The management and technical evaluation requirements of chemical drug substances

1. The management and technical evaluation requirements of chemical drug substances Huo Xiumin State Food and Drug Administration Center for Drug Evaluation March 2010

2. I. Drug substance management of SFDA II. The information requirements and the main points of evaluation of CMC III. Problems and Solutions IV. Summary Main Contents

3. 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 Registration 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. -----Production and sales can be conducted only after having obtained the registration certificate. I. Drug substance management of SFDA

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 production processes, specification, and test methods should be submitted.

5. Principles: The consistent requirements between import and domestic research drugs Synthetic process study and reference materials Structure identification test and reference materials Quality study test and reference materials Specification and its drafting instructions, the source and purity of standards or the reference substances Certificate of Analysis of three batches of samples Stability test materials The selection basis and specification of primary packaging materials and containers II. The information requirements and the main points of evaluation of CMC

6. Synthetic process study and reference materials Basis for design of process route Complete process (chemical reaction equation, the starting materials, the various step reaction type, reaction conditions and reaction intermediates, final product purification / purification methods, etc). Key synthetic steps and critical process parameters affecting the quality It 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 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, optical rotation, IR method, NMR method, mass spectrometry), and the comparison with reference data. Preparation Process

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 materials, 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 Process

8. Production process and its validation Focus on: the presence or absence of changes of the 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 parameters 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. Preparation Process

9. Structure identification test and reference materials Chemical name, molecular structure formula (including the three-dimensional configuration), molecular formula, molecular weight Purification methods and purity of test samples (purity determination method) With the generic drugs, the reference substances can be available, and the source, purity and other information of reference substances can be provided Test 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 conformation, crystal solvent (or the crystal water) and the crystal forms, etc. Structure identification

10. 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 crystal water are consistent with the target product or the product by imitated. Structure identification

11. Quality study and reference materials Quality study tests include the determination of study items and methodology study. --Determination of study items --Methodology study includes the method selection and method validation Quality Study

12. --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.), physical 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 introduced 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 bacterial toxins or pyrogens, sterility, etc. Specification

13. 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 effects 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 process Specification

14. --Method selection and method validation The selection of analysis methods should 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 impurities 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 used Specification

15. Focus on: The specificity of identifying item methods, the specificity of examination item methods, sensitivity and accuracy, the accuracy and repeatability of assay methods, and the method validation results can confirm the feasibility of methods Specification

16. Specification and the drafting instructions, the source and purity of standards or reference substances ----Specification is consist of three aspects, including the test items, analysis methods and the limits ----The analytical method should only be confirmed to become a specification method by the method validation Specification

17. Determination of specification items and limits --Item settings have both universal and also targeted (for the characteristics of the product itself), 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 considered, 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 than the quality of the products used for safe, effective test samples, otherwise they will be re-evaluated the safety and effectiveness Specification

18. Focus on: Whether the items of specification to control the product quality can reflect the characteristics and quality changes of the product, the feasibility 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 Specification

19. The drafting instructions of specification The drafting instructions of specificationare 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 items can not listed in the specification Specification

20. The source and purity of Standard or reference substances The 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 the scientific nature of the standardized testing methods and the reliability of test results Specification

21. Analysis report of three batches of samples The analysis report of three continuous batches of samples with full review should be provided according to requirements of specification and with the signature of department leader Inspection Report

22. Stability test materials The batch, lot number, size, packing cases of stability test samples Stability protocol (impact factor tests, accelerated tests and long-term tests, and their observation indicators of quality) Test methods used Test results and analysis and evaluation of results post-marketing stability protocol and commitments Stability Study

23. 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 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 packaging, storage conditions and expiry period (retest period) Stability Study

24. The selection basis and specification of primary packaging materials and containers Based on China’s current drug management regulation, as an important component of pharmaceutical drugs ----- primary packaging materials and containers 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 transportation, etc. Packaging materials and containers

25. Principles: import and domestic research drugs have a consistent requirement The application registration for Domestic drug substances should in accordance with the requirements of submitting the application materials according to the Annex 2 of Drug Registration Management Regulation of SFDA Also, 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 SFDA For 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. III. Problems and Solutions

26. The format of application materials SFDA "Drug Registration Management Regulation" Annex 2 format√ CTD format √ Application for an import registration of drug products Registration 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 domestic 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 body of responsibility Questions and Solutions

27. 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 usually 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 Solutions

28. Solutions According to the relevant provisions of the "Drug Registration Regulation” of SFDA In accordance with the API Management and Assessment Model of U.S. FDA and the EU EDQM -----the relevant study dataare required to submit for API suppliers and drug products manufacturers respectively, and the RP part of the review process can be started only based 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 requested to provide the supplementary RP content. Problems and Solutions

30. Drug substances quality control evaluation is a prerequisite for quality evaluation of drug products Submitting drug substances quality control information for imported drug products is the management requirements of SFDA AP part of the DMF used in drug substances can be provided by the certificate holder of drug products RP part of the DMF can be submitted directly to SFDA by drug substances suppliers (DMF holder) IV Summary

31. Thank you!