ICH guidelines

Special emphasis on Q series guidelines

1. ICH Guidelines : Q -series Prpared By Vinayak R Bodhankar M. Pharm F.y ( Sem – I) P’ceutical Quality Assurance Roll no. : 01 Guided by Dr. P. N. Kendre Sanjivani College of Pharmaceutical Education & Research, Kopargaon

2. Contents Introduction Composition of ICH ICH guidelines : QSEM Q Family Q - series guidelines References

3. ICH ICH stands for International Conference On Harmonization.(Technical requirement for registration of pharmaceuticals for human use) ICH is a joint initiative involving both regulators and research based industry representative of EU, Japan and US in scientific and technical aspect of testing procedure required to access and ensure safety, quality, and efficacy of the medicines.

4. Composition of ICH ICH is comprised from the six cosponsoring parties as well as three observers & IFPMA (International Federation of Pharmaceuticals Manufacturers Associations) Japan : MHW (Ministry of Health & Family Welfare) : JPMA (Japan Pharmaceutical Manufacturers Association) Europe : EC (European Commission) : EFPIA (European Federation of Pharmaceutical Industries Associations) USA : FDA : PhRMA (Pharmaceutical Research & Manufacturers of America)

5. Observer WHO (World Health Organization) Canada EFTA (European Free Trade Associations)

6. ICH guidelines ICH guidelines are divided into four major categories : 1. Q (Quality) : those relating to chemical & pharmaceutical quality. 2. S (Safety) : those relating to in vivo & in vitro pre clinical studies. 3. E (Efficacy) : those relating to clinical studies in human subjects. 4. M (Multidisciplinary topics )

7. “Q – Family” Q1 : Stability Testing Q2 : Analytical validation Q3 : Impurities Q4 : Pharmacopoeias Q5 : Biotechnological products Q6 : Specifications Q7 : GMP Q8 : Pharmaceutical development Q9 : Quality risk management Q10 : Pharmaceutical quality system Q11 : Development & Manufacture of drug substances

8. Q1 It is a set of five guidelines. (Q1A to Q1F) Q1A (R2) : Stability testing of New drug substances and products. Feb 2003 This is the guidance for analysis of the products in different environmental conditions. Zone Type of climate Storage conditions I Temperature 21 C 45%RH II Subtropical & mediterrean 25 C 60% RH III Hot/Dry 30 C 35% RH Iva Hot,/Humid (Tropical) 30 C 65% RH IVb Hot/ Higher humidity 30 C 75% RH

9. Q1 B Stability Testing : Photostability testing of New Drug Substances & Products. Nov 1996 Photostability studies are conducted with objective that light exposure does not leads to unacceptable changes in the dosage form. Photodegradation leads to changes in Physical appearance as well as Chemical compostion . Photodegradation may observed as Discoloration of the products.

10. Q1 C Stability Testing for New Dosage Forms. Nov 1996 This guideline extend the stability guidance for new formulation of already approved medicines and defines the circumstances under which reduced stability data is accepted. Q1 D Bracketing and Matrixing designs for stability testing of New drug substances and Products. Feb 2002 Bracketing and Matrixing are the procedures used to reduce the amount of stability testing required.

11. Bracketing & Matrixing Bracketing : It is the design of stability schedule such that only samples on the extremes of certain design factors (e.g., strength, container size) are tested at all time points as in a full design. Matrixing : it 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 points.

12. Example of Bracketing Design Bracketing on strength & container size Strength 50 mg 75 mg 100 mg Batch 1 2 3 1 2 3 1 2 3 Container size 15 ml T T T T T T 100 ml 500 ml T T T T T T Example of Matrixing Design Two strength, matrixing on time point Time points (months) 3 6 9 12 18 24 36 S T R E N G T H S1 Batch1 T T T T T T Batch2 T T T T T T Batch3 T T T (T) T T T S2 Batch1 T T T (T) T T T Batch2 T T T T T T Batch3 T T T T T T T : Sample tested (T) : Sample tested if full shelf life data will not be available before approval

13. Q1 E Evaluation for Stability data. Feb 2003 This guidelines involving the methods used for evaluating stability data found after analysis. Regression Analysis is most commonly used method for this purpose. Q1 F Stability data Package for Registration applications in the climatic zone III and IV. Feb 2003 (Withdrawn in 8 th june 2006)

14. Q2 (R1) Validation of Analytical Procedures : Text and Methodology Oct 1994 Actual experimental data along with the statistical interpretation is required for validation of analytical procedures. Four types of analytical procedures are used for Validation : 1. Identification test 2. Quantitative test for Impurity content 3. Limit test 4. Quantitative test for active moiety in the drug product

15. Typical Validation Characteristics :

16. Q3 A(R2) Impurities in New drug substances Oct 2006 This is the guidance addresses the chemistry and safety aspect of impurities and defines the threshold for reporting, identification and qualification. Classification of Impurities : 1. Organic Impurities : Starting materials, reactions by products, etc. 2. Inorganic Impurities : Reagents, catalyst, Heavy metals, etc. 3. Residual Solvents

17. Identification threshold : A limit above which a degradation product should be identified. Qualification threshold : A limit above which a degradation product should be qualified. Reporting threshold : A limit above which a degradation product should be reported.

18. Threshold for Degradation products in New drug Products Reporting threshold Maximum daily dose Threshold ≤ 1 g 0.1 % > 1 g 0.005 % Identification threshold Maximum daily dose Threshold < 1 mg 1.0 % or 5µg TDI, whichever is lower 1mg – 10 mg 0.5 % or 20µg TDI, whichever is lower >10 mg – 2 g 0.2 % or 2mg TDI, whichever is lower Qualification threshold Maximum daily dose Threshold < 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 %

19. E.g. The maximum daily dose is 750 mg a) Identification threshold (0.10% 1.0 mg per day intake whichever is lower) 750 mg -------- 100 % X mg -------- 0.10 % Impurity % in mg (X) = 750*0.10/100 = 0.75 mg 0.75 mg is lower than 1.0 mg, Identification threshold is 0.10% b) Qualification threshold (0.15% or 1.0mg per day intake whichever is lower) 750 mg --------- 100 % X mg --------- 0.15 % X = 750*0.15/100 = 1.125 mg (which is greater than 1mg) So calculate as per 1.0 mg X = 100*0.1/750 = 0.13 % The qualification threshold is 0.13 %

20. Q3 B (R2) Impurities in New drug products. Jun 2006 These are the guidelines on impurities in new drug products and advice in regards to impurities in product containing new or chemically synthesized drug substances.

21. Q3 C (R5) Impurities : Guidelines for residual solvents. Feb 2011 Classification of Residual solvents : Class – I : Solvents to be avoided e.g Benzene, Carbon tetrachloride Class – II : Solvents to be limited e.g Chloroform, methanol Class – III : Solvents with low toxic potential to man e.g Acetone, butanol , ethanol

22. Q3 D Guidelines for Elemental Impurities. Dec 2014 Objective of these guidelines is to limit the metal impurities in the drug products.

23. References : ICH guidelines Index http://www.ich.org Guidance for Industry Q3B (R2) impurities in new drug products U.S department of Health and human services. ICH Quality Guidelines: An Implementation Guide by Andrew Teasdale David Elder Raymond W. Nims Pages (1-280)