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DR. K. VENKATESWARA RAJU ICH – GUIDELINES INTRODUCTION  ICH stands for “International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use”.  Which is international non-profit Association which is unique in bringing together the regulatory authorities and pharmaceutical industries.  Where European Union Japan and the USA involve in scientific and technical discussions of the testing procedures required to assess and ensure the safety quality and efficacy of medicines.  These are the three pillars on which the health of the patients depend.  ICH Guidelines accepted as law in several Countries to ensure and access the Q S E of medicines but are only used as guidance for the U.S Food and Drug Administration. Need to Harmonize  Many time-consuming and expensive test procedures in order to market new products internationally.  Over rising costs of health care making safe and efficacious new treatments available to patients in need.  Divergence in technical requirements from country to country. ORIGIN OF ICH  Harmonization of regulatory requirements was pioneered by the EU Europe in the 1980s as the Europe move towards the development of single market.  The success achieved in Europe demonstrated that harmonization was feasible.

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 At the same time there were discussions between Europe Japan and the US on possibilities for harmonization.  The birth of ICH took place at a meeting in April 1990. ICH MEMBERS  EU  EFPIA European federation of pharmaceutical industries’ associations.  MHLW Ministry of health Labor and welfare Japan.  JPMA Japan Pharmaceuticals manufacturers Association.  US FDA.  PhRMA pharmaceutical research and manufacturers association.  Observers: WHO TPP Canada.  International federation of Pharmaceutical manufacturers association. OBJECTIVES OF ICH  Promote public health by early availability of drug in the market.  Improve efficiency of new drug development Reduce registration cost.  Less expensive drugs for patients.  Prevent the duplication of clinical trials in humans.  Minimize the animal use without compromising in safety efficacy of the product.  Mutual acceptance of clinical data by regulatory authority.  Reducing testing duplication.

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The guidelines of ICH are broadly categorized into four types. QUALITY GUIDELINES  Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice GMP risk management. Safety Guidelines  ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity genotoxicity and reprotoxicity. A recent breakthrough has been a non-clinical testing strategy for assessing the QT interval prolongation liability: the single most important cause of drug withdrawals in recent years. Efficacy Guidelines  The work carried out by ICH under the Efficacy heading is concerned with the design conduct safety and reporting of clinical trials. It also covers novel types of medicines derived from biotechnological processes and the use of pharmacogenetics/genomics techniques to produce better targeted medicines. Multidisciplinary Guidelines  Those are the cross-cutting topics which do not fit uniquely into one of the Quality Safety and Efficacy categories. It includes the ICH medical terminology MedDRA the Common Technical Document CTD and the development of Electronic Standards for the Transfer of Regulatory Information ESTRI.

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QUALITY GUIDELINES  Q1A - Q1F: Stability  Q2: Analytical Validation  Q3A - Q3D: Impurities  Q4 - Q4B: Pharmacopoeias  Q5A - Q5E: Quality of Biotechnological Products  Q6A- Q6B: Specifications  Q7: Good Manufacturing Practice  Q8: Pharmaceutical Development  Q9: Quality Risk Management  Q10: Pharmaceutical Quality System  Q11: Development and Manufacture of Drug Substances  Q12: Lifecycle Management DRAFT FORM  Q13: Continuous Manufacturing of Drug Substances and Drug Products CONCEPT PAPER  Q14: Analytical Procedure Development CONCEPT PAPER SAFETY GUIDELINES  S1A - S1C: Carcinogenicity Studies  S2: Genotoxicity Studies  S3A - S3B: Toxicokinetic and Pharmacokinetics  S4: Toxicity Testing  S5: Reproductive Toxicology  S6: Biotechnological Products  S7A - S7B: Pharmacology Studies  S8: Immunotoxicology Studies

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 S9: Nonclinical Evaluation for Anticancer Pharmaceuticals  S10: Photo safety Evaluation  S11: Nonclinical Pediatric Safety EFFICACY GUIDELINES  E1: Clinical Safety for Drugs used in Long-Term Treatment  E2A - E2F: Pharmacovigilance  E3: Clinical Study Reports  E4: Dose-Response Studies  E5: Ethnic Factors  E6: Good Clinical Practice  E7: Clinical Trials in Geriatric Population  E8: General Considerations for Clinical Trials  E9: Statistical Principles for Clinical Trials  E10: Choice of Control Group in Clinical Trials  E11 - E11A: Clinical Trials in Pediatric Population  E12: Clinical Evaluation by Therapeutic Category  E14: Clinical Evaluation of QT  E15: Definitions in Pharmacogenetics / Pharmacogenomics  E16: Qualification of genomic biomarkers  E17: Multi-Regional Clinical Trials  E18: Genomic Sampling

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MULTIDISCIPLINARY GUIDELINES  M1: MedDRA Terminology  M2: Electronic Standards  M3: Nonclinical Safety Studies  M4: Common Technical Document.  M5: Data Elements and Standards for Drug Dictionaries  M6: Gene Therapy  M7: Mutagenic impurities  M8: Electronic Common Technical Document eCTD  M9: Biopharmaceutics Classification System-based Biowaivers  M10: Bioanalytical Method Validation The Impact of ICH Quality on industry: 1. The ICH guidelines in the quality area have provided recommendations in two of the key areas that define bulk drug and drug product quality- stability data and impurities- and led to significant reduction in duplicate testing. 2. Prior to there was no harmonized approach to the data requirements in these areas. With stability for example it was typical to run studies at “room temperature” as defined by the company concerned and appropriate to the locality. 3. There was also no humidity control. This resulted in registrations in different regions requiring new stability data if the climatic zone was different to that where the original study had been conducted.

