INTERNATIONAL COUNCIL FOR HARMONIZATION

Objective of ICH
Participants of ICH
ICH Structure
ICH Working Groups
Steps of ICH Harmonization

1. I NTERNATIONAL C OUNCIL FOR H ARMONIZATION Mr. Vinayak R. Bodhankar M. Pharm. (Ph.D.*)

2. At the 1990 International Council for Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, a committee of representatives from industry and regulatory agencies was established. International Council for Harmonization Unique harmonization project involving the regulators and research-based industries of US, EU and Japan - started in 1990. Harmonization: Process of creating uniform standards.

3. Objective of ICH To develop international standards for Quality, Safety, Efficacy . To increase cost efficiency, and to minimize delays in product development. More efficient use of resources (human, animal, material) in the R&D process. Quicker access of safe and effective new medicines to patients. Mutual acceptance of clinical data by regulatory authority. Promote public health by early availability of drug in the market.

4. Participants of ICH The Six parties to ICH represent the regulatory bodies and research based industry in the 3 regions – Europe, japan, and USA, where the vast majority of new medicines are currently developed. The Six ICH participants are as follows: European Commission – European Union European Federation of Pharmaceutical Industries and Associations Ministry of Health, Labor, and Welfare, Japan Japan Pharmaceutical Manufacturers Association USFDA Pharmaceutical Research & Manufacturers of America

5. ICH Structure Steering Committee Quality Safety Efficacy Secretariat Decision-making body Working Groups ( D evelopment + Implementation) Steering Committee & Working Groups meet twice a year

6. STEERING COMMITTEE : It is the body that governs the ICH, determines the policies, select topics for harmonization and monitor the progress of harmonization. SECRETARIAT : The Secretariat staff is responsible for day-to-day management of ICH, namely preparations for, and documentation of, meetings of the Steering Committee and its Working Groups.

7. ICH Working Groups Depending on the type of harmonization activity needed, the Steering Committee will endorse the establishment of three types of working groups: Expert Working group (EWG): Develop a harmonized guideline that meets the objective. Implementation Working group: Develops questions and answers to facilitate implementation of existing guidelines. Informal Working group: Develop or finalize a business plan.

8. Steps of ICH Harmonization STEP 5--Implementing Guidelines in ICH Regions STEP 4--Adopting Harmonized Guidelines STEP 3--Consulting with Regional Regulatory Agencies : Comment Period STEP 2--Agreeing on Draft Text STEP 1--Building Scientific Consensus

9. Step 1 – Consensus Building The EWG works to prepare a consensus (general agreement) draft of the technical document via e-mail, web conferences, etc. If approved by the ICH Management Committee, the EWG will organize meetings to discuss on the draft. This draft is signed by the EWG, upon reaching into an agreement and the forwarded to the Steering Committee.

10. Step 2 – Confirmation of Consensus on the Technical document & Adoption of Draft guideline by Regulatory Members The Steering Committee checks the technical document and agrees based on the report of the EWG. On the basis of the technical document, the ICH Regulatory Members will take the actions that are necessary to prepare a draft guideline. After preparation, the regulatory members will declare the draft guideline approved.

11. Step 3 – Regulatory Consultation Step 3 occurs in three distinct stages: 1. Regional regulatory consultation: the regulatory authorities and industry associations in other regions can also comment on the draft guideline to the ICH Secretariat. 2. Discussion of the regional committee comments: the EWG works to address the comments received and prepares the Experts Draft Guideline. 3. Finalization of the Experts Draft Guideline: Experts Draft Guideline is signed by the ICH Regulatory Members and then forwarded to SC to request adoption of the ICH process.

12. Step 4 – Adoption of an ICH Harmonised Guideline The Steering Committee agrees to the Expert Draft Guideline if there is sufficient agreement on the guideline, and then declared as the ICH Harmonized Guideline. Step 5 – Implementation of the ICH Harmonised Guideline The Harmonized Guidelines moves immediately to the final step of the process that is the regulatory implementation. The step is carried out according to the national or regional procedures in the ICH regions.

13. This group’s work resulted in guidelines in four major categories: { EXPERT WORKING GROUPS} Chemical and pharmaceutical Q uality assurance, Safety in pre-clinical studies. Efficacy of clinical studies, and Multidisciplinary topics such as medical terminology and electronic standards for transmission of regulatory documents. The guidelines for each of these categories are identified by the letters Q for quality , S for safety , E for efficacy , and M for multidisciplinary

14. Harmonization achievements in the Quality area include conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) and risk management. QUALITY

15. ICH has produced a comprehensive set of safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity and reproductive toxicity. SAFETY

16. It 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. EFFICACY

17. 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 ). MULTIDISCIPLINARY

18. Mr. P. B. Jadhav

19. Mr. P. B. Jadhav

20. Quality Q1 Stability: Subdivide into 6 – Q1A – Q1F Q1A: Stability testing of new drug substances and products Provides evidence on how the quality of drug substance varies with time under the influence of environmental factors. Q1B: Photo stability testing of new drug substance or product Evaluates the light sensitivity and stability of the drug substance or product. Q1C: Stability testing of new dosage forms Provides evidence of stability of new formulations of approved medicines.

