ICH [ Q ] Guidelines

OBJECTIVES
AIM
ICH ORGANISATION STRUCTURE
ICH MEMBERS
ICH VARIOUS GUIDELINES
ICH GUIDELINES CATEGORIES
[Q] QUALITY GUIDELINES

1. PRESENTED BY – PATIL ABHISHEK SHARAD DEPARTMENT OF PHARMACEUTICS RAJARAMBAPU COLLEGE OF PHARMACY, KASEGAON , SANGLI ICH [ Q ] Guidelines

2. 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.

3. 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. Each regulatory co-sponsor implements the guidelines according to its National or Regional requirements. They are intended to be used in combination with any regional requirements.

4. OBJECTIVES Promote public health by early availability of drug in the market. Maintaining safeguards on quality, safety and efficacy. Improve efficiency of new drug development ,Reduce registration cost. Less expensive drugs for patients. Prevent the duplication of clinical trails in humans. Minimize the animal use with out compromising in safety ,efficacy of the product. Mutual acceptance of clinical data by regulatory authority. Reducing testing duplication .

5. AIM 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. More economical use of human, animal, and material resources. Elimination of unnecessary delay in the global development & availability of new medicines. Maintaining safeguards on Quality, safety, efficacy and regulatory obligations to protect public health.

6. ICH ORGANISATION STRUCTURE ICH structure consists : ICH Steering Committee. ICH Coordinators. ICH Secretariat. ICH Working Groups. The ICH Global Cooperation Group (GCG) and the ICH MedDRA Management Board are subcommittees of the ICH Steering Committee.

7. ICH MEMBERS European Commission - European Union (EU). European Federation of Pharmaceutical Industries and Associations (EFPIA). Ministry of Health, Labour and Welfare, Japan (MHLW). Japan Pharmaceutical Manufacturers Association (JPMA). US Food and Drug Administration (FDA). Pharmaceutical Research and Manufacturers of America ( PhRMA ).

8. ICH VARIOUS GUIDELINES ICH has developed over 50 harmonised Guidelines aimed at eliminating duplication in the development and registration process, so that a single set of studies can be generated to demonstrate the quality, safety and efficacy of a new medicinal product. Quality-14 Guidelines. Safety -14 Guidelines. Efficacy -20 Guidelines. Multidisciplinary -5 Guidelines. Electronic Standards for the Transfer of Regulatory Information (ESTRI, E2B). Common Technical Document (CTD & eCTD ). Medical dictionary for adverse event reporting and coding of clinical trial data ( MedDRA ).

9. ICH GUIDELINES CATEGORIES Q (QUALITY) (Q1-Q11) S (SAFETY) (S1-S10,M3) E (EFFICACY) (E1-E16, Except E13) M ( Multidisciplinary) (M1-M8) i.e., those relating to chemical and pharmaceutical Quality Assurance (Stability Testing, Impurity Testing, etc.) i.e., those relating to in vitro and in vivo pre-clinical studies (Carcinogenicity Testing, GenotoxicityTesting , etc.) i.e., those relating to clinical studies in human subject (Dose Response Studies, Good Clinical Practices, etc.) i.e.,crosscutting Topics which do not fit uniquely into one of the above categories ( MedDRA , ESTRI, M3, CTD, M5).

10. [Q] 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 Q13 : Continuous Manufacturing of Drug Substances and Drug Products Q14 : Analytical Procedure Development

11. Q1(STABILITY) Q1A-STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS, The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. GENERAL CASE

12. Q1B--PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS A systematic approach to photostability testing is recommended covering, as appropriate, studies such as: i ) Tests on the drug substance. ii) Tests on the exposed drug product outside of the immediate pack. iii) Tests on the drug product in the immediate pack and if necessary. iv) Tests on the drug product in the marketing pack.

13. PROCEDURE - Samples should be exposed to light providing an overall illumination of not less than 1.2 million lum . hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product And after exposure to light the absorbance of sample is taken in UV visible spectrophotometry to know the actual content of drug after degradation by light and after that decision is made, either the product is photosensitive or not.

