合成原料药DMF起草大纲.

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）、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 requirea full description of the physical and chemical characteristics of the drugsubstance. This requirement may be satisfied by the submission of informationsuch 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 if applicable); stereochemistry(identifying chiral centers, cis-trans isomerism, etc.); enantiomer orsolid-state form ratios (e.g., for racemates, and for defined admixtures ofisomers or enantiomers or solid-state forms); solubility profile (aqueous andnonaqueous as applicable); partition coefficients; solution pH; dissociationconstant(s); melting or boiling point; refractive index; specific gravity. Fordrug substances that are proteins, see the "CRC Handbook of Biochemistryand Molecular Biology," "Methods in Enzymology," and related monographsfor 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. Additionalinformation 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)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 andchemical test results. These may include the 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 andgeometric isomers); X-ray analysis; degradative

analysis (e.g., amino acidsequencing and/or analysis); chromatographic

profile; other tests (e.g.,functional group analysis, derivatization, complex

formation).

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 thelisting should not be considered limiting (i.e., more analysis may be required asthe state of the art progresses and the nature of the new drug substancedemands). The actual data and the details of its interpretation should beplaced 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 drugsubstance. See the "Guideline for Submitting Documentation for theStability of Human Drugs and Biologics" for assistance in fulfilling thisrequirement.

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 definingidentity, quality, and purity should be provided. The analytical test methodsshould be briefly described. The source of the starting material need not beidentified, 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 specificidentity test should be performed, as well as an assay, with limits forimpurities. In those cases where impurities (e.g., positional isomers ofaromatic compounds) could be carried through to the drug substance, a purityprofile should be provided (e.g., chromatography with quantitation/identificationof impurities). Assurances or statements of quality from the supplier areacceptable for the profile, provided that the manufacturer establishes thereliability of the supplier's analyses through validation, initially and atappropriate intervals. These statements from suppliers should includespecifications 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 methodsfor each such material should be stated, and/or a statement of quality provided.The applicant should describe the specific identity test performed (unlessomitting such a test has been otherwise justified, e.g., because of hazard).The extent of additional testing performed – whether by the supplier or by theapplicant -- should be based on the role of the chemical in the synthesis. Forexample: a base (e.g., sodium hydroxide) used to neutralize excess acid in asynthetic 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 additionaltesting.

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, fromstarting material(s) to the bulk new drug substance. The description shouldcontain a diagrammatic flow chart of the whole synthesis and a writtenstatement for each step of the synthesis.

（1）合成流程图 Flowchart 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，以及引入到结构中的分子）Chemical structures of reactants (i.e., startingmaterials and

intermediates, and also moleculesincorporated into the structure) and

products;

(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 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.） Aratio or mixture of products (e.g., two or more isomers) produced by a reactionshould 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 Descriptionof 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 detail

included toward the final steps ofthe 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 chemicalnames and amounts);

(3)  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。 Purificationprocedures 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 thecrude new drug substance, as well as its purification, should be provided infull detail. (See section II.D.2.c below regarding purification of the drugsubstance.)

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 which includes verifiedranges for the operating parameters (refer to section II-E [Process Controls]and section IV [CGMP]) and for the expected yield, the applicant should providea written example of actual practice, clearly identified as an example for thereviewer's information. This example should not be merely a copy of batchrecords 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, conditions, catalysts,

isolation, and/or purificationprocedures) should be reported. Comparative

analytical data for the materialproduced by each variant synthetic method

should 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 andits isolation from the final reaction 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 item6, 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 tothe amount of crude product, whether it is filtered while hot, whether adecolorizing agent is used, the rate of cooling and the final temperature, theuse 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 lastparagraph of section II.D.2.b.; see also section II.G.);

(5)   提纯产品的收率范围（重量和百分比） The yield range (weightand 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 thepurification procedure improves the purity, such as before-and-afterchromatographic 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 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。Proposedchanges in the synthesis should be submitted to the application as a supplementfor an approved NDA or as an amendment to an IND, a DMF, or a pending NDA. Anapproved supplement is required [21 CFR 314.70(b) (1) (iv)] to change themethod of synthesis approved in the NDA for the drug substance, including achange 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/orintermediates are different from those approved in the NDA), comparativeanalytical data (i.e., a complete purity profile) for the drug substance madeby each route should be provided. A special case, where the proposed change isto 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 changein the solvent used for the final crystallization of the new drug substance,the new drug substance should be examined for changes in crystalline formand/or solvation; refer to section II.G. The new drug substance must meet itsoriginal 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 supplementalapplication. The application should contain evidence that the

change affords material (compound orintermediate) of equivalent quality and

purity, but morphology need not beconsidered.

