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International Conference on Harmonization (ICH):

International Conference on Harmonization (ICH)



ICH Guidelines:

ICH Guidelines ICH is neither a forum of global politics nor a trade negotiation, but a scientific forum ICH covers “new drugs” ICH guidelines provide “how to collect data scientifically for marketing authorization”

Philosophy/Purpose of ICH:

Philosophy/Purpose of ICH Eliminate Duplication in Tests to meet Different Regulatory Requirements More Efficient Use of Resources Timely Access of Patients to Safe and Effective “New Drugs”


What Does the Pharmaceutical industry do? chemists biologists molecular geneticists drug metabolists pharmacists clinicians statisticians patents marketing/sales and many more!!



ICH Conferences :

ICH Conferences ICH 1 - Nov1991 - Brussels ICH 2 - Oct 1993 - Orlando ,Florida ICH 3 - Nov 1995 - Yokohama, Japan ICH 4 - July 1997 - Brussels ICH 5 - Nov 2000 - San Diego - US ICH 6 - Nov 2003 - Osaka, Japan ICH 7 - 2007 - Europe ? Cancelled ? ICH Public meetings ………..ICH Steering Committees ---- Regional meet with non-profit organizations

Working Groups:

Working Groups SAFETY EFFICACY QUALITY MULTIDISCIPLINARY STEERING COMMITTEE Endorses topics, guidelines and monitors progress

Qs, Ss Es and Ms:

Qs, Ss Es and Ms Q1………………………… Q11 S1………………………….S8 E1………………………….E14. M1…………………………M6

Quality :Q1 to Q11:

Quality :Q1 to Q11 Q1- Stability Q2- Analytical validation Q3- Impurities Q4 – Pharmacopoeias Q5- Quality of Biotechnological products Q6 – Specifications Q7 – GMP for APIs Q8 – Pharmaceutical development Q9- Quality Risk Management Q10 – ‘ Quality Management ’ agreed ‘ in principle ’ Q 11- DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (CHEMICAL ENTITIES AND BIOTECHNOLOGICAL/BIOLOGICAL ENTITIES )

Q1 :

Q1 Stability Q1A(R2) Stability Testing of New Drug Substances and Products Q1B Stability Testing : Photostability Testing of New Drug Substances and Products Q1C Stability Testing for New Dosage Forms Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products Q1E Evaluation of Stability Data Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV


Q2 Analytical Validation Q2(R1) New title: Validation of Analytical Procedures: Text and Methodology


Q3 Impurities Q3A(R1) Impurities in New Drug Substances Q3B(R2) Impurities in New Drug Products Q3C(R3) Impurities: Guideline for Residual Solvents


Q4 Pharmacopoeias Q4 Pharmacopoeias Q4A Pharmacopoeial Harmonisation Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC)


Q5 Quality of Biotechnological Products Q5A(R1) Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin Q5A Q5B Quality of Biotechnological Products : Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products Q5B Q5C Quality of Biotechnological Products : Stability Testing of Biotechnological/Biological Products Q5C Q5D Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products Q5D Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process


Q6 Specifications Q6A Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (including Decision Trees) Q6B Specifications : Test Procedures and Acceptance Criteria for Biotechnological/Biological Products


Q7 Good Manufacturing Practice Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients


Q8 Pharmaceutical Development Q8 Pharmaceutical Development


Q9 Quality Risk Management Q9 Quality Risk Management

Risk Management across the Product lifecycle for drug ( medicinal) products:

Risk Management across the Product lifecycle for drug ( medicinal) products Research Preclinical Phase Clinical Phases Launch Quality ICH Q9 Safety Efficacy Manufacturing & Distribution GLP GCP GMP GDP End of life cycle


Q10 ‘ Quality management ’ agreed ‘ in principle ’ Waiting for Q9 to progress .


