Ich guidlines q and s

This is the short notes on ICH guidlines Q and S.

1. ICH Guidelines BASHANT KUMAR SAH Mpharm 1 st pharmaceutics Nargund college of pharmacy

2. What does ICH stands for ? The complete name of ICH is the " International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ". ICH is a joint initiative involving both regulators and research-based industry representatives of the European Union, Japan and the USA in scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines.

3. What is the goal of ICH ? The goal of ICH is to promote international harmonization by bringing together representatives from the three ICH regions (EU, Japan and USA) to discuss and establish common guidelines . Another goal of ICH is to make information available on ICH , ICH activities and ICH guidelines to any country or company that requests the information, and to promote a mutual understanding of regional initiatives in order to facilitate harmonization processes related to ICH guidelines regionally and globally, and to strengthen the capacity of drug regulatory authorities and industry to utilize them . The ICH Global Cooperation Group (GCG) was formed in 1999 and is charged with this task.

4. ICH Guidelines 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, Genotoxicity Testing, 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)

5. Quality Q1-Stability Q2-Analytical Validation Q3-Impurities Q4-Pharmacopoeias Q5-Quality of Biotechnological Products Q6-Specifications Q7-Good Manufacturing Practice Q8-Pharmaceutical Development Q9-Quality Risk Management Q10-Pharmaceutical Quality System

6. 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

7. 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

8. procedure samples should be exposed to light providing an overall illumination of not less than 1.2 million lux 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.

9. 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 .

10. 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.17

11. 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; Accuracy Precision Repeatability Intermediate Precision Specificity Detection Limit Quantitation Limit Linearity Range Furthermore revalidation may be necessary in 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 require validation as well.

12. 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

13. 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

14. Maximum Daily Dose 1 Threshold 2,3  1 g 0.1% > 1 g 0.05% Maximum Daily Dose 1 Threshold 2, 3 < 1 mg 1.0% or 5 µg TDI, whichever is lower 1 mg - 10 mg 0.5% or 20 µg TDI, whichever is lower >10 mg - 2 g 0.2% or 2 mg TDI, whichever is lower > 2 g 0.10% Maximum Daily Dose 1 Threshold 2,3 < 10 mg 1.0% or 50 µg TDI, whichever is lower 10 mg - 100 mg 0.5% or 200 µg TDI, whichever is lower >100 mg - 2 g 0.2% or 3 mg TDI, whichever is lower > 2 g 0.15% Notes on Attachment 1 1 The amount of drug substance administered per day 2 Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic. 3 Higher thresholds should be scientifically justified. A ttachment 1: Thresholds for Degradation Products in New Drug Products Reporting Thresholds Identification Thresholds Qualification Thresholds

15. Illustration of Thresholds for Reporting, Identification, and Qualification of Degradation Products in New Drug Products as a Function of Maximum Daily Dose 1 1 Note : Actual threshold values should be taken from the preceding table in this attachment.

16. 'Raw' Result   (%)     Reported Result (%) (Reporting Threshold = 0.1%)   Total Daily Intake (TDI) of the Degradation Product (rounded result in μg) Action Identification Threshold 0.2% exceeded? Qualification Threshold 200 μg TDI exceeded? 0.04 Not reported 20 None None 0.2143 0.2 100 None None 0.349 0.3 1 150 Yes None 1 0.550 0.6 1 300 Yes Yes 1 Example 1: 50 mg Maximum Daily Dose Reporting threshold: 0.1% Identification threshold: 0.2% Qualification threshold: 200 μg

17. 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.

18. 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 TABLE 1. Class 1 solvents in pharmaceutical products (solvents that should be avoided).

19. Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1 410 Chlorobenzene 3.6 360 Chloroform 0.6 60   Cumene 0.7 70 Cyclohexane 38.8 3880 1,2-Dichloroethene 18.7 1870 Dichloromethane 6.0 600 1,2-Dimethoxyethane 1.0 100 N,N- Dimethylacetamide 10.9 1090 N,N- Dimethylformamide 8.8 880 1,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 Ethyleneglycol 6.2 620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-Methoxyethanol 0.5 50 Methylbutyl ketone 0.5 50 Methylcyclohexane 11.8 1180 N- Methylpyrrolidone 5.3 530 Nitromethane 0.5 50 Pyridine 2.0 200 Sulfolane 1.6 160 TABLE 2. Class 2 solvents in pharmaceutical products. PDE-permitted daily exposure PPM-parts per million (1mg/litre)

20. TABLE 3. Class 3 solvents which should be limited by GMP or other quality-based requirements. Acetic acid Heptane Acetone Isobutyl acetate Anisole Isopropyl acetate 1-Butanol Methyl acetate 2-Butanol 3-Methyl-1-butanol Butyl acetate Methylethyl ketone tert-Butylmethyl ether Methylisobutyl ketone Dimethyl sulfoxide 2-Methyl-1-propanol Ethanol Pentane Ethyl acetate 1-Pentanol Ethyl ether 1-Propanol Ethyl formate 2-Propanol Formic acid Propyl acetate

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 ; T he 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. Safety S1-Carcinogenicity Studies S2-Genotoxicity Studies S3-Toxicokinetics and Pharmacokinetics S4-Toxicity Testing S5-Reproductive Toxicology S6-Biotechnological Products S7-Pharmacology Studies S8-Immunotoxicology Studies S9-Nonclinical evaluation for anticancer pharmaceuticals S10-Photosafety Evaluation

30. S1-Carcinogenicity Studies S1A: Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use is continuous for at least 6 months . This document provides a consistent definition of the circumstances under which it is necessary to undertake carcinogenicity studies on new drugs. These recommendations take into account the known risk factors as well as the intended indications and duration of exposure . The objectives of carcinogenicity studies are to identify a tumorigenic potential in animals and to assess the relevant risk in humans.

