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ICH 技术指导原则概述 ICH Guidelines Introduction 国家食品药品监督管理局 丁 建 华 2009年12月12日，北京 ICH Briefing Birth of ICH : April 1990, in Brussels Main topics covers: Safety, Quality and Efficacy Regions involved: Europe, Japan , USA Purposes: to produce harmonized technical guidelines, reduce duplication Model of function: dialogue between regulatory authorities and the pharmaceutical industry 1 ICH Structure ICH Steering Committee: final decision maker for ICH guideline 6 Parties - EU and EFPIA - MHLW (PMDA) and JPMA - FDA and PhRMA EWG IWG 3 Observers: WHO, EFTA, and Canada (represented by Health Canada). 6 RHIs: APEC, ASEAN, GCC, PANDRH, SADC ICH Working mechanism Concept paper proposed, EWG formed for each of the topic of Q, S and E A 5-Steps decision-making model accepted from guideline initiation to implementation, Step 2 draft guidelines on web for comments till Step 4, final guideline approved by Steering Committee as final Step 5 guidelines IWG established for implementation, Q&A on ICH Web for each guidelines GCG established 1999, China SFDA first attended Oct. 23, 2009 2 ICH meetings Usually internal experts meeting each ICH activity for a week, followed by a public meeting for updates until ICH 6 ICH meeting hosted by US, JAPAN, EU in each June and Oct. in a shifted manner From June, 2007 in Japan, the first regional public meeting for ICH updates From June, 2008 in US, the first Regulatory Forum and DRA （Drug Regulatory Authority）invited as member to attend ICH GCG discussion and listen to other topics The Technical Data Target Common Technical Data The Scientific Information which demonstrates Safety Quality Efficacy and meets the Regulatory Requirements in EU, Japan and the USA 3 ICH Guidelines Code System Q = Quality Guidelines，Quality assurance, Pharmaceutical development, GMP S = Safety Guidelines - nonclinical testing E = Efficacy Guidelines - Clinical testing M = Multidisciplinary - Regulatory Communications - Medical Dictionary - Electronic transmission of data - Common Technical Document ICH Technical Guidelines (total 71) 5 Multidisciplinary 10 Quality Topics (38 guidelines) guidelines 9 Safety Topics (13 guidelines) M Q S E 9 Efficacy Topics (15 guidelines) 4 ICH Guidelines: Quality Overview Impurities Validation Pharma- copoeias Stability GMP Biotech Specific- ations Pharmaceutical Development Risk Management Quality System 10 Subject Areas Quality Guidelines 6 Guidelines on Stability topics Q1 Stability 5 Q1: Stability Guidelines Q1A(R2): Stability Testing of New Drug Substances and Products (Second Revision) - This gives recommendations on the stability testing protocols which should be followed to assess the stability of new drug substances and products. - Recommendations are given on temperature and humidity levels as well as the duration of trials - The Guideline has been extensively revised second times and was finalised in Feb 2003 Q1: Stability Guidelines Q1B: Photostability Testing of New Drug Substances and Products - Guidance on the basic testing protocol required to evaluate the light sensitivity and stability of new drugs and products. Q1C: Stability Testing for New Dosage Forms - Extends the main stability guideline for new formulations of already approved medicines and defines the circumstances under which reduced stability data can be accepted 6 Q1: Stability Guidelines Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products - The parent guideline Q1AR allows for a reduced number of samples to be tested, where justified, and this guideline covers expands on acceptable bracketing and matrixing study designs Q1E: Evaluation of Stability Data - Recommendations on how stability data generated in accordance with the parent guideline can be used to propose a retest period or shelf life Q1: Stability Guidelines Q1F: Stability Data Package for Registration in Climatic Zones III and IV - long term storage condition for a registration application for drug substances and products intended to be marketed in Climatic Zones III and IV - Takes account of WHO Guidelines - Must be read in conjunction with the parent guideline 7 Quality Guidelines 1 Guidelines on Analytical Validation Q2 Analytical Validation Q2: Analytical Validation Q2(R1): Validation of Analytical Procedures: Text and Methodology - analytical methods and discusses the characteristics that must be considered during the validation of the analytical procedures that are included as part of registration applications. Addendum Validation of Analytical Procedures: Methodology - Extends the previous text to include the actual experimental data for the validation of analytical procedures. 