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1、1 1The management and technical evaluation requirements of chemical drug substancesState Food and Drug AdministrationCenter for Drug EvaluationMarch 2010Huo Xiumin2 2Main ContentsI.Drug substance management of SFDAII.The information requirements and the main points of evaluation of CMCIII.Problems a
2、nd SolutionsIV.Summary3 3I.Drug substance management of SFDA Article 25 of Drug Registration Regulation:When an application is only made for registration of drug products,the drug substances used for investigation must have a Drug Approval Number,Import Drug Certificate or Pharmaceutical Product Reg
3、istration Certificate,and must have been obtained from legal channels.Any investigative drug substance which does not have a Drug Approval Number,Import Drug Certificate or Pharmaceutical Product Registration Certificate must be approved by the SFDA.-Drug substances will be approved by the SFDA.-Pro
4、duction and sales can be conducted only after having obtained the registration certificate.4 4 Article 95 of Drug Registration Regulation:For an imported drug products application,.For drug substances and excipients that have not yet been approved by SFDA,standardized study information of relevant p
5、roduction processes,specification,and test methods should be submitted.5 5II.The information requirements and the main points of evaluation of CMCPrinciples:The consistent requirements between import and domestic research drugspSynthetic process study and reference materialspStructure identification
6、 test and reference materialspQuality study test and reference materialspSpecification and its drafting instructions,the source and purity of standards or the reference substancespCertificate of Analysis of three batches of samplespStability test materialspThe selection basis and specification of pr
7、imary packaging materials and containers6 6pSynthetic process study and reference materialsBasis for design of process routeComplete process (chemical reaction equation,the starting materials,the various step reaction type,reaction conditions and reaction intermediates,final product purification/pur
8、ification methods,etc).Key synthetic steps and critical process parameters affecting the qualityIt should be described that if the special reagents,solvents,catalysts,or special reaction conditions are used.The major items and limits are included in the internal control standards of the key starting
9、 materials and key intermediates.For the chiral materials and chiral intermediates,the chirality control indicator should be included.Process control methods(HPLC method or TLC method controlling reaction process)，the qualitative identification of each of reaction intermediates(melting/boiling point
10、,optical rotation,IR method,NMR method,mass spectrometry),and the comparison with reference data.Preparation Process7 7 Focus on:The processes of pilot scaling up and the preparation of clinical samples,including the manufacture site,batch and batch size,the quality control indicators of starting ma
11、terials,reagents,solvents and intermediates,the process parameter scope of the key steps,the use conditions of organic solvents,the studies of impurities and analysis method validation,etc.Preparation Process8 8Production process and its validation Focus on:the presence or absence of changes of the
12、process routes of the production scale,as well as small scale and pilot scale,starting materials,reaction reagents,solvent level(from AR to a chemical pure or industrial pure),process parameters,etc Production process validation protocol and validation report(validation batches,scale,key process par
13、ameters of validation,and outcome evaluation,etc.)Evaluation:the feasibility of the proposed process for commercial production and whether the products meeting the specification can be produced stably by using the specified raw materials and equipment and according to the proposed process.Preparatio
14、n Process9 9pStructure identification test and reference materialsChemical name,molecular structure formula(including the three-dimensional configuration),molecular formula,molecular weightPurification methods and purity of test samples(purity determination method)With the generic drugs,the referenc
15、e substances can be available,and the source,purity and other information of reference substances can be providedTest methods(elemental analysis,UV,IR,MS,NMR,thermal analysis,powder X-ray diffraction,etc.),and the instruments and testing conditions used,including the tests for the three-dimensional
16、conformation,crystal solvent(or the crystal water)and the crystal forms,etc.Structure identification1010 Focus on:whether the method used is in line with its structural test requirements,and the test results of the planar structure,three-dimensional configuration,crystal forms,crystal solvent and cr
17、ystal water are consistent with the target product or the product by imitated.Structure identification1111pQuality study and reference materialsQuality study tests include the determination of study items and methodology study.-Determination of study items-Methodology study includes the method selec
18、tion and method validationQuality Study1212 -Determination of the study items Based on product characteristics,preparation process and stability study results,the quality study items are determined Study items include:description(appearance,color,smell,taste,crystallinity,hygroscopicity,etc.),physic
19、al and chemical properties(melting point,optical rotation,solubility,absorption coefficient,etc.),identification,examination(General impurities:chloride,sulfate,heavy metals,arsenic salt,residue on ignition,etc.Impurity:the starting materials,intermediates,polymers,vice reaction products,isomers int
20、roduced during the production process,as well as degradation products occurred during storage,residual solvents,crystal form,particle size,dry weight loss,or moisture,solution clarity and color,pH,etc.)and assay.For the drug substances for injection(sterile powders-packing),if necessary,examine the
21、bacterial toxins or pyrogens,sterility,etc.Specification1313 Focus on:Whether the quality study items are comprehensive(it is necessary to consider the general requirements,but also targeted requirements),and can fully reflect the circumstances of product characteristics and quality changes The effe
22、cts of starting materials and reagents,reaction intermediates and side reaction products,as well as organic solvents on the quality of final products should be considered during the preparation processSpecification1414 -Method selection and method validation The selection of analysis methods should
23、be aimed at selected research items and the experimental purpose The method selection should have the basis,including the basis of references and tests Pharmacopoeia methods can be used for the conventional items The comparison study with two or more methods will be used for the examination of impur
24、ities and assay to compare the pros and cons of methods and choose the best of them The method validation should be conducted for the analytical methods usedSpecification1515Focus on:The specificity of identifying item methods,the specificity of examination item methods,sensitivity and accuracy,the