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 CFR314.70(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 supplementis required (21 CFR 314.70(b) (1)) if an applicant wants to shorten thesynthesis approved in the NDA or develop a new synthetic method by redefiningthe starting material, in order to employ a compound later in the synthesisthat has become commercially available. This compound must have been anintermediate 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 at least two full steps before the new drug substanceif possible (i.e., it should be prior to the final intermediate). Additional informationon the characterization and purity profile of the starting material may beneeded, depending on the adequacy of the literature references cited (copiesshould 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 publishedmaterial (i.e., additional information about testing for impurities) maysuffice. For compounds described in patents, both complete characterization anda full purity profile will usually be needed. Analytical test procedures usedto qualify each new source/supplier of the new starting material should be described.A general testing protocol may be suitable.

递交者应该通过直接的比较（如：通过分析和使用）证明该化合物与用于临床试验用的新原料药等效，同时应该证明该化合物的符合承诺的标准。使用至少是试验性规模（如:要大于实验室规模）。 The applicant should demonstrate by direct comparison(i.e., both by analyses and by a use test) thatthe compound is equivalent to the material used to make the new drug substanceemployed in the clinical trials, and that the acceptance tests andspecifications for the compound are adequate. The use test should be at leaston a pilot scale (i.e., larger than bench scale).

应该提供用该材料所生产的前三批产品的完整检验结果。该检验的广度和深度要和用于检测一个新的参考标准品的相同。A commitment to submit results from thorough examination of the firstthree full-scale batches made with the material should be provided. The examinationshould be similar in scope and extent to the testing involved in qualifying anew reference standard.

对于依据联邦法典21 CFR 314.70(c)(3)所做的改变类型，只要有对合成过程的充分描述文件，就可以。这样的改变，无需FDA的事先批准就可以执行。For changes of the type permitted by 21 CFR 314.70(c) (3), an adequatesynthesis description on file would facilitate a conclusion that changes insite of manufacture of the new drug substance do not require prior FDA approvalfor implementation.

1、  参照标准品 Reference Standard

原始递交的申报文件应该包括任何所使用的参照标准品的制备过程的描述， 包括对提纯步骤的描述，参见II.F.3.The original applicationshould include a full description of the preparation of any reference standardsubstance used, including the description of the purification steps. See alsosection II.F.3. II.D.4.

五、生产过程的控制

1、中间体和生产过程的控制 Intermediates and In-process Controls

相关法规要求在合成过程中选择一些中间环节实施控制（检测项目与参数要求），以保证合成和提纯工序顺利进行，并保证检测后的中间体适合于以后的加工。申请者可以根据对整个合成工艺的开发和确认的经验，自行确定对那些中间体或加工环节进行检测及进行那些检测项目。在早期的开发阶段，每一个步骤通常都进行了检验（至少是对反应的内容），每一个中间体至少都进行与纯度有关参数的测定，包括纯度的估计。随着合成经验的积累，应选择关键的反应步骤和中间体进行监控。在递交新药申请(NDA)时，生产过程的控制点应该已经选定，相关控制参数和检验方法也已确立，以满足法律的要求。The regulations require that controls (specifications and tests) beemployed at selected intermediate stages of the synthetic process to assurethat the synthetic and purification procedures are operating properly and thatthe intermediate tested is suitable for subsequent processing. The choice ofwhich intermediate(s) or steps in the process to test, and the kind of testingrequired, are the responsibility of the applicant based on his experienceduring the development and verification of the total synthetic process. Inearly development work, every step would usually have been examined (at leastfor extent of reaction) and every intermediate at least partially characterizedwith some estimate of purity. As experience is gained with the synthesis, thecritical reaction steps and intermediates to be monitored are selected. At thetime of NDA submission, in-process control points should have been selected andappropriate specifications and tests established to meet the requirements ofthe regulations.

这里描述的整个操作都是合成工艺验证的一个部分。应当解释选择相关控制点和中间体的根据。应当证明控制参数和检测方法对合成过程的控制是充分的。应当依据相关控制点（控制参数和检测方法）来提供控制参数范围的书面描述。通常，较宽的参数范围需要更严格的控制（参见：II.E.b.（回收和再加工））。在新药申请(NDA)被批准后，随着经验的积累，可能需要修改生产过程的控制程序。该控制程序的改变需要额外的验证（参见：IV）。This whole operation is part of the process validation ofthe synthesis. The basis for selecting control points and intermediates shouldbe explained, and the adequacy of the specifications and tests to control thesynthetic process demonstrated. The ranges for the operating parameters in thewritten description of the synthesis should be chosen in light of the controls (specificationsand tests). Generally, broad operating ranges will require stricter controls.(See also section II.E.b. (recovery and rework) below.) With additional experiencesubsequent to NDA approval, the choice and nature of in-process controlprocedures may require modification. Changes in in-process control procedureswill require additional validation (see section IV).