8 Quality Guidelines 3 Guidelines on impurities Q3 Impurities Q3: Impurities Q3A(R2): Impurities in New Drug Substances (Revised Guideline) - Provides the limits and qualification of impurities in new drug substances produced by chemical syntheses. Q3B(R2): Impurities in New Drug Products (Revised Guideline) - Extension of the main guideline on impurities in new drug substances and makes recommendations on the content and qualification of impurities that may arise in the drug products due to degradation of the active ingredient or interaction with other components - Guidelines revised to keep pace with changing scientific knowledge and practice 9 Q3: Impurities Q3C(R4): Impurities: Guideline for Residual Solvents - Recommends the use of less toxic solvents in the manufacture of drug substances and dosage forms, and sets pharmaceutical limits for residual solvents (organic volatile impurities) in drug products - PDE for N-methylpyrrolidone（N-甲基吡咯烷酮 ）: Maintenance revision to include the permissible daily exposure （PDE) for NMP (Class 2) - PDE for Tetrahydrofuran (四氢呋喃）: Maintenance revision to include the permissible daily exposure for TFH (into Class 2 from Class 3) Quality Guidelines Pharmacopoeias Harmonisation Project Q4 Pharmacopoeias 10 Q4: Pharmacopoeial Harmonisaiton ICH EWGs work with the Pharmacopoeias: - European Pharmacopoeia - Japanese Pharmacopoeia - United States Pharmacopoeia No specific ICH guidelines or monographs - These are the responsibility of the pharmacopoeial authorities Project to focus and accelerate harmonisation - Monographs for harmonisation proposed to the Pharmacopoeial Development Group (PDG) Q4 covers 17 projects( - to be continued) Q4 PharmacopoeiasQ4A Pharmacopoeial HarmonisationQ4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions Q4B Annex 1 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Residue on Ignition/Sulphated Ash General Chapter Q4B Annex 2 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Extractable Volume of Parenteral Preparations General Chapter Q4B Annex 3 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Particulate Contamination: Sub-Visible Particles General Chapter Q4B Annex 4A Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests General Chapter Q4B Annex 4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-organisms General ChapterQ4B Annex 4C Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Microbiological Examination of Non-Sterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use General ChapterQ4B 11 Q4 covers 17 projects Annex 5 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Disintegration Test General ChapterQ4B Annex 6 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Uniformity of Dosage Units General Chapter Q4B Annex 7 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Dissolution Test General Chapter Q4B Annex 8 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Sterility General Chapter Q4B Annex 9 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Tablet Friability General Chapter Q4B Annex 10 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Polyacrilamyde Gel Electrophoresis General Chapter Q4B Annex 11 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Capillary Electrophoresis General Chapter Q4B Annex 12 Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Analytical Sieving General Chapter Quality Guidelines 5 Guidelines on Biotechnology topics Q5 Biotechnology 12 Q5: Quality of Biotechnological Products Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin - Testing and evaluation of the viral safety of biotechnology products derived from characterised cell lines of human or animal origin. - The purpose is to provide a general framework for virus testing experiments for the evaluation of viral clearance and the design of viral tests and clearance evaluation studies. Q5B: Quality of Biotechnological Products : Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products - Advises on the types of information that are considered valuable in assessing the structure of the expression construct used to produce recombinant DNA derived proteins Q5: Quality of Biotechnological Products Q5C: Stability Testing of Biotechnological/Biological Products - Addition to the stability guidance (Q1A) dealing with the particular aspects of stability test procedures needed to take account of the special characteristics of products in which the active components are typically proteins and/or polypeptides Q5D: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/ Biological Products - Provides broad guidance on appropriate standards for the derivation of human and animal cell lines and microbes used to prepare biotechnological/biological products and for the preparation and characterization of cell banks to be used for production. Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process - objective is to provide principles for assessing the comparability of biotechnological/biological products before and after changes are made in the manufacturing process for the drug substance or drug product. 