ICH Guidelines Q1 - Q10

ICH Quality Guidelines.

1. ICH GUIDELINES (Q1-Q10) MADE BY: BHAGYASHREE BHANAGE, ANKITA GAITONDE,HETAL GANDHI, ASHVINI INGLE. 1

2.   ICH : Is International Conference of Harmonization of technical requirements for registration of pharmaceuticals for human use.  Aim : It is a unique project that brings together the regulatory authorities of Europe, Japan & U.S. and experts from the pharmaceutical industries to discuss the scientific and technical aspects of the product registration. 2

3. The “Q-Family Q 1 – Stability Testing Q 2 – Analytical Validation Q 3 – Impurities Q 4 – Pharmacopoeias Q 5 – Biotechnological Products Q 6 – Specifications Q 7 – Good Manufacturing Practices Q 8 – Pharmaceutical Development Q 9 – Quality Risk Management Q 10 – Pharmaceutical Quality System 3

4. Q1A(R) STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS. 4

5. - For new API and related medicinal products. - To provide evidence on how the quality of an API/finished product changes with time under the influence of environmental factors such as temperature, humidity and light and to establish a re-test period/shelf-life for the API or finished product. 5

6. - Stress testing required for API - Long-term and accelerated testing required for API and product, where necessary intermediate testing. - Minimum of three representative batches. - Testing over a minimum of 12 months at LT and 6 months at accelerated conditions (with defined testing frequency) 6

7. - Storage conditions for the “general case”, aqueous products in semi-permeable containers, products to be stored in a refrigerator and a freezer. - Stability commitment. 7

8. Study Storage condition Minimum time period covered by data at submission Long term* 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 12 months Intermediate 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months 8

9. Q1B STABILITY TESTING: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS. 9

10. - Describes requirements on photostability testing and defines light exposure to be applied. - To be tested on API – if not photosensitive, no further testing required. - If photosensitive, to be continued on exposed finished product and product in primary package, product in marketing package, where relevant. - Where necessary, impact of light during manufacturing process to be evaluated. - Confirmatory testing required, where applicable. 10

11. Q1C STABILITY TESTING FOR NEW DOSAGE FORMS 11

12. GENERAL This document is an annex to the ICH parent stability guideline and addresses the recommendations on what should be submitted regarding stability of new dosage forms by the owner of the original application, after the original submission for new drug substances 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. 12

13. Q1D BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS 13

14. - Describes possibilities to apply reduced test designs, i.e. bracketing and matrixing . - Defines situations where reduced testing can be applied without additional justification, with justification or where it is not applicable. - Bracketing: testing of extremes only. - Matrixing : testing of a different samples of factor combinations at different time points during the study. - Provides example designs. 14

15. Bracketing bracketing is the design of a stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size and/or fill) are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested. Matrixing is the design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point. Matrixing Each storage condition should be treated separately under its own matrixing design . 15

16. Strength 50 mg 75 mg 100 mg Batch 1 2 3 1 2 3 1 2 3 Container size 15ml T T T T T T 100ml 500ml T T T T T T Bracketing on strength and container size T: Sample tested; (T): Sample tested if full shelf life data will not be available before approval. 16

17. Time point (months) 3 6 9 12 18 24 36 Batch 1 T T T T T T S1 Batch 2 T T T T T T Strength Batch 3 T T T ( T) T T T Batch 1 T T T ( T) T T T S2 Batch 2 T T T T T T Batch 3 T T T T T T 17

18. Q1E EVALUATION FOR STABILITY DATA 18

19. Objectives of the 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 “Q1A(R) Stability Testing of New Drug Substances and Products” (hereafter referred to as the parent guideline) to propose a retest period or shelf life in a registration application. 19

20. Q1F WITHDRAWN 20

21. Q2(R1) VALIDATION OF ANALYTICAL PROCEDURES: TEXT AND METHODOLOGY 21

22. Typical validation characteristics which should be considered are listed below: Accuracy Precision Repeatability Intermediate Precision Specificity Detection Limit Quantitation Limit Linearity Range 22

23. 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. 23

24. Q3A Impurities in New Drug Substances 24

25. INTRODUCTION This document is intended to provide guidance for registration applications on the content and qualification of impurities in new drug substances produced by chemical syntheses and not previously registered in a region or member state. Impurities in new drug substances are addressed from two perspectives : Chemistry aspects include classification and identification of impurities, report generation, listing of impurities in specifications, and a brief discussion of analytical procedures Safety aspects include specific guidance for qualifying those impurities that were not present, or were present at substantially lower levels, in batches of a new drug substance used in safety and clinical studies. 25

26. Q3B(R2) IMPURITIES IN NEW DRUG PRODUCTS 26

27. Objective of the guideline 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. Scope of the guideline 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 (collectively referred to as “degradation products” in this guideline). 27

28. Q3C(R5) IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS 28

29. Objective The objective of this guideline is to recommend acceptable amounts for residual solvents in pharmaceuticals for the safety of the patient. Since there is no therapeutic benefit from residual solvents, all residual solvents should be removed to the extent possible to meet product specifications, good manufacturing practices, or other quality-based requirements. Scope of the guideline Residual solvents in drug substances, excipients , and in drug products are within the scope of this guideline. 29