设计控制为得是： Controls may be designed to

(a)  证明已获得了想要生产的产品 demonstrate that the desired product has been obtained;

(b)  确定关键的物理特征（如：熔点、旋光度等）determine a key physical property (e.g., melting point,optical rotation, etc.);

(c)  确定中间体的纯度和杂质  determinepurity/impurity of the intermediate;

(d) 确定收率是限定在通常的操作范围之内 determinethat the yield is within the normal operating range.

在某些情况下，对中间体的控制是不可行的（如：它们处于溶液状态或直接加工成下一个化合物）。如有可能，检测也可仅限于对合成过程的监控（如：反应是否完成）。In some cases no controls for the intermediate may befeasible (e.g., where they are held in solution, or are directly processed tothe next compound). When appropriate, testing may consist only of a testdesigned to monitor the progress of the synthesis (i.e., reaction completion).

上面所列的部分或全部生产过程中的控制在每一个控制点都应该符合控制检测的要求。关键、核心和最后的中间体（参见：术语表）通常至少应当符合以上所列过程控制的要求。为减少最终的大规模清除，从第一个中间体到原料药本身,中间体的纯度应该逐渐提高。Some or all of the abovekinds of process controls should be met at each point selected for in-processcontrol testing. Pivotal, key, and final intermediates (see Glossary, andbelow) would ordinarily require at least the in-process controls listed above.To eliminate the need for heroic final cleanups, it is expected that the degreeof purity of intermediates will increase progressively, from the first intermediateon to the drug substance itself.

2、关键中间体（见术语表）Pivotal intermediate(s) (See Glossary.)

应该用足够的细节（如详细描述其特征）描述任何关键中间体，并作为控制参数与检验的一个部分，对其进行严格的检查，其中还包括通过层析法，以避免忽略由替代合成方法产生的杂质。如此严格的检验无需经常进行，但是当供应商或合成发生改变时，要做以上检查。当关键中间体接近成为最终中间体时，对其进行的检测程度和纯度要求也应该增加Any pivotal intermediate should be described in adequatedetail (i.e., be well characterized) and be subject to rigorous examinationprocedures as part of the specifications and tests, including thoroughchromatographic examination so as to avoid overlooking impurities arising fromalternative syntheses. Such rigorous examination need not be routine but may beneeded in special circumstances such as when the supplier or synthesis ischanged. The degree of testing and the level of purity required for a pivotalintermediate should increase as its position in the synthesis scheme approachesthe final intermediate.

3、核心中间体（参见术语表）Key intermediate(s) (See Glossary.)

对核心中间体，应制定充足的规格，以保证能生产出所需的分子结构和纯度的最终产品。检测程序应该能够标明，所需要的转换（如：手性的引入或立体定向反应）已经按照预想的方式发生，并在预期的收率范围内，同时通过定量分析表明，不需要的材料（如：异构体、副产品、起始原料）已经限制在既定限度之内。The specifications shouldbe adequate to assure that the molecular architecture necessary for the finalproduct, as well as the requisite degree of purity, have been attained. Testprocedures should thus show that the desired transformation (such asintroduction of chirality, or a stereospecific reaction) has occurred in themanner expected and within the normal yield range expected, and show byquantitative determination(s) that undesired materials (e.g., isomers,by-products, starting materials) are within established limits.

4、最终中间体（参见术语表） Final intermediate (see Glossary.)

关于最终中间体的规格和检验应该与原料药的规格和检验同样广泛和严格，因为这是最终反应前的最后监控纯度和杂质的机会。Specifications and tests for final intermediate should be nearly asextensive and stringent as those for the new drug substance itself, becausethis is the last opportunity to monitor purity and impurities before the finalreaction.

5、返工Reprocessing

对不符合加工规格要求的中间体， 可以按照新药申请(NDA)中所描述的提纯方法进行进一步提纯。当采用替代的提纯方法时，获得的产品应象第一次一样，接受最后加工操作与检验。Intermediates which do not meet in-process specifications may be furtherpurified using the same purification procedure described in the NDA. When analternate purification procedure is used, the recovered material should besubjected to the same final processing operation and the same testing as forthe first time.