14. Q1C- Stability Testing for New Drugs and Products NEW DOSAGE FORMS A new dosage form is defined as a drug product which is a different pharmaceutical product type, but contains the same active substance as included in the existing drug product approved by the pertinent regulatory authority. Such pharmaceutical product types include products of different administration route (e.g., oral to parenteral ), new specific functionality/delivery systems (e.g., immediate release tablet to modified release tablet) and different dosage forms of the same administration route (e.g., capsule to tablet, solution to suspension). Stability protocols for new dosage forms should follow the guidance in the parent stability guideline in principle. However, a reduced stability database at submission time (e.g., 6 months accelerated and 6 months long term data from ongoing studies) may be acceptable in certain justified cases.

15. Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products. Q1E: Evaluation of Stability Data This guideline addresses the evaluation of stability data that should be submitted in registration applications for new molecular entities and associated drug products. The guideline provides recommendations on establishing shelf lives for drug substances and drug 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. WHO conducted a survey amongst their member states to find consensus on 30°C/65% RH as the long term storage conditions for hot-dry and hot-humid regions.

16. Q2(R1): VALIDATION OF ANALYTICAL PROCEDURES; TEXT AND METHODOLOGY Types of Analytical Procedures to be Validated : - Identification tests - Quantitative tests for impurities' content - Limit tests for the control of impurities - Quantitative tests of the active moiety in samples of drug substance or drug product or other selected component(s) in the drug product. Typical validation characteristics are; o Accuracy o Precision o Repeatability o Intermediate Precision o Specificity Detection Limit o Quantitation Limit o Linearity o Range Furthermore revalidation may be necessaryin the following circumstances: - -changes in the synthesis of the drug substance - changes in the composition of the finished product changes in the analytical procedure. The degree of revalidation required depends on the nature of the changes. Certain other changes may requirevalidation as well.

17. Q3A- IMPURITIES IN NEW DRUG SUBSTANCES This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical synthesis and not previously registered in a region or member state. The following types of drug substances are not covered in this guideline: Biological/biotechnological, peptide, oligonucleotide , radiopharmaceutical, fermentation product and semi-synthetic products derived therefrom , herbal products, and crude products of animal or plant origin. Impurities can be classified into the following categories: Organic impurities (process- and drug-related) Inorganic impurities Residual solvents

18. Q3B- IMPURITIES IN NEW DRUG PRODUCTS This document provides guidance for registration applications on the content and qualification of impurities in new drug products produced from chemically synthesised new drug substances not previously registered in a region or member state. This guideline addresses only those impurities in new drug products classified as degradation products of the drug substance or reaction products of the drug substance with an excipient and/or immediate container closure system.

19. Q3C- IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. The guideline recommends use of less toxic solvents and describes levels considered to be toxicologically acceptable for some residual solvents. Classification of Residual Solvents by Risk Assessment Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards.for ex. Class 2 solvents: Solvents to be limited Non- genotoxic animal carcinogens or possible causative agents of other irreversible toxicity such as neurotoxicity or teratogenicity . Solvents suspected of other significant but reversible toxicities. Class 3 solvents: Solvents with low toxic potential Solvents with low toxic potential to man; no health-based exposure limit is needed. Class 3 solvents have PDEs of 50 mg or more per day.

20. TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided). Solvent Concentration limit ( ppm ) Concern Benzene 2 Carcinogen Carbon tetrachloride 4 Toxic and environmental hazard 1,2- Dichloroethane 5 Toxic 1,1- Dichloroethene 8 Toxic 1,1,1- Trichloroethane 1500 Environmental hazard

21. Q3D- GUIDELINE FOR ELEMENTAL IMPURITIES Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline: The evaluation of the toxicity data for potential elemental impurities; The establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern Application of a risk-based approach to control elemental impurities in drug products for ex. Cd,Pb,As,Hg,V,Pd,etc .

22. Q4B-EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON RESIDUE ON IGNITION/SULPHATED ASH GENERAL CHAPTER It is further divided into following 14 annex • Q4B Annex 1: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Residue on Ignition/ Sulphated Ash. • Annex 2:Test for Extractable Volume of Parenteral Preparations • Annex 3: Test for Particulate Contamination: Sub-Visible Particles • Annex 4A: Microbiological Examination of Non-Sterile Products: Microbial Enumeration Tests • Annex 4B: Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-organisms • Annex 4C: Microbiological Examination of Non-Sterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use • Annex 5:Disintegration Test • Annex 6: Uniformity of Dosage Units • Annex 7: Dissolution Test • Annex 8: Sterility Test • Annex 9: Tablet Friability • Annex 10: Polyacrylamide Gel Electrophoresis • Annex 11: Capillary Electrophoresis • Annex 12: Analytical Sieving • Annex 13: Bulk Density and Tapped Density of Powders • Annex14 :Bacterial Endotoxins Test

