The management and technical evaluation requirements of chemical.ppt
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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
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