FDA认识到，有时操作条件（如时间和温度）会偏离新药申请(NDA)中的描述。应当制定一个方案，规定当反应条件或操作控制参数超出通常的范围时（如：偏离或较小的背离），应当采用什么样的程序，来使该批中间体或原料药合格。该方案应该为确保该批产品合格所使用的额外分析检验。这样的检验应该比日常要求的控制参数和检验范围更广。如需要，可以使用非常规分析方法。例如,对超出正常条件的新原料药批产品（如：反应条件超出一般范围），应该按使用分析标准参照品是否合格的程序来进行检验。FDArecognizes that operating conditions (such as time and temperature) occasionallydeviate from the NDA description. A protocol should be provided for theprocedure which will be used to qualify the batch of intermediate or drug substanceas meeting specifications when reaction conditions or operating parameters falloutside the typical/normal range (i.e., "excursions," or minor deviations).The protocol should describe the additional analytical testing which will beused in qualification of the batch. The testing should be more extensive thanrequired by routine specifications and tests and may include, as appropriate, theuse of nonregulatory analytical methods. For example, batches of new drug substancein this category (i.e, when reaction conditions are outside the norm) should beexamined by discerning analytical procedures such as those used for ReferenceStandard qualification.

对于母液的处理和二次回收应当制定控制程序并进行描述。参见II.D.3.d.。虽然重复使用母液和二次回收是常见的并被CGMP接受，当杂质含量积累时，它并不完全被接受的。同时，广泛的回收母液或反复回收是不鼓励的（参见：CGMP第IV节和“关于大宗药用化学物制造的现场检查指南”）。In-process control procedures should be established and described for the handlingof mother liquors and recovery of second crops when this is done; see sectionII.D.3.d. While the re-use of mother liquors and recovery of second crops maybe common/normal practice and is acceptable from a CGMP viewpoint, it is notnecessarily acceptable (i.e., when impurity levels build up), and extensiverecycling of mother liquors or repeated recoveries of additional crops isdiscouraged (refer to section IV (CGMP) and the "Guideline for Inspectionof Bulk Pharmaceutical Chemical Manufacture" in this regard.)

母液的回收程序应该包括在批产品生产纪录中。新药申请(NDA)中应规定对不符合标准的原料药的再加工程序，这一过程通常是通过从最终溶媒中进行一次或多次再结晶来完成。不需要额外的分析检验。The recovery procedures should be included in batch production records. Provisionshould be made in the NDA for the typical and usual reprocess procedure fordrug substance which fails to meet specifications, usually by one or moreadditional recrystallizations from the final solvent. Extraordinary analytical examinationis not required in this case.

不符合既定标准的单一批产品可以通过适当的程序来纯化， 然后按照新药申请(NDA)中所描述的最终提纯过程处理，前提是，用于最终纯化的材料纯度，与通常加工情况下的材料纯度相同。A single batch of drugsubstance which fails to meet specifications may be purified by an appropriateprocedure and then processed by the same final purification procedure describedin the NDA, provided that the purity of the reprocessed material being sotreated in the final purification step is as good as the normal drug substanceat this stage of processing.

一些可再利用的散装原料药（如：累积的未使用的分析样品，未使用的批产品，由客户退回的产品）可以用同样的方法加工。Some types of bulk drug substance for salvage (e.g.,accumulated unused analytical samples, unused portions of lots, bulk returnedfrom customers) may be processed in this fashion.

这些再加工的原料药应该接受如上面所描述的（如：对稍微背离正常加工条件下所生产出的原料药）额外分析检验。再加工操作和其原因应该记录。依照目前法规，在没有额外提纯(经过新药申请(NDA)所描述的最终提纯步骤的处理)情况下， 为使不合格的批可再利用而进行的混批是不能接受的。Suchreworked drug substance batches should be subjected to additional analyticalexamination, as indicated above (i.e., for drug substance resulting from minordeviations of process conditions). The rework operation, and the reason for it,should be documented. The blending of batches or lots for the purpose of salvagingunsatisfactory batches, without subsequent additional purification by anappropriate procedure and processing by the final purification step described inthe NDA, is not permitted under current guidelines.

如果在新药申请（NDA）中没有提到，要经常使用某一标准的（经过验证的）再加工程序，对不合格原料药进行处理，那么，应提供这方面的补充资料。参见“化学原料药生产现场检查指南”。If not part of the original NDA, a supplement should be submitted to theNDA when a standard (validated) reprocessing procedure for unsatisfactory bulkdrug substance is to be routinely employed; refer to the "Guide toInspection of Bulk Pharmaceutical Chemical Manufacturing."