23. Q5A-Q5E---Quality of Biotechnological Products: Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin: This document is concerned with testing and evaluation of the viral safety of biotechnology products derived from cell lines of human or animal origin (i.e. mammalian, avian, insect) The objective is to provide a general framework for virus testing experiments for the evaluation of virus clearance and the design of viral tests and clearance evaluation studies. Three principal, complementary approaches have evolved to control the potential viral contamination of Biotechnology products a) selecting and testing cell lines and other raw materials, including media components, for the absence of undesirable viruses which may be infectious and/or pathogenic for humans. b) Testing the capacity of the processes to clear infectious viruses. c) testing the product at appropriate steps for absence of contminating infectious viruses.

24. Q6 : Specifications for New Drug Substances and Products Bulk drug substance and final product specifications are key parts of the core documentation for world-wide product license applications. This leads to conflicting standards for the same product, increased expenses and opportunities for error as well as a potential cause for interruption of product supply. Q6A: Specifications : Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products : Chemical Substances The main objective of this guideline is to establish a single set of global specifications for new drug substances and new drug products. This guideline addresses specifications, i.e., those tests, procedures, and acceptance criteria which play a major role in assuring the quality of the new drug substance and new drug product during shelf life.

25. Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients The main objective of this guideline is that to maintain the quality of the active pharmaceutical ingredients: Personnel Buildings and Facilities Process equipment Documentation and Records

26. Q8(R2): Pharmaceutical Development This guideline is intended to provide guidance on the contents of Pharmaceutical Development of drug products. The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The Pharmaceutical Development section also describe the type of dosage form and the formulation that are suitable for the intended use. Q8 gives information about Drug Substance, Excipients , Container Closure System.

27. Q9: Quality Risk Management The purpose of this document is to offer 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, 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.

28. Q10: Pharmaceutical Quality System This document establishes a new ICH tripartite guideline describing a model for an effective quality management system for the pharmaceutical industry, referred to as the Pharmaceutical Quality System. Comprehensive model for an effective pharmaceutical quality system is based on International Standards Organization (ISO) quality concepts, includes applicable Good Manufacturing Practice (GMP) regulations

29. Q11: Development and Manufacture of Drug Substances: This new guidance is proposed for Active Pharmaceutical Ingredients (APIs) harmonising the scientific and technical principles relating to the description and justification of the development and manufacturing process (CTD sections S 2.2. - S 2.6) of Drug Substances including both chemical entities and biotechnological/biological entities. Q12: Lifecycle Management : This new guideline is proposed to provide guidance on a framework to facilitate the management of post-approval Chemistry, Manufacturing and Controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. Adoption of this new ICH Guideline will promote innovation and continual improvement, and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments.

30. Q13: Continous manufacturing of drug substances and drug Products : This topic was endorsed by the Assembly in June 2018. This new Guideline is proposed to: • Capture key technical and regulatory considerations that promote harmonisation , including certain Current Good Manufacturing Practices (CGMP) elements specific to Continuous Manufacturing (CM). • Allow drug manufacturers to employ flexible approaches to develop, implement, or integrate CM for the manufacture – drug substances and drug products – of small molecules and therapeutic proteins for new and existing products, • Provide guidance to industry and regulatory agencies regarding regulatory expectations on the development, implementation, and assessment of CM technologies used in the manufacture of drug substances and drug products.

31. Q 14 Analytical procedure development : The new guideline is proposed to harmonise the scientific approaches of Analytical Procedure Development, and to provide the principles relating to the description of Analytical Procedure Development process. This new guideline is intended to improve regulatory communication between industry and regulators and facilitate more efficient, sound scientific and risk-based approval as well as post-approval change management of analytical procedures.

32. REFERENCES ICH guidlines of quality and safety http://www.ich.org/products/guidelines/quality/article/qualityguidelines. html http://www.ich.org/products/guidelines/safety/article/safetyguidelines. Html ICH GUIDELINES PRESENTATIONS BY FOLLOWING : 1. PRSENTED BY : MANISH SHANKARPURE M.PHARM ( QUALITY ASSURANCES AND TECHNIQUES ) 2. BASHANT KUMAR SAH Mpharm 1st pharmaceutics Nargund college of pharmacy 3. JAYA PRAKASH V REGULATORY AFFAIRS REG NO: 218311