21. Quality Q1D: Bracketing and Matrixing designs for stability testing of new drug substances or products Bracketing: it is the design of a stability schedule such that samples are tested at all times on the extreme of factors. The design assumes that the stability of any intermediate level is represented by the stability of the extremes tested. Matrixing : It is the design of a stability schedule such that a selected subset of the total number of samples are tested at a specific time point for all the factors combinations.

22. Quality Q1E - Evaluation of Stability Data:- The guideline addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities. Establishes shelf lives for drug substances or products intended for storage at or below room temperature Q1F – Stability data package for registration applications in climatic zones III and IV: Describes harmonized global stability testing requirements in order to facilitate access to medicines by reducing the number of different storage conditions.

23. Quality Q2 - Analytical Validation The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. It gives the validation parameters needed for a variety of analytical methods and the characteristics that must be considered during the validation. Types of analytical procedures to be validated:- Limit tests Identification tests Characteristics include: accuracy, precision, detection limit, quantitation limit, etc.

24. Quality Q3 - Impurities Q3 guidelines are subdivided into 3 :- Q3A - Q3C Q3A – Impurities in a New Drug Substances Q3B - Impurities in a New Drug Products The guideline addresses the chemistry and safety aspects of impurities. Impurities are of 3 types:- organic, inorganic, and residual impurities. Chemistry aspects include classification and identification of impurities, listing of impurities, generating reports etc. Safety aspects include specific guidance for qualifying those impurities that were not present or were at lower levels in batches of drug substance or product used in safety or clinical trials Q3C: Impurities in Residual Solvents - prescribes the limits of certain solvents

25. Quality  Q4 - Pharmacopoeias Q4 describes a process for the evaluation and recommendation given by EWG for selecting pharmacopoeial texts to facilitate their recognition by regulatory authorities for use in different ICH regions. It involves mainly the tests for :- • Microbiological examination of non-sterile products • Test for particulate examination • Disintegration and dissolution test • Uniformity tests, sterility tests • Tablet friability, bulk density, tapped density of powders etc.,

26. Quality  Q5- Quality of Biotechnological Products Q5A - Q5E Q5A is concerned with testing and evaluation of viral safety of biotechnology products derived from cell lines of human or animal origin. Provides a general framework for virus testing experiments. Q5B is concerned with the analysis of expression construct in cells used for production of rDNA derived products. Q5C is concerned with the stability testing of biotechnological products. Q5D is concerned with derivation and characterization of cell substrates. Q5E is subjected with the comparability of biological to changes in their manufacturing process.

27. Quality Q6- Specifications Q6 are related to the specifications for a new drug substances and products. Main objective of this guideline is to establish a set of specifications for the drug substance or product. Description, identification, assay, and impurities are the universal tests considered applicable for the drug. Specific tests for Drug Substance include, particle size, water content, microbial limits, physicochemical properties, etc. Specific tests for Drug Products include, dissolution, disintegration, hardness, friability uniformity tests etc.

28. Quality Q7- Good Manufacturing Practices This document is intended to provide guidance regarding GMP for the manufacturing of API under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the requirements for quality and purity. Q7 mainly involves the following:- Active Pharmaceutical Ingredient Organization & Personnel Buildings & Facilities Process Equipment's Documentation & Records

29. Quality Q8- Pharmaceutical Development Q8 is intended to provide guidance on the contents of pharmaceutical development of drug products. The aim of Q8 is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. Q8 also describes the type of dosage form and the formulation that are suitable for the intended use. Q8 gives information about drug substance, drug product, excipients, and container - closure system.

30. Quality Q9 – Quality Risk Management Q9 offers a systematic approach to quality risk management. This guideline provides principles and tools for quality risk management that can be applied to all aspects of pharmaceutical quality including :- Development Manufacturing and distribution Inspection and submission or review processes of use of raw materials, solvents, excipients, packaging and labelling materials used in drug substances an drug products.

31. Quality  Q10 - Pharmaceutical Quality System Q10 establishes a new ICH guideline describing a model for an effective quality management system for the pharmaceutical industry. Comprehensive model for an effective pharmaceutical quality system is based on International Standards Organization (ISO) quality concepts which also includes the GMP regulations.

32. ICH Stability Testing Guideline Stability is defined as the capability of a particular formulation in a specific container/closure system to remain within its physical, chemical, microbiological, etc. specifications. Stability testing is a complex set of procedures involving considerable cost, time consumption, and scientific expertise in order to build in quality, safety and efficacy in a drug formulation. The choice of test conditions is based on analysis of the effect of climatic conditions in 3 regions. The world is divided into 4 climatic zones.

33. ICH Climatic Zones

34. ICH Climatic Zones Climatic Zone Climate definition Major countries / Region Long term testing conditions I Temperature UK, US, North Europe, Russia 21 C / 45% RH II Subtropical & Mediterranean Japan, South Europe 25 C / 60% RH III Hot and Dry India, Iraq 30 C / 35% RH IVa Hot and Humid Iran, Egypt 30 C / 65% RH IVb Hot & Very Humid Brazil, Singapore 30 C / 75% RH