当原料药要从制剂中回收时， 应当参见“关于提交制剂产品生产和控制文件的指南”。这样的操作需要提供补充资料。When drug substance is to be recovered from dosage forms, reference should also be made to the "Guidelinefor Submitting Documentation for the Manufacture of and Controls for DrugProducts." This type of operation will require a supplement.

六、成品的控制

相关法律要求制定规格参数和分析方法（如：新原料药的放行控制），以帮助确保原料药的特性、浓度、质量和纯度达到要求并且每批均一致。应该提交以下信息，以定义这些控制参数和检验方法。The regulations require specifications and analytical methods (i.e.,release controls for the new drug substance) to help assure that the properidentity, strength, quality, and purity of the drug substance have beenattained and are consistent from batch to batch. The following informationshould be submitted to define these specifications and test methods:

1、抽样Sampling

CGMP条例中有关于抽样的描述（参见：IV）。应该描述抽样计划，制定该计划的依据；抽样应该满足相关统计学的考虑。Samplingrequirements are covered by CGMP regulations (see section IV). The samplingplan should be described, giving the basis for the plan; it should satisfy appropriatestatistical considerations.

2、放行控制Release Controls

对放行中可能使用的规格和检验标准，举例如下：Examplesof specifications and tests that may be applicable are as follows:

(1) 外观/描述 Appearance/description

(2) 物理特性（如：熔化范围、旋光率、折射率、晶形、粒度）

对有手性中心或其它结构要求的原料药，相关的控制参数和检验应该能够保证，所生产出原料药具有治疗活动所需特征。参见第III部分。 Physical properties (e.g., melting range, specificrotation, refractive index, crystalline form, particle size). For drugsubstances with chiral centers or other configurational requirements, thespecifications and tests should assure that material (whether a singleenantiomer or isomer, a racemate, or a known ratio of isomers) with therequisite properties for therapeutic activity has been produced. See sectionIII in this regard.

同样，当药物的固态特性（参见II.G），如：多态现象或分子大小，会影响生理学或药理学活性（如：药物的生物效率），则相关控制参数和检验应该提供对这些特性的适当的限度（无论是单独形式或混合物形式）。Similarly, when the solid-state properties (see section II.G.) of the newdrug substance, such as polymorphism or particle size, are known to affect physiologicalor pharmacological activity (i.e, bioavailability of the drug product), thespecifications and tests should provide appropriate limits for these properties(whether as single forms or as admixtures).

(3) 鉴别检查 （如：红外线(IR)、核磁共振的(NMR)和质谱测定法(MS)）

Specific identity test(s) (i.e.,infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS)).

鉴别检查应该能够区别新原料药和相关化合物。如果只进行一个鉴别检验，应当首推红外线(IR)光谱（溴化钾颗粒）。其它的鉴别检验（如：紫外光谱，各种色析法的相对保留时间[R[f] 或T[R]值]，将被认为是确认性的而不是专属性的。鼓励进行额外的（确认）检验，但多个确认性鉴别将能取代一个特定性鉴别。The specific identitytest(s) should be capable of distinguishing the new drug substance from relatedcompounds. If only one specific identity test is performed, an IR spectrum (KBrpellet) is preferred. Other identity tests (such as UV spectra, or relativemobility [R[f] or T[R] values] by various chromatographic methods) areconsidered confirmatory rather than specific. Doing additional (confirmatory)tests is encouraged; however, doing several confirmatory tests will not substitutefor a specific identity test.

(4) 杂质档案和限度（也就是说明在原料中存在的起始原料、中间体、副产品、降解品、溶媒和其它杂质的情况，以及其它关于这些杂质的限度）Impurity profile and limits (i.e., tests to detect, identify, andquantitate the presence of starting materials and intermediates, by-products, degradationproducts, solvents, and other impurities, as well as proposed/recommendedlimits for such impurities).

如果通过适当的努力可达到的话，对杂质不仅应当检测其含量，还应当确认其是什么化合物。Impurities should not only be detected and quantitated, but should also beidentified and characterized when this is possible with reasonable effort.

在分析方法开发和验证中，应当解决下述问题

During the development and validation of theanalytical methods the following concerns should be addressed:

(1)  该方法能够检测杂质与溶解杂质（如：方法的灵敏性和专属性） Ability of the method to detect andresolve impurities (i.e., the sensitivity and specificity of the methods);

(2)  定量和线性Quantitation, and linearity of response;

(3)  杂质特性（如：起始原料、中间体、降解物）nature of the impurity (e.g., starting material,intermediate, degradation product);

(4) 分类(如：主要的或次要的、毒性的或较小毒性的、已知或未知的[如：还未被从化学上确定的]) classification (e.g.,major or minor, toxic, known or unknown [i.e., not yet chemically identified orcharacterized]);

(5) 杂质的分离纯化与结构证明（如：鉴别和特征），需要时与权威样品进行比较 isolation,purification, and proof of structure (i.e., identification and characterization),including the preparation of authentic specimens for comparison when needed.