30. GENERAL PRINCIPLES Class 1 solvents: Solvents to be avoided Known human carcinogens, strongly suspected human carcinogens, and environmental hazards. 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. 30

31. Q3D Impurities: Guideline for Metal Impurities 31

32. It is proposed that a new harmonised tripartite guideline be developed to provide a globalpolicy for limiting metal impurities qualitatively and quantitatively in drug products and ingredients. 32

33. Q4A PHARMACOPOEAL HARMONISATION. 33

34. Q4B ANNEX 1(R1) EVALUATION AND RECOMMENDATION OF PHARMACOPOEIAL TEXTS FOR USE IN THE ICH REGIONS ON RESIDUE ON IGNITION/SULPHATED ASH GENERAL CHAPTER. This annex is the result of the Q4B process for Residue on Ignition/ Sulphated Ash. 34

35. Q4B ANNEX 2(R1) TEST FOR EXTRACTABLE VOLUME OF PARENTERAL PREPARATIONS GENERAL CHAPTER This annex is the result of the Q4B process for the Test for Extractable Volume of Parenteral Preparations General Chapter. 35

36. Q4B ANNEX 3(R1) TEST FOR PARTICULATE CONTAMINATION: SUB-VISIBLE PARTICLES GENERAL CHAPTER This annex is the result of the Q4B process for Test for Particulate Contamination: Sub-Visible Particles. 36

37. Q4B ANNEX 4A(R1) MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: MICROBIAL ENUMERATIONS TESTS GENERAL CHAPTER 37

38. Q4B ANNEX 4B(R1) This annex is the result of the Q4B process for Microbiological Examination of Non-Sterile Products: Tests for Specified Micro-organisms . 38

39. Q4B ANNEX 4C(R1) MICROBIOLOGICAL EXAMINATION OF NON-STERILE PRODUCTS: ACCEPTANCE CRITERIA FOR PHARMACEUTICAL PREPARATIONS AND SUBSTANCES FOR PHARMACEUTICAL USE. 39

40. Q4B ANNEX 5(R1) DISINTEGRATION TEST GENERAL CHAPTER. 40

41. Q4B ANNEX 6(R1) UNIFORMITY OF DOSAGE UNITS GENERAL CHAPTER. 41

42. Q4B ANNEX 7(R2) DISSOLUTION TEST GENERAL CHAPTER. 42

43. Q5A(R1) VIRAL SAFETY EVALUATION OF BIOTECHNOLOGY PRODUCTS DERIVED FROM CELL LINES OF HUMAN OR ANIMAL ORIGIN. 43

44. INTRODUCTION This document is concerned with testing and evaluation of the viral safety of biotechnology products derived from characterised cell lines of human or animal origin (i.e., mammalian, avian, insect) and outlines data that should be submitted in the marketing application/registration package. The scope of the document covers products derived from cell cultures initiated from characterised cell banks. It covers products derived from in vitro cell culture, such as interferons , monoclonal antibodies and recombinant DNA-derived products including recombinant subunit vaccines, and also includes products derived from hybridoma cells grown in vivo as ascites 44

45. 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) assessing the capacity of the production processes to clear infectious viruses; c) testing the product at appropriate steps of production for absence of contaminating infectious viruses. 45

46. Q5B QUALITY OF BIOTECHNOLOGICAL PRODUCTS: ANALYSIS OF THE EXPRESSION CONSTRUCT IN CELLS USED FOR PRODUCTION OF R-DNA DERIVED PROTEIN PRODUCTS 46

47. Q5C STABILITY TESTING OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS . 47

48. SCOPE The guidance stated in this annex applies to well- characterised proteins and polypeptides, their derivatives and products of which they are components, and which are isolated from tissues, body fluids, cell cultures, or produced using rDNA technology. Thus, the document covers the generation and submission of stability data for products such as cytokines ( interferons , interleukins, colony-stimulating factors, tumour necrosis factors), erythropoietins , plasminogen activators, blood, plasma factors, growth hormones and growth factors, insulins , monoclonal antibodies, and vaccines consisting of well- characterised proteins or polypeptides. 48

49. Q5D DERIVATION AND CHARACTERISATION OF CELL SUBSTRATES USED FOR PRODUCTION OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS. 49

50. SCOPE This guideline covers cell substrates having a cell banking system. In this document, “cell substrate” refers to microbial cells or cell lines derived from human or animal sources that possess the full potential for generation of the desired biotechnological/biological products for human in vivo or ex vivo use. 50

51. Q5E COMPARABILITY OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS SUBJECT TO CHANGES IN THEIR MANUFACTURING PROCESS. 51

52. The goal of the comparability exercise is to ensure the quality, safety and efficacy of drug product produced by a changed manufacturing process, through collection and evaluation of the relevant data to determine whether there might be any adverse impact on the drug product due to the manufacturing process changes. 52

53. THANK YOU 53