Q11 Q 11- D evelopment and manufacture of drug substances (chemical entities and biotechnological/biological entities )

Regulatory or formal stability testing:

Regulatory or formal stability testing 2006.01.09. Dr. Pogány - Guilin 23 /61 Storage temperature (°C) Relative humidity (%) Minimum time period covered by data at submission (months) Accelerated: 40±2 75±5 6 Intermediate: 30±2 6 5±5 12 Long term: 25±2 60 ±5 12 (6)

Impurities :

Impurities ICH Topic Q 3 B (R2) Impurities in New Drug Products Organic Impurities Inorganic Impurities Residual solvents LISTING OF DEGRADATION PRODUCTS IN SPECIFICATIONS QUALIFICATION OF DEGRADATION PRODUCTS Quantification of the degradants Limits of impurities

Limits of impurities:

Limits of impurities Unspecified : NMT 0.1% NMT 500 mcg /day intake

Efficacy : E1- E14:

Efficacy : E1- E14 Clinical Safety E1 The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life Threatening Conditions E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2B(R3) Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports E2C(R1) Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs E2D Post-Approval Safety Data Management: Definitions and Standards for Expedite Reporting E2E Pharmacovigilance Planning Clinical Study Reports E3 Structure and Content of Clinical Study Reports Dose-Response Studies E4 Dose-Response Information to Support Drug Registration

Efficacy :

Efficacy Ethnic Factors E5 (R1) Ethnic Factors in the Acceptability of Foreign Clinical Data Good Clinical Practice E6(R1) Good Clinical Practice Clinical Trials E7 Studies in Support of Special Populations: Geriatrics E8 General Consideration of Clinical Trials E9 Statistical Principles for Clinical Trials E10 Choice of Control Group and Related Issues in Clinical Trials E11 Clinical Investigation of Medicinal Products in the Pediatric Population Guidelines for Clinical Evaluation by Therapeutic Category E12 Principles for Clinical Evaluation of New Antihypertensive Drugs Clinical Evaluation E14 The Clinical Evaluation of QT/ QTC Interval Prolongation and Pro arrhythmic Potential for Non- Anti arrhythmic Drugs   


Safety: Carcinogenicity studies S1A : Need for Carcinogenicity studies for Pharmaceuticals S1B : Testing for carcinogenicity for pharmaceuticals SC1(R1) : Dose selection for carcinogenicity of Pharmaceuticals & Limit dose Genotoxicity studies S2A Guidance on Specific Aspects ofRegulatory Genotoxicity Tests for Pharmaceuticals S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals Toxicokinetics and Pharmacokinetics S3A Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies


Safety Toxicity Testing Single Dose Toxicity Tests S4 Duration of Chronic Toxicity Testing in Animals (Rodent and Non Rodent Toxicity Testing) Reproductive Toxicology S5(R2) New title: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility Previously: Detection of Toxicity to Reproduction for Medicinal Products Biotechnological Products S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals


Safety Pharmacology Studies S7A Safety Pharmacology Studies for Human Pharmaceuticals S7B The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals Immunotoxicology Studies S8 Immunotoxicity Studies for Human Pharmaceuticals Joint Safety/Efficacy  (Multidisciplinary) Topic M3(R1)  Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals    

Multidisciplinary Guidelines:

Multidisciplinary Guidelines M1: Medical Terminology M2: Electronic Standards for transmission of Regulatory Information ESTRI M3: Timing of Pre-clinical Studies in relation to Clinical Trials M4: The Common Technical Document M5: Data elements & standards for drug dictionaries M6: SOPs for maintenance of ICH terminologies lists action

What is CTD ?:

What is CTD ? Common Technical Document ICH M4 – deals with CTD A harmonized format for a regulatory dossier that is considered acceptable in US, Japan Europe and Canada

What is CTD ?:

What is CTD ? The CTD refers to an application format The CTD is a prescribed organization of the information required to be submitted. Each regulatory authority retains the ability to address its own regional specific requirements for needed documentation.


Not part of CTD Module 1 Module 2 Module 3 Module 4 Module 5 Quality Nonclinical Study Reports Clinical Study Reports Regional Administrative Information Nonclinical Summary Clinical Summary Nonclinical Overview Clinical Overview Quality Overall Summary Organisation of the CTD CTD

Number of copies required:

Number of copies required


Module 1 Module 3 Module 4 Module 5 Quality Nonclinical Study Reports Clinical Study Reports Regional Administrative Information Nonclinical Summary Clinical Summary Nonclinical Overview Clinical Overview Quality Overall Summary 1.1 ToC of Mod 1 or overall ToC, incl. Mod 1 2.3 2.6 2.7 2.4 2.5 CTD ToC (Mod 2,3,4,5) CTD Introduction 4.1 ToC for 3.1 ToC for Mod 3 2.1 2.2 Mod 4 5.1 ToC for Mod 5 15 5 15 5 15 15 15 2 2 2 2 2