在申请文件中杂质部分应该表明，上述各项都已考虑（如：新原料药中的杂质检验是充分的，并已做了合理的努力来鉴别和描述它们的特征）。The section on impurities in the application should demonstrate that allthe above points have been considered (i.e., that the examination of the newdrug substance for impurities has been adequate, and that reasonable effortshave been made to fully identify and/or characterize them).

应该提供:1、已知杂质的结构；2、杂质的分析方法验证；3、杂质的规格与检测方法，参照II.F.3.节（参照标准）。Structures of known impurities, and validation of theanalytical methods, should be provided (following the Specifications and Tests)and be referenced in section II.F.3. (Reference Standard).

所有主要的杂质应分别限定。应该提供每一种杂质的单位的最大量。如果有杂质的毒性信息或已设立了毒性限度，应当提供这些信息。All major impurities should be individually limited. Themaximum amount per unit does of every individual impurity should be provided.If there is information on toxicity or information on toxic limits that havebeen set for these impurities, this information should be provided.

在动物和临床实验中使用的每批原料药，应当提供杂质的分析结果列表，列出所有杂质（单个与总杂质，并包括那些未知的）。A summary tabulation of the results from the analytical examination of individualbatches of the drug substance used in animal and clinical testing, listing allimpurities (individually as well as total, and including those which areunidentified), should be provided.

（5）含量测定 Assay

如果可能，对原料药的含量测定应该有专属性，因为它也用于稳定性研究。可以用同样的方法测量原料药和杂质（如：HPLC法）。由于需要一个专属的鉴别检验，所以用合适的方法（如：色谱法）能控制杂质的可能干扰时，化验的专属性不是最重要的；在这种情况下，可以采用非专属性的化验方法，如：电位滴定。The assay for the drug substance should be specific if possible, since itcan then be used for stability-indicating purposes. It may be practical tomeasure the drug substance and impurities by the same procedure (e.g., highpressure liquid chromatography (HPLC)). Since a specific identity test is required,assay specificity is not essential when impurities which might interfere arecontrolled (and limited) by suitable (e.g., chromatographic) methods; in thesecircumstances non-specific assay methods, such as a potentiometric titration,may be employed.

新原料药DNA的制定一个含量的范围和杂质的限度，应该基于实际的生产结果（如：通过对单批产品的分析）。最好是按照实际储存条件下的化合物的稳定性，制定再检测日期。 The assay limits established in the NDA for the new drug substance, aswell as the limits for impurities, should be based on actual manufacturingresults (i.e., from analyses of individual batches). A retest date, based onthe stability of the compound under actual storage conditions, is desirable.

微粉化的原料应该检测粒度与粒度分布，这些通常在日常化验中不包括在内。

通常化验项目如下：

Microencapsulated compounds shouldalso be tested for particle size and

dissolution rate. Not included inthis listing, but generally provided as part of

the specifications and tests, are

(1)  水份含量或干燥失重 moisture content or loss on drying;

(2)  炽残残渣 residue on ignition;

(3)  残留溶媒 residual solvents;

(4)  重金属 heavy metals.

应该提供一个合理的物料平衡控制标准 The specifications should provide a reasonable material balance.

七、固态原料药的控制

1、固态原料药与生物利用度的关系 Solid-State DrugSubstance Forms: Relationship to Bioavailability

有关法律要求，如果适用， 应当用适当的控制参数来描述原料药的特征，以确保原料药的生物利用度（参见：21 CFR 314.50(3)(ii), 和 320.52(e)[4-1-85版]）。一些原料药的固态特性（如：多晶型或无定型，溶剂化作用或水合作用，各种包涵性复合物，粒度或比表面积），可能极大地影响着固态和悬浮态形式的制剂药品的溶出度与生物利用度。这些性质对溶液制剂和水溶性高的原料药不是很重要。The regulations require, where appropriate, specifications characterizingthe drug substance so as to assure the bioavailability of the drug product (see21 CFR 314.50(3) (ii), and 320.52(e)[4-1-85 edition]). Certain solid-stateproperties of the drug substance (e.g., polymorphic form or amorphism,solvation or hydration, various types of inclusion complexes, and particle sizeor surface area) may profoundly affect dissolution and bioavailability fromsolid dosage forms or suspension drug products. These properties are lessimportant for solution dosage forms and for drug substances which are highlywater soluble.

