Ich guidelines Q1A(R2)

This guideline is a revised of the ICHQ1A –stability data package for new drug substance /DRUG PRODUCT .The [urpose of guideline to define stability data package that sufficient for a registration application within the 3 regions of EU ,JAPAN & USA & to maintain the quality of drug products, in relation to safety , efficacy & acceptability throughout the propose shelf life.

1. ICH GUIDELINES Q1A Surendra Negi Research Associate Windlas healthcare (P) ltd. Dehradun

2. C ontents Introduction Purpose & goal of ICH Structure & protocols Q1A (R2)

3. WHAT DOES ICH STANDS FOR ? The complete name of ICH is the ‘’ INTERNATIONAL CONFERENCE ON HARMONIZAT ION ‘’ of technical requirements for registration of pharmaceuticals for human use. BIRTH OF ICH The birth of ICH took at a meeting in April 1990 hosted by the EFPIA in Brussels. The meeting held by representatives of regulatory agencies and industry associations of Europe ,Japan and USA .Topic selected for harmonization would divided into safety, Quality and Efficacy which are basis for approving and authorizing new drug product.

4. PURPOSE OF ICH The objective of ICH is to increase international harmonization of technical requirements to ensure that safe, effective & high quality medicines are developed and registered in the most efficient & cost- effective manner. To eliminates of duplication in the development and registration process i.e, eliminate the duplications of clinical trials, evaluations of safety, quality ,efficacy and other technical requirements.

5. Goal OF ICH To promote international harmonisation by bringing together the representatives from the three region(EU, Japan, USA) to established a common guidelines. TO make the information available on ICH,ICH activities and guidelines to any country or company that request the information and facilitate harmonization processes related to ICH guidelines regionally and globally.

6. STRUCTURE OF ICH It is a joint initiative involving both regulators bodies & research-based industry as equal partners . The parties involved from the European Union, Japan & the USA are- 1. European Commission ( EC ) 2 . European Federation of Pharmaceutical Industries & Association ( EFPIA ) 3. Ministry of Health, labour & Welfare ( MHLW ),Japan 4. Japan Pharmaceutical Manufacturers Association ( JPMA ). 5 . US Food & Drug Administration ( FDA ). 6. Pharmaceutical research & manufacturers of America. ( PhRMA ).

7. Three observers which represent non-ICH countries and regions are: 1. World Health Organization (WHO). 2. European Free Trade Area ( EFTA ). 3. Canada.

8. ICH GUIDELINES ICH has developed over 45 harmonized guidelines which are divided into 4 major categories 1.QUALITY topics 2. SAFETY TOPICS 3. EFFICACY TOPICS 4.MULTIDISCIPLINARY TOPICS Q QUALITY topics Q1A : Stability Testing of New Drug substances &Drug Product. Q1B : Photostability Testing of New Drug Substances & Product . Q1C : Stability Testing of New Drug Forms. Q2 : Analytical Validation. Q3A : Impurities in New Drug Substances. Q3B : Impurities in New Drug Products. Q4 : pharmacopoeias Q5 : Stability Testing of Biotechnological\Biological Product. Q6: Specifications Q7: Good manufacturing practice Q8: Pharmaceutical Development Q9: Quality Risk Management Q10: Pharmaceutical Quality system

9. 2. ‘S’ SAFETY TOPICS – related to in vivo & in vitro pre clinical studies. eg. S1- Carcinogenicity testing. S2- Genotoxicity testing. 3. ‘E’ EFFICACY TOPICS- related to clinical studies in human subject. eg. E4- Dose response studies. E5- Carcinogenicity testing. E6- Good clinical practices. (GCP).

10. 4. ‘M’ MULTIDISCIPLINARY TOPICS M1 - Medical technology. M2- Electronic standards for transmission of regulatory information. M3- Timing of pre clinical studies in relation to clinical trials. M4- Common technical documents. M5- Data elements & standards for drug dictionaries.

11. STABILITY DATA GENERATION The key step in the data generation is writing a stability protocol. A properly designed test protocol contains in general the following information: Type, size & no. of batches. Type, size & source of containers & closures. Container storage orientation. Test parameters. Test methods. Acceptance criteria. Sampling time points. Test storage conditions.

12. GLOBAL CLIMATIC ZONE Havens gathered the climatic data in