What is eCTD ?:

What is eCTD ? Electronic format of the ICH Common Technical Document Moving towards a paperless submission environment


eCTD Electronic Common Technical Document ICH has given specification Electronic submission is easier and has many advantages The philosophy of eCTD is to use open standards. Open standards including proprietary standards which through their widespread use can be considered can be considered as de facto standard are deemed to be appropriate in general eCTD contains 5 modules

5 modules of eCTD:

5 modules of eCTD Module1- Administrative information & Prescribing information – Regional specific information Module 2-Summaries Module 3- Quality Module 4- Non-clinical study reports Module 5- Clinical study reports

Module 1:

Module 1 The CTD does not describe the 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

Module 2 Summaries:

Module 2 Summaries Introduction Overall quality summary Non-clinical overview Clinical overview Non-clinical written and tabulated summaries Clinical summary

Module 3 - Quality:

Module 3 - Quality Quality parameters of Drug substance Quality parameters of Drug product Reference standards Container and closure system Stability studies of Drug substance & Drug product Control of excipient Control of Drug product

Module 4 – Non clinical study reports:

Module 4 – Non clinical study reports Pharmacology Pharmacodynamics Safety pharmacology Drug interactions Pharmacokinetics ADME Toxicology In-vitro and in-vivo evaluations IVIVC Carcinogenicity Short term and long term studies Reproductive and development toxicity Literature references

Module 5 – Clinical data:

Module 5 – Clinical data Listing of all clinical studies Clinical study reports BA BE BA/BE IVIVC Bio-analytical reports PK PD PK/PD Efficacy and safety reports Reports of PMS

Where are we today…:

Where are we today… Working on becoming a standards based organization eCTD is just such a standard Accepting IND, NDA, ANDA, BLA, DMF and related submissions in eCTD format Moving towards a paperless submission environment

Where are we going…:

Where are we going… Secure electronic transmission of eCTD submission Structured Product Labeling Electronic submission in XML format

Electronic Submission Guidances Using eCTD Specifications:

Electronic Submission Guidances Using eCTD Specifications Providing Regulatory Submissions in Electronic Format - Human Pharmaceutical Product Applications and Related Submissions Includes NDA, ANDA, BLA, IND, DMF and associated submissions Preferred Format for Submissions

Electronic Submissions Using eCTD Specifications:

Electronic Submissions Using eCTD Specifications Guidance Published August, 2003 eCTD Specifications FDA eCTD Table of Contents Headings and Hierarchy FDA Module 1 Specification FDA Modules 2 to 5 Specification Study Tagging File Specification Specifications Available On-Line http://www.fda.gov/cder/regulatory/ersr/default.htm Current eNDA/eANDA Guidances remain available as an alternative to the eCTD for NDA and ANDA only

Resources for Industry:

Resources for Industry CTD and eCTD Subject Matter Experts FDA is making EVS processing and review tools available to industry Download free from FDA web site Tools provided on an as-is basis No support from FDA will be provided 3 rd party developers are creating tools to support generation and validation of submission prior to FDA submission Coming Soon

Just don’t ask…:

Just don ’ t ask… No paper unless required for original signatures No Word files or file formats not specified in the guidance No electronic submissions or records sent directly to a reviewer or project manager No electronic desk copies

Traditional Signatures:

Traditional Signatures What are the functions of a pen and ink signature?

Functions of a Traditional Signature:

Functions of a Traditional Signature   ¨       identification; ¨       authentication; ¨       declaration of will; ¨       authorization; ¨       safeguard against undue haste; ¨       non-repudiation of origin and receipt; ¨       notice of contents; ¨       integrity; and ¨       originality. .

Non-cryptographic means of authenticating identity:

Non-cryptographic means of authenticating identity PIN and a Password (shared secret); a smart card; a digitized signature; and Biometrics.

cryptographic electronic signature:

cryptographic electronic signature PKI or Public Key Infrastructure Also known as Digital Signatures Highly Secure .

Advantage of eCTD:

Advantage of eCTD Only module one has to be changed in submitting to various countries Module 2 to 5 remains same Quicker submissions , quicker process and there by quicker approvals


Benefits Our mission is to provide relief and hope for millions of people around the world — And we must do so as quickly as possible because … The patient is waiting!

Conclusion :




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