对难溶性原料药（如：灰黄霉素、呋喃妥因），粒度的大小对药物的作用影响很大，粒度的大小不同也可能会影响原料药的毒性。For drug substances with limited aqueous solubility (e.g., griseofulvin, nitrofurantoin),particle size can have a large effect on the behavior of the drug product, andsignificant differences in particle size may also affect toxicity.

当存在生物利用度的问题或原料药是从多个来源获得时，鉴别、检验、控制固体形态的差异显得尤其重要。Identifying, characterizing, and controlling the differences insolid-state forms is especially important when a bioavailability problem existsand/or the drug substance is obtained from multiple sources.

提交新药申请（NDA）数据时，申请者应该已确定药品是否存在于多种固体形态以及其是否影响药品的溶出度与生物利用度，粒度的大小对药品的溶出度与生物利用度是很重要。没有必要用与合成工艺无关的技术去“制造”另外的固体形态。By the time of an NDA submission, the applicant shouldhave established whether (or not) the drug substance exists in multiplesolid-state forms, whether these affect the dissolution and bioavailability ofthe drug product, and whether particle size is important for dissolution andbioavailability of the drug product. It is not necessary to `create' additionalsolid-state forms by techniques or conditions irrelevant to the syntheticprocess.

申请者应该提供信息说明为何和怎样得出以下结论 The applicant should provide information describing how and why it hasbeen concluded that

(a)  当药品按照新药申请(NDA)中的方法进行生产和储存时， 没有发生固体形态改变；achange in solid-state form does not occur when the drug substance is manufacturedand stored according to the NDA directions; or

(b)  产生了不同的形态但没有导致生物利用度的问题 different forms occurbut do not result in a bioavailability problem; or

(c)  多态现象、溶剂化作用或粒度大小对生物利用度有重要影响polymorphism, solvation, or particle size has animportant effect on bioavailability.

应该简要描述化验方法并证明其是合适的。对于(a) 和 (b)两种情况，适用性是指有关程序能够检测和区分多晶型物（或溶媒化物）。对于情况(c)，适用性是指该程序可以检测和估计混合物中的多晶型物和溶剂化物，或者它可以测量颗粒尺寸。The test methods used should be briefly described and be shown to besuitable. In cases (a) and (b), suitability means that the procedure(s) can,with reasonable certainty, detect and distinguish between polymorphs (orsolvates) should they occur. For case (c), suitability means that theprocedure(s) can detect and quantitate polymorphs and/or solvates in admixturesof such forms, or measure particle size.

为了生产所需要的固体形态的原料药，应该建立适度的生产和控制程序（如果需要，包括在线的中控）。应该强调的是，生产工艺（或储存条件）对生产特定的同质多形异构体或溶剂化物是直接相关的。控制方法只是决定结果。Appropriate manufacturing and control procedures (including in-processtesting when needed) should be established for the production of the desiredsolid-state form(s). It should be emphasized that the manufacturing process (orstorage condition) is responsible for producing particular polymorphs orsolvates; the control methods merely determine the outcome.

当考虑具体的固体形态的差异时，就会发现其中有互相依赖的关系，因此，如有可能，应该对相同颗粒大小的样品进行比较。While specific kinds of differences in solid-state forms are consideredseparately below, there is some interdependence; thus comparisons should, ifpossible, be performed on samples of similar particle size.

2、多态现象 Polymorphism

由于晶体点阵的分子排列不同，一些原料药以几种不同的晶型存在（多晶型物），这样他们显示了不同的物理性质。同样的原料药也存在于非晶形态中。这些不同的形态在熵能含量上不同，但在构成上相同。影响多态现象（或溶剂化物）的关键因素是最终溶媒和分离条件的选择。参见之前的注释(II.D.2.d.)。Some drug substances exist in several differentcrystalline forms ("polymorphs"), due to a different arrangement ofmolecules in the crystal lattice, which thus show distinct differences in theirphysical properties. The same drug substance may also exist in a noncrystalline(amorphous) form. These various forms differ in their thermodynamic energycontent, but not in composition. One of the critical factors affectingpolymorphism (or solvation) is the choice of final solvent and isolationconditions in the synthesis. As noted previously (II.D.2.d.),

当最终结晶溶媒发生改变时，必须有证据证明没有发生固体形态的转型改变。常规的储存条件以及一些产品的制造条件（如：药片压制或在颗粒化过程中使用一种有机溶媒）也会导致转型。问题是：晶型是否稳定，或它是否是依赖于时间和工艺？

when a change is made in the finalcrystallization solvent, evidence must be

provided that no transformation insolid-state form has occurred. Routine

storage conditions, as well as someconditions of product manufacture (e.g.,

tablet compression, or use of anorganic solvent during granulation) may also

cause transformations. The questionis: Is the crystalline (or amorphous) form

stable, or is it time and/or processdependent?

