Ich guideline for stability testing

Ich guidelines

1. ICH GUIDELINE FOR STABILITY TESTING Presented By - Mr. Shu bham J. Gore M.Pharmacy (pharmaceutics ) 1 15/09/2018

2. CONTENT- Introduction Objective of Stability testing Variables affecting the stability Adverse effects of instability of drugs Stability Testing Terminologies ICH Q1A(R2) ICH Q1B ICH Q1C ICH Q1D ICH Q1E Reference

3. INTRODUCTION- 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 EU , Japan and the US in scientific and technical discussions of the testing procedures required to assess and ensure the safety, quality and efficacy of medicines. DRUG STSBILITY- “A measure of how pharmaceutical products maintains its quality attribute over a time.”

4. OBJECTIVE OF STABILITY TESTING-  "…… 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 & light, & enables recommended storage conditions , re-test periods & shelf lives to be established ”

5. Variables affecting the stability- Formulation Packaging Site and method of manufacture API Finished product Batch size Batch to batch variability Process validation Quality risk management Container labelling Changes to product

6. ADVERSE EFFECTS OF INSTABILITY OF DRUGS- Loss of active drug (e.g. aspirin hydrolysis, oxidation of adrenaline) Loss of vehicle (e.g. evaporation of water from o/w creams , evaporation of alcohol from alcoholic mixtures ) Loss of content uniformity (e.g. creaming of emulsions , impaction of suspensions) Loss of elegance (e.g. fading of tablets and colored solutions ) Reduction in bioavailability (e.g. ageing of tablets resulting in a change in dissolution profile) Production of potential toxic materials ( e.g.breakdown products from drug degradation )

7. I AM STABLE TOXICOLOGIC STABILITY MICROBIOLOGICAL STABILITY PHYSICAL STABILITY CHEMICAL STABILITY THEARAPEUTICAL STABILITY

8. TYPES OF STABILITY- CHEMICAL: Each active ingredient retains its chemical integrity and labeled potency within the specified limit. PHYSICAL : The physical stability properties includes appearance , palatability, uniformity, dissolution and suspend ability are retained. MICROBIOLOGICAL: Sterility or resistance to microbial growth is retained according to specified requirement. THERAPEUTIC : Therapeutic activity remains unchanged . TOXICOLOGIC : No significant increase in toxicity occurs.

9. STABILITY TESTING- Development studies- Characterise compatibility with common excipients. Characterise stability profile of API (E.g . susceptibility to acid, base, light, oxygen etc ) Characterise stability profile of early formulations (Especially susceptibility to heat, humidity & light) Confirmatory studies- Long term & accelerated studies on the product as it is to be registered

10. Q1A : Stability Testing of New Drug Substances and Products- General Stress Testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Statements/Labelling

11. GENERAl - Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. STRESS TESTING- Main tool that predict the stability problems . Foundation for developing and validating analytical methods. For an API the following approaches may be used: When available, it is acceptable to provide relevant data published in the scientific literature to support the identified degradation pathways and products .

12. ROLL OF STRESS TESTING- Stress testing of the active substance can help in Identification of degradants Identification of degradation pathways Determination of which type(s) of stress affect the molecule: Photo-stability High Temperature Low Temperature Oxidation pH extremes Water

13. Oxidation- Typically done by placing the drug substance in aqueous solution of hydrogen peroxide. Goal is significant degradation (typically 10-30% of API ) Can identify degradants Determine whether protective packaging is required Determine if an antioxidant should be considered for the drug product formulation .

14. Ph - Typically done by adding drug substance to buffered aqueous solutions at pH values from 1-10 Decide if the molecule will survive passage through the stomach Is enteric coating necessary? the drug be given by injection?

15. TYPICAL STRESS CONDITION-

16. SELECTION OF BAtCHES - Data from formal stability studies should be provided on at least three primary batches of the active substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as, and using a method of manufacture and procedure that simulates the final process to be used for , production batches.