31. S1B: Testing for Carcinogenicity of Pharmaceuticals This document provides guidance on the need to carry out carcinogenicity studies in both mice and rats, and guidance is also given on alternative testing procedures which may be applied without jeopardizing safety . 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 harmonize current practices and improve the design of studies.

32. S2– Genotoxicity S2(R1): Guidance on Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use This guidance is a combination of ICH S2A and S2B guidelines S2A: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals This document provided specific guidance and recommendations for in vitro and in vivo tests and on the evaluation of test results. It includes terms related to genotoxicity tests to improve consistency in applications .

33. S2B: Genotoxicity : A Standard Battery for Genotoxicity Testing for Pharmaceuticals : This document addresses two fundamental areas of genotoxicity testing: the identification of a standard set of assays to be conducted for registration, and the extent of confirmatory experimentation in any particular genotoxicity assay in the standard battery The purpose of this guideline is to optimize the standard genetic toxicology battery for prediction of potential human risks, and for interpretation of results, with the ultimate goal of improving risk characterization for carcinogenic effects that have their basis in changes in the genetic material.

34. S3A –S3B--- Toxicokinetics and Pharmacokinetics: S3A: Note for Guidance on Toxicokinetics : The Assessment of Systemic Exposure in Toxicity Studies ICH guidelines do not require toxicokinetic studies to be conducted , except in pregnant, lactating animals, before initiating reproductive studies. In this context, toxicokinetics is defined as the generation of pharmacokinetic data, either as an integral component in the conduct of non-clinical toxicity studies or in specially designed supportive studies, in order to assess systemic exposure. This document gives guidance on developing test strategies in toxicokinetics and the need to integrate these pharmacokinetics into toxicity testing, in order to aid in the interpretation of the toxicology findings and and their relevance to clinical safety issues

35. S3B: Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies Tissue distribution studies are essential in providing information on distribution and accumulation of the compound and/or metabolites, especially in relation to potential sites of action; this information may be useful for designing toxicology and pharmacology studies and for interpreting the results of these experiments. This document gives guidance, when the repeated dose tissue distribution studies should be considered (i.e., when appropriate data cannot be derived from other sources). It also gives recommendations on the conduct of such studies

36. S4: Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing ) The objective of this guidance is to set out the considerations that apply to chronic toxicity testing in rodents and non rodents as part of the safety evaluation of a medicinal product Rodents(a study of 6 months duration) Non-rodents(a study of nine months duration).

37. S5: Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility This document provides guidance on tests for reproductive toxicity. It defines the periods of treatment to be used in animals to better reflect human exposure to medical products and allow more specific identification of stages at risk. It should encourage the full assessment on the safety of chemicals on the development of the offspring .

38. S6: Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals This document covers the pre-clinical safety testing requirements for biotechnological products. It addresses the use of animal models of disease, determination of when genotoxicity assays and carcinogenicity studies should be performed, and the impact of antibody formation on duration of toxicology studies. The primary goals of preclinical safety evaluation are: 1 ) to identify an initial safe dose and subsequent dose in humans; 2 ) to identify potential target organs for toxicity and for the study of whether such toxicity is reversible; 3 ) to identify safety parameters for clinical monitoring

39. S7A: Safety Pharmacology Studies for Human Pharmaceuticals This guideline was developed to protect clinical trial participants and patients receiving marketed products from potential adverse effects of pharmaceuticals This document addresses the definition, objectives and scope of safety pharmacology studies. It also addresses which studies are needed before initiation of Phase 1 clinical studies as well as information needed for marketing.

40. S7B : The Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) By Human Pharmaceuticals This guideline describes a non-clinical testing strategy for assessing the potential of a test substance to delay ventricular repolarization. This guideline includes information concerning nonclinical assays and integrated risk assessments.

41. S8 : Immunotoxicity Studies for Human Pharmaceuticals This guideline addresses the recommendations on nonclinical testing for immunosuppressant. The guideline might also apply to drugs in which clinical signs of immunosuppressant are observed during clinical trials and following approval to market. The term immunotoxicity in this guideline will primarily refer to immunosuppressant, i.e. a state of increased susceptibility to infections or the development of tumors.

42. S9: Nonclinical Evaluation for Anticancer Pharmaceuticals This guideline provides information for pharmaceuticals that are only intended to treat cancer in patients with late stage or advanced regardless of the route of administration, including both small molecule and biotechnologyderived pharmaceuticals . It describes the type and timing of nonclinical studies in relation to the development of anticancer pharmaceuticals and references other guidance as appropriate . This guideline aims to facilitate and accelerate the development of anticancer pharmaceuticals and to protect patients from unnecessary adverse effects, while avoiding unnecessary use of animals and other resources

43. REFERENCES ICH g uidlines of quality and safety http:// www.ich.org/products/guidelines/quality/article/quality-guidelines.html http:// www.ich.org/products/guidelines/safety/article/safety-guidelines.html

44. THANK YOU