应该用合适的分析程序来判断是否有多晶型态现象发生。以下是一些物理化学测量的例子和技术：Appropriate analytical procedures should be used to determine whether (ornot) polymorphism occurs. Some examples of physico-chemical measurements and techniquesare

(1) 熔点 (包括：热态镜检法)  melting point (including hot-stagemicroscopy);

(2) 红外线光谱（不在溶媒中） infrared spectra(not  in solution);

(3)  X光颗粒衍射;X-ray powder diffraction;

(4)  热分析方法（如：差示扫描量热法(DSC)），示差热分析(DTA), 热解重量分析TGA));thermal analysis methods(e.g., differential scanning calorimetry (DSC), differential thermal analysis(DTA), thermogravimetric analysis (TGA));

(5) 拉曼光谱学 Raman spectroscopy;

(6)  比较的内在溶出速率 Comparative intrinsic dissolutionrate;

(7)  电子显微镜扫描 (SEM)scanning electron microscopy (SEM).

这些方法不是按其鉴别和测定能力排列的。申请者有责任选择方法用以提供有关多态现象的证据，如果生物利用度受到了影响，也应该提供和证明有关控制固体形态药品的规格和检验的适用性的内容。These methods are not ranked in order of their discriminating orquantitating ability. It is the applicant's responsibility to select themethod(s) used to provide evidence concerning polymorphism, and if bioavailabilityis affected, to provide and demonstrate the suitability of the specificationsand tests (including preparation and provision of reference standards) for thecontrol of the solid-state form of the drug substance.

3、溶剂化物（包括水合作用） Solvation (includinghydration)

制造和储存原料药的条件可能会导致离析或形成溶剂化物或水化的原料药。这通常可以通过干燥法检测，或者通过卡尔菲舍滴定法（对水合物）检测。其它方法(如：TGA)提供的信息可能也是必要的，因为有些溶剂化物通常在溶剂的沸点以上是稳定的。当溶剂化作用或水合作用影响到生物利用度时，应建立适当的制造和控制程序。Conditions used in manufacture and/or storage of the drug substance mayresult in the isolation or formation of a solvated or hydrated drug substance.This is most directly assessed by testing for loss on drying (LOD) or by KarlFischer titration (for hydrates). Information from other methods (e.g., TGA)may be necessary, because some solvates are known to be stable at temperaturesabove the boiling point of the solvent. When solvation or hydration affects bioavailability,appropriate manufacturing and control procedures should be established.

4、粒度大小（和表面面积） Particle Size (and surface area)

原料药的粒度分布和表面面积可能会影响药品的溶出度与生物利用度。所以，申请者要改变粒度分布和表面积以使药物具有更多的有利特性。对于难溶性的原料药（如：低于每毫升5毫克 的）在标明检测限度的情况下，应当说明具有代表性粒度分布和任何改变程序后的粒度分布。也应该提供原料药粒度分布对溶出度（制剂产品）影响的情况。当原料药的粒度分布/表面积与制剂产品的生物利用度有关的时候，应该提供有关改变粒度分布/表面积的程序描述和用于检测的方法。同时应该提供用于生产的控制规格和控制方法。Particle size distribution and surface area of the drug substance mayaffect the dissolution and bioavailability of the drug product. Therefore, anapplicant may conduct operations to alter particle size/surface area in orderto achieve more favorable properties for the drug substance. For drug substanceswith low aqueous solubility (e.g., less than 5 milligrams per milliliter) boththe typical original particle size distribution and the particle sizedistribution after any alteration procedures should be presented (preferablygraphically), with detection limits indicated. The effect of drug substanceparticle size on dissolution (of the drug product) should also be provided.When particle size/surface area of the drug substance is relevant to thebioavailability of the drug product, the description of the procedure(s) usedto alter particle size/surface area and the methods used for examination shouldbe provided, and appropriate specifications and tests established for control.

a.Pivotal intermediate - means an intermediate which may be prepared by more thanone manufacturing process to provide material of suitable quality for use inthe production of a drug substance.

b.Key intermediate - means an intermediate in which an essential molecularcharacteristic(s) is first introduced into the structure and for whichsignificant in-process controls are needed to ensure the purity of the drugsubstance.

c.Final intermediate - means the last intermediate isolated and controlled duringthe manufacturing process; prior to the final step which provides the crudedrug substance.

谢谢分享。。。。。