)品與副產(chǎn)品混合比率 ( 如：兩個(gè)或更多異構(gòu)體 )應(yīng)該顯示在流程圖 上。重要的副產(chǎn)品和雜質(zhì)， 尤其是那些干擾分析過程或有毒性的， 應(yīng)當(dāng)被分別表 示出來(參見：第 II.D.2.c. 和 II.F.3. ) A ratio or mixture of products

29、(e.g., two or more isomers) produced by a reaction should be shown in the flow chart. 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

30、 the synthesis 每一個(gè)合成步驟的書面描述以及更詳細(xì)的最后加工步驟的描述應(yīng)該包括以下內(nèi) 容 The written statement for each step of the synthesis, with greater detail included toward the final steps of the process, should include the following:(1) 用于反響的典型設(shè)備 Typical equipment used for the reaction;(2) 反響物(本步驟所使用的起始原料或中間體，包括化學(xué)名稱和數(shù)量) Reactant

31、s (starting material or intermediate used in the step, with chemical names and amounts);(3) 溶媒、催化劑和試劑(注明化學(xué)名稱和數(shù)量) Solvents, catalysts, and reagents (chemical names and amounts);(4) 反響條件(溫度，pH值，時(shí)間，壓力等)Conditions (temperature, pH, time, pressure, etc.);(5) 反響完成的檢測，如果有的話。 Tests for completion of reactio

32、n, if employed;(6) 別離的程序 Workup and isolation procedures;(7) 原料藥和中間體的純化過程，如果有。 Purification procedures for drug substance and for intermediates, if employed;(8) 收率范圍(初品和 /或精品的重量和百分比)Yield ranges (crude and/orpurified; weight and percent).應(yīng)該提供原料藥最后合成、別離和提純的詳細(xì)信息。(參見第局部關(guān)于原料藥提純的內(nèi)容 )。 The final step of t

33、he synthesis and the isolation of the Crude new drug substanCe, as well as its purifiCation, should be provided in full detail. (See seCtion II.D.2.C below regarding purifiCation of the drug substanCe.)除了提供合成的書面描述，還包括經(jīng)過確認(rèn)的操作參數(shù)范圍參見第II節(jié)-E工藝控制和第IV節(jié)CGMP以及預(yù)期收率，遞交者同時(shí)要提供實(shí)際操作的書面 實(shí)例BPR，明確指出它是供審閱官參考。這個(gè)例證不應(yīng)該僅僅

34、是批生產(chǎn)紀(jì)錄的拷貝，它應(yīng)該包括更詳細(xì)的內(nèi)容。 Besides providing a written desCription ofthe synthesis 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, clear

35、ly identified as an example for the reviewer's information. This example should not be merely a copy of batch records but should contain more detail.應(yīng)該描述所采取的替代措施 (如：替代起始原料、 反響物、 溶媒、條件、催化劑、 分析和提純過程) 。應(yīng)該提供每一不同合成方法所生產(chǎn)的原料的比擬性分析數(shù)據(jù) Any alternate method or permissible variation that may be employed (e.

36、g., alternate starting materials, reactants, solvents, conditions, catalysts, isolation, and/or purification procedures) should be reported. Comparative analytical data for the material produced by each variant synthetic method should be provided.( 3)原料藥的純化 Purification of the drug substance 應(yīng)該詳細(xì)描述原

37、料的提純情況和其從最終反響混合物中別離的情況。 其中應(yīng)該包 括以下內(nèi)容：The description of the purification of the crude new drug substance and its isolation from the final reaction step mixture should be given in detail, and should include:(1) 原料藥的收率范圍 The yield ranges of the crude product;(2) 任何用于判斷原料產(chǎn)品純度的檢驗(yàn)。 (參見下面第 6條) Any tests pe

38、rformed on the crude product to determine its purity (see item 6, below);(3) 詳細(xì)的別離和純化過程的記錄(如：對于重結(jié)晶過程：所使用的溶媒，與原 料產(chǎn)品相關(guān)的溶媒的數(shù)量，溶媒在熱時(shí)候是否被過濾，是否使用了脫色劑， 冷卻溫度與和最終溫度，母液的使用和再使用，溶媒是否進(jìn)行了二次回收。A detailed description of the isolation and purification procedures (e.g., for recrystallization: the solvent used, the qu