13 Quality Guidelines 2 Guidelines on Specifications Q6 Specifications Q6: Guidelines on Specifications Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances - The process of selecting tests and methods and setting specifications for testing chemically derived drug substances and their dosage forms Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products - Guidance on justifying and setting specifications for proteins and polypeptides that are derived from recombinant or non- recombinant cell cultures - Scope initially limited to well-characterized biotechnological products but the concepts may be applicable to other biologicals as appropriate 14 Quality Guidelines 1 Guideline on Good Manufacturing Practice Q7 GMP Q7: Good Manufacturing Practice Q7A: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients - Step 5 November 2000 - Undertaken because of the lack of harmonised requirements for active ingredients - Global implications as APIs have wide geographical sources - Wider consultation and EWG membership than for other topics - GMP for pharmaceutical products not addressed initially as technical standards were already harmonised 15 Pharmaceutical Development 1 Guideline on Pharmaceutical Development Q8 Pharmaceutical Development Pharmaceutical Development Q8(R2): Pharmaceutical Development - Step 5 in November 2005. - to provide guidance on the contents of Section 3.2.P.2 (Pharmaceutical Development) for drug products as defined in the scope of Module 3 of the Common Technical Document (ICH topic M4). - not apply to contents of submissions for drug products during the clinical research stages of drug development. - annex describes the principles of quality by design (QbD). 16 Quality Risk Management 1 Guideline on Quality Risk Management Q9 Quality Risk Management Quality Risk Management Q9: Quality Risk Management - Step 5 in November 2005. - provides principles and examples of tools of quality risk management that can be applied to all aspects of pharmaceutical quality including development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances and drug (medicinal) products, biological and biotechnological products, including the use of raw materials, solvents, excipients, packaging and labeling materials. 17 Pharmaceutical Quality System 1 Guideline on Pharmaceutical Quality System Q10 Pharmaceutical Quality System Pharmaceutical Quality System Q10: Pharmaceutical Quality System - Step 5 in June 2008 - applies to pharmaceutical drug substances and drug products, including biotechnology and biological products, throughout the product lifecycle. should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognizing the differences among, and the different goals of each stage. 18 ICH Guidelines: Safety Overview Kinetics Genotoxicity Toxicity Cancer drug Nonclinical Carcino- genicity Immunoto xicology Pharma- cology Reprotox Biotech 9 Subject Areas Safety Guidelines 3 Guidelines on Carcinogenicity Studies S1 Carcinogenicity 19 S1: Carcinogenicity Studies S1A: Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals - Provides a definition of the circumstances under which it is necessary to undertake carcinogenicity studies on new drugs. - Takes into account the known risk factors as well as the intended indications and duration of exposure. S1B: Testing for Carcinogenicity of Pharmaceuticals - Guidance on the need to carry out carcinogenicity studies in both mice and rats - Guidance also given on alternative testing procedures which may be applied without jeopardising safety. S1: Carcinogenicity Studies S1C(R2): Dose Selection for Carcinogenicity Studies of Pharmaceuticals - This document addresses the criteria for the selection of the high dose to be used in carcinogenicity studies on new therapeutic agents to harmonise current practices and improve the design of studies. -S1CR: Addition of a Limit Dose and Related Notes - This is an Annex to S1C providing additional guidance on the limit dose and circumstances when it may need to be exceeded 20 Safety Guidelines 2 Guidelines on Genotoxicity Studies S2 Genotoxicity S2: Genotoxicity Studies S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use - to optimize the standard genetic toxicology battery for prediction of potential human risks, and to provide guidance on interpretation of results, with the ultimate goal of improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material. The revised guidance describes internationally agreed upon standards for follow-up testing and interpretation of positive results in vitro and in vivo in the standard genetic toxicology battery, including assessment of non-relevant findings. S2A: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals - specific guidance and recommendations for in vitro and in vivo tests and on the evaluation of test results. It includes a glossary of terms related to genotoxicity tests to improve consistency in applications. 21 Safety Guidelines 2 Toxicokinetics and Pharmacokinetics S3 Kinetics S3：Toxicokinetics and Pharmacokinetics Studies S3A: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies - This document gives guidance on developing test strategies in toxicokinetics and the need to integrate pharmacokinetics into toxicity testing, in order to aid in the interpretation of the toxicology findings and promote rational study design development. S3B: Pharmacokinetics: Gui