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4. ICH harmonization provided standard sets of conditions taking account of the climatic zones in each of the three regions. 5. This means that the information on stability generated in any one of the three regions is mutually acceptable in the other two areas provided it meets the requirements of the guideline. This removed the duplicate testing. 6. The impurities guidelines Impurities in New Drug Substances Q3A Impurities in New Drug Products Q3B and Impurities: Guideline for Residual Solvents Q3C also served as with the stability guidelines to provide scientific agreement on the recording and reporting of impurity levels. 7. Guidelines were also provided on how changes in impurity profile over the course of a development program should be managed. The result of this is that it should be possible to determine a single specification for any drug substance or product that is acceptable across the three ICH regions. This makes the supply chain far simpler and minimizes supply error. 8. The ICH has also produced a parallel set of guidelines covering the specification issues associated with biotechnological products. Standardization through the guidelines has been a very positive step for the biotechnology industry and has certainly had a significant favorable impact on both development times and resource utilization. 9. Duplication of research was reduced related to the stability testing impurity profiles. ICH STABILITY GUIDELINES

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Definitions and storage conditions for four climatic zones:- Storage conditions for general case:- Type of study Storage Condition Minimum time period covered by data at submission Long term 30ºC ± 2ºC and 65RH ± 5RH 12 Months Accelerated 40ºC ± 2ºC and 75RH ± 5RH 6 Months Climatic Zone Definition Storage Condition Examples I Temperate climate 21ºC ± 2ºC and 45RH ± 5RH Northern Europe Canada. II Mediterranean and subtropical climate 25ºC ± 2ºC and 60RH ± 5RH Southern Europe US Japan. III Hot dry climate 30ºC ± 2ºC and 35RH ± 5RH Egypt Sudan. IV Hot and humid climate 30ºC ± 2ºC and 75RH ± 5RH Central Africa south Pacific.

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Common technical document Introduction: Common technical document CTD is a format that was created by the ICH in an attempt to harmonize the format of a drug approval’s applications in all 3 ICH regions i.e. the USA Europe and japan. The CTD was agreed upon in November 2000 in san Diego California the USA. CTD is a common format/ template to provide the information to the drug regulatory authorities in the 3 ICH regions. It is not a “single” dossier with a “single” content since legal requirements and applicant preferences differ in the 3 different ICH regions. The CTD as defined by the ich m4 expert working groupEWGdoes not cover the full submission that is to be made in a region.it describes only module 2 to 5 which are common across all regions. The CTD does not describe the content of module 1 the regional administrative information and prescribing information nor does it describe documents that can be submitted as amendments or variations to the initial application. The CTD is a set of specifications for the submission of regulatory data in the application for obtaining market approval for pharmaceuticals. the format of the CTD is not to be confused with its content or submission type rather it is the means by which information in a submission is organized. Specifications for the organization of content of CTD For modules 2-5 the ICH specifies the organization and content for CTD. For module 1 the ICH specifies the regional sections the specific regulatory authority i.e. FDA Singapore health Canada and india specifies the organization and content for CTD therefore regional section content may vary between different ICH regions. Objectives of ICH behind CTD

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1. To present a well-structured common format for the preparation for approvals applications which will be submitted to regulatory authorities. 2. To significantly reduce the time and resources needed to compile applications for registration of human pharmaceuticals and ease the preparation of electronic submissions. 3. To facilitate the regulatory reviews and communication with the applicant by using a standard document of common elements. 4. To prevent unnecessary duplication of work. Benefits of the CTD 1.Complete well organized submissions 2. More predictable format 3.More consistent reviews 4.Easier analysis across applications 5.Eaiser exchange of information 6.Facilitates electronic submissions

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ORGANIZATION OF THE COMMON TECHNICAL DOCUMENT The common technical document is organized in to five modules OBJECTIVES OF CTD GUIDELINE This guideline is intended to provide recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline Q1AR stability testing of new drug substances and products. MODULE 1 A regional specific module containing administrative information and is unique to each regulatory authority. MODULE 2 Contains overviews written summaries and tabulated summaries of the data contained in modules34 and 5 MODULE 3 Contains quality data relating to the drug substances and drug product MODULE 4 Contains non clinical data MODULE 5 Contains clinical date

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Stability protocol and report 1.Batches tested 2.General information 3.Container/closure system 4.Literature and supporting data 5.Stability-indicating analytical method 6.Testing plan 7.Test parameters 8.Test results 9.Other requirements Post -approval commitments 10.Conclusion

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