39、antity 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 re-use of any mother liquors, and if second crops are obtained);(4) 替代的提純步驟(參見 II.D.2.b. 中的最后一段；參見 II.G )Alt

40、ernative purification procedures (see the last paragraph of section II.D.2.b.; see also section II.G.);Evidence(5) 提純產(chǎn)品的收率范圍 (重量和百分比) The yield range (weight and percent) of the purified product;(6) 證明提純過程增加純度的有關(guān)證據(jù)，例如色析法的前后比照 demonstrating that the purification procedure improves the purity, such as

41、 before-and-after chromatographic illustrations.當(dāng)提純工藝被驗(yàn)證后， 只需提供最初產(chǎn)品批次的檢驗(yàn)相關(guān)信息。 This testing and information may be necessary only on initial production batches, once the purification process has been verified or validated.( 4)合成的變化 Changes in the synthesis相關(guān)合成的變化應(yīng)該作為DMF勺補(bǔ)充來提交。為改變新藥物遞交(NDA )中已經(jīng)批 準(zhǔn)的有關(guān)原

42、料藥的合成方法， 制劑遞交者也需要提交一個(gè)批準(zhǔn)的補(bǔ)充文件， 這包 括有關(guān)溶媒的改變。 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 314.70(b) (1) (iv) to change the method of synthesi

43、s approved in the NDA for the drug substance, including a change in solvents.當(dāng)合成的路線發(fā)生改變時(shí)(如：反響和中間體與新藥遞交(NDA)所批準(zhǔn)的相關(guān)內(nèi)容不同時(shí))，應(yīng)該提供每一合成路線的比擬分析數(shù)據(jù) (如：完整的純度檔案數(shù)據(jù)) 。 下面我們將討論有關(guān)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 ND

44、A), 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 proposed change is to redefine the starting material, is discussed below.當(dāng)用于原料藥最終結(jié)晶的溶媒發(fā)生變化時(shí)， 應(yīng)該檢查原料藥有關(guān)晶形和溶劑化物 的變化； 參見 II.G 。原料藥必須符合有關(guān)晶形和溶劑化物的原定規(guī)格。

45、 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 II.G. The new drug substance must meet its original specifications for crystalline form an

46、d/or solvation.有關(guān)其它的反響和提純的溶媒改變也需要一份補(bǔ)充遞交， 補(bǔ)充遞交中應(yīng)該提供該 改變可以產(chǎn)生同等質(zhì)量和純度的產(chǎn)品 (化合物或中間體) 的證據(jù)，但無需考慮形 態(tài)學(xué)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 eq

47、uivalent quality and purity, but morphology need not be considered.如果遞交者想縮短新藥遞交(NDA)中批準(zhǔn)的合成方法或者通過重新定義起始原料 時(shí)，那么需要提交一個(gè)補(bǔ)充文件 (21 CFR314.70(b) (1) 。該起始原料是一種可從 商業(yè)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(zhǔn)的中間體，而且，必須滿足起始材料 "b" 和 "c" 標(biāo)準(zhǔn)要求。 An approved supplement is required (21 CFR 314.70(b) (1) if

48、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 has become commercially available. This compound must have been an intermediate in the approved NDA synthes

49、is, and must meet both the "b" and "c" criteria for starting material.在完成原料藥的合成之前， 該化合物至少在兩個(gè)完整的合成階段前使用。 依據(jù)所 引用的參考文獻(xiàn) (應(yīng)該提供相關(guān)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(xiàn)資料(如提供的復(fù)印件)。 The compound should be used at least two full steps before the new drug substance if possible (i.e., it s

50、hould 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).對于學(xué)術(shù)期刊所引用的化合物， 詳盡的出版材料就夠了 (如： 有關(guān)雜質(zhì)檢驗(yàn)的額 外信息)。在有關(guān)專利中所規(guī)定的化合物，需要提供