25、accuracy and repeatability of assay methods,and the method validation results can confirm the feasibility of methodsSpecification1616pSpecification and the drafting instructions,the source and purity of standards or reference substances-Specification is consist of three aspects,including the test it
26、ems,analysis methods and the limits-The analytical method should only be confirmed to become a specification method by the method validation Specification1717Determination of specification items and limits-Item settings have both universal and also targeted(for the characteristics of the product its
27、elf),and can sensitively reflect the changes in product quality-Limit determination at the first should be based on drug safety and efficacy considerations,and analytical methods errors.Under the premise of ensuring safe and effective products,the actual situation of production process can be consid
28、ered,as well as taking into account the influences of the circulation and the use R&D staff should pay attention to the scale of industrial production of products and carry out the safe,effective study of the quality consistency of the samples -In other words,commercial production can not be lower t
29、han the quality of the products used for safe,effective test samples,otherwise they will be re-evaluated the safety and effectivenessSpecification1818 Focus on:Whether the items of specification to control the product quality can reflect the characteristics and quality changes of the product,the fea
30、sibility of methods and ease of operation,as well as the science and rationality of limits,and whether the specification can effectively control the consistency between batches of product quality Specification1919The drafting instructions of specificationThe drafting instructions of specification ar
31、e the comment of specification,R&D staff will describe in detail the various items settings and the basis of limit determination in the specification drafting instructions(the relevant research data,measured data and literature data should be noted to list),and some reasons why several research item
32、s can not listed in the specificationSpecification2020The source and purity of Standard or reference substancesThe standardized test materials must be provided in the case of self-production standards or reference substances Focus on:the legality of the source of standards or reference substances,or
33、 the scientific nature of the standardized testing methods and the reliability of test resultsSpecification2121pAnalysis report of three batches of samplesThe analysis report of three continuous batches of samples with full review should be provided according to requirements of specification and wit
34、h the signature of department leaderInspection Report2222pStability test materialsThe batch,lot number,size,packing cases of stability test samplesStability protocol(impact factor tests,accelerated tests and long-term tests,and their observation indicators of quality)Test methods usedTest results an
35、d analysis and evaluation of resultspost-marketing stability protocol and commitmentsStability Study 2323 Focus on:Whether the stability research samples are representative,and the study contents are comprehensive(impact factor tests,accelerated tests and long-term tests),the observation indicators
36、of quality are reasonable and can reflect the changes in the quality of the sample,the setting conditions and observation time are reasonable,and the requirements of detection methods and limits are reasonable Whether the stability protocol design,implementation,and observation can support the packa
37、ging,storage conditions and expiry period(retest period)Stability Study2424pThe selection basis and specification of primary packaging materials and containers Based on Chinas current drug management regulation,as an important component of pharmaceutical drugs-primary packaging materials and contain
38、ers must be approved by SFDA,the pharmaceutical packaging material registration certificate and specification should be provided.Focus on:whether the registration certificate for pharmaceutical packaging material and containers can be available,as well as the applicability for medicine storage and t
39、ransportation,etc.Packaging materials and containers 2525III.Problems and SolutionsPrinciples:import and domestic research drugs have a consistent requirementpThe application registration for Domestic drug substances should in accordance with the requirements of submitting the application materials
40、according to the Annex 2 of Drug Registration Management Regulation of SFDApAlso,the application registration for imports drug substances should in accordance with the requirements of submitting the application materials according to the Annex 2 of Drug Registration Management Regulation of SFDApFor
41、 the application registration for drug products,there is a larger gap between the study materials of quality control for drug substances used and the requirements of the Annex 2 of Drug Registration Management Regulation of SFDA.2626pThe format of application materialsSFDA Drug Registration Manageme
42、nt Regulation Annex 2 formatCTD format pApplication for an import registration of drug productsRegistration application for imports preparations of self-produced drug substances The application material requirements of drug substances should be consistent with the registration requirements of the do
43、mestic drug substances Import registration application for outsourcing preparations of drug substances The application material requirements of both drug substances and drug products should be consistent with the registration requirements of the domestic drug substances -Technological security -Main
44、 body of responsibilityQuestions and Solutions2727 For the registration applications of import preparations of drug substances,the specification and analysis report of drug substances,simple chemical reaction equations and the structure test pattern,or DMF registration number,CEP numbers should usua
45、lly be submitted.Without a detailed production process,structure identification,the specification and stability research materials,the reasonableness of specification and controllability of product quality can not be determined.Problems and Solutions2828pSolutionsAccording to the relevant provisions
46、 of the Drug Registration Regulation”of SFDAIn accordance with the API Management and Assessment Model of U.S.FDA and the EU EDQM -the relevant study data are required to submit for API suppliers and drug products manufacturers respectively,and the RP part of the review process can be started only b
47、ased on the written authorization of permission of API suppliers An AP copy of DMF will be included in the application information submitted by the applicant of drug products.This AP part can be determined through the review the adequacy of the AP content,if not fully,the DMF holder will be requeste
48、d to provide the supplementary RP content.Problems and Solutions29293030IV SummarypDrug substances quality control evaluation is a prerequisite for quality evaluation of drug products pSubmitting drug substances quality control information for imported drug products is the management requirements of SFDApAP part of the DMF used in drug substances can be provided by the certificate holder of drug productspRP part of the DMF can be submitted directly to SFDA by drug substances suppliers(DMF holder)3131
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