17. CONTAINER AND CLOSURE SYSTEM- The stability studies should be conducted on the active substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

18. SPECIFICATION- Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The testing should cover, as appropriate, the physical , chemical, biological, and microbiological attributes . e.g . appearance, assay, degradation.

19. TESTING FREQUENCY- For long term studies: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually At accelerated storage conditions : (6 month study) Minimum three points including t 0 and t final , e.g. 3 6 ( initial) ( final) At intermediate storage conditions: (12 month study) Four points including t 0 and t final , e.g. 6 9 12 ( initial) ( final)

20. STORAGE CONDITION- A drug substance should be evaluated To test its thermal stability Its sensitivity to moisture(if applicable) The long-term testing (minimum of 12 months) on at least 3 primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed re-test period.

21. GENERAL CASE-

22. STORAGE IN REFRIGERATOR-

23. STORAGE IN A FREEZER-

24. EVALUATION- Minimum of 3 batches of drug substance is tested. The degree of variability of individual batches affects the confidence that a future production batch will remain within specification throughout the assigned re-test period. The analyst must found the batch to batch variability & if it is small than only it is accepted & it can be done by different statistical test's ( P value for level of significance for rejection). Where the data show so little degradation and so little variability then it is normally unnecessary to go through the statistical analysis; providing a justification for the omission should be sufficient.

25. STATEMENT/LABELING- A storage statement should be established for the labelling based on the stability evaluation of the active substance. Where applicable, specific instructions should be provided, particularly for active substances that cannot tolerate freezing . Terms such as “ambient conditions” or “ room temperature ” must be avoided.

26. STABILITY-INDICATING QUALITY PARAMETER- Stability studies should include testing of those attributes of the Drug product that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets: appearance hardness friability moisture content dissolution time degradants assay microbial purity

27. ACCELARATED STABILITY- This stability study run under more stressful conditions than expected for long term storage to account for any changes outside the label storage conditions The goal is to get a quick understanding of what may be expected from a long term study.

28. Q2B: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS- Photo-stability testing studies include : ( Single batch) (no photo-stability studies after administration) Test on drug substance. Test on exposed drug product outside the immediate pack. Test on drug product in the immediate pack. Test on drug product in the marketing pack . Light source- Option 1: Artificial daylight lamp combining both visible & UV output similar to D65 & ID65. Option 2: Cool white fluorescent & near UV lamp(320-400nm)

29. PROCEDURE-

30. Q1C: Stability Testing for New Dosage Forms- 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 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. 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 may be acceptable in certain justified cases.

31. Q1d:( Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products)- BRACKETING- It is the design of a stability schedule such that only samples on the extremes of certain design factors, e.g., strength, package size, 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. Where a range of strengths is to be tested, bracketing is applicable if the strengths are identical or very closely related in composition.

32. Cont … e.g.: for a tablet range made with different compression weights of a similar basic granulation. Bracketing can be applied to different container sizes or different fills in the same container closure system.

33. 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 is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

34. Q1E: EVALUATION OF STABILITY DATA- Data Presentation- Data for all attributes should be presented in an appropriate format (e.g ., tabular, graphical, narrative) and an evaluation of such data should be included in the application. The values of quantitative attributes at all time points should be reported as measured (e.g., assay as percent of label claim ).

35. If a statistical analysis is performed, the procedure used and the assumptions underlying the model should be stated and justified. A tabulated summary of the outcome of statistical analysis and/or graphical presentation of the long-term data should be included.

36. EXTRAPOLATION- Extrapolation is the practice of using a known data set to infer information about future data (e.g. by using regression line analysis) Extrapolation to extend the retest period or shelf life beyond the period covered by long-term data can be proposed in the application, particularly if no significant change is observed at the accelerated condition .

37. Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV Describes harmonised 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.

38. REFERENCE- ICH Official web site- www.ich.org