51、其完整的特性和純度檔案。 應(yīng)該描述用于檢驗(yàn)每一批新起始原料的分析檢測程序。 建立一個(gè)通用的檢驗(yàn)方案 通常就可以了。 For compounds cited in journal articles, an elaboration of the published material (i.e., additional information about testing for impurities) may suffice. For compounds described in patents, both complete characterization and a full purity pr

52、ofile 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.遞交者應(yīng)該通過直接的比擬 (如： 通過分析和使用) 證明該化合物與用于臨床試 驗(yàn)用的新原料藥等效， 同時(shí)應(yīng)該證明該化合物的符合承諾的標(biāo)準(zhǔn)。 使用至少是試 驗(yàn)性規(guī)模(如:要大于實(shí)驗(yàn)室規(guī)模) 。 The applicant

53、 should demonstrate by direct comparison (i.e., both by analyses and by a use test) that the compound 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 compound are adequate. The use test should

54、 be at least on a pilot scale (i.e., larger than bench scale).應(yīng)該提供用該材料所生產(chǎn)的前三批產(chǎn)品的完整檢驗(yàn)結(jié)果。 該檢驗(yàn)的廣度和深度要 和用于檢測一個(gè)新的參考標(biāo)準(zhǔn)品的相同。 A commitment to submit results from thorough examination of the first three full-scale batches made with the material should be provided. The examination should be similar in scope a

55、nd extent to the testing involved in qualifying a new reference standard.對于依據(jù)聯(lián)邦法典 21 CFR 314.70(c) (3) 所做的改變類型，只要有對合成過程的 充分描述文件，就可以。這樣的改變，無需 FDA 的事先批準(zhǔn)就可以執(zhí)行。 For changes of the type permitted by 21 CFR 314.70(c) (3), an adequate synthesis description on file would facilitate a conclusion that changes

56、 in site of manufacture of the new drug substance do not require prior FDA approval for implementation.4、 參照標(biāo)準(zhǔn)品 Reference Standard 原始遞交的申報(bào)文件應(yīng)該包括任何所使用的參照標(biāo)準(zhǔn)品的制備過程的描述， 包 括對提純步驟的描述， 參見 II.F.3. The original application should include a full description of the preparation of any reference standard substan

57、ce used, including the description of the purification steps. See also section II.F.3. II.D.4.五、生產(chǎn)過程的控制1、中間體和生產(chǎn)過程的控制 Intermediates and In-process Controls 相關(guān)法規(guī)要求在合成過程中選擇一些中間環(huán)節(jié)實(shí)施控制 檢測工程與參數(shù)要求 ， 以保證合成和提純工序順利進(jìn)行， 并保證檢測后的中間體適合于以后的加工。 申 請者可以根據(jù)對整個(gè)合成工藝的開發(fā)和確認(rèn)的經(jīng)驗(yàn)， 自行確定對那些中間體或加 工環(huán)節(jié)進(jìn)行檢測及進(jìn)行那些檢測工程。 在早期的開發(fā)階段， 每一個(gè)步驟

58、通常都進(jìn) 行了檢驗(yàn) 至少是對反響的內(nèi)容 ，每一個(gè)中間體至少都進(jìn)行與純度有關(guān)參數(shù)的 測定，包括純度的估計(jì)。 隨著合成經(jīng)驗(yàn)的積累， 應(yīng)選擇關(guān)鍵的反響步驟和中間體 進(jìn)行監(jiān)控。在遞交新藥申請NDA時(shí)，生產(chǎn)過程的控制點(diǎn)應(yīng)該已經(jīng)選定，相關(guān)控 制參數(shù)和檢驗(yàn)方法也已確立，以滿足法律的要求。 The regulations require that controls specifications and tests be employed at selected intermediate stages of the synthetic process to assure that the synthetic a

59、nd purification procedures are operating properly and that the intermediate tested is suitable for subsequent processing. The choice of which intermediates or steps in the process to test, and the kind of testing required, are the responsibility of the applicant based on his experience during the development and verification of the total synthetic process. In early development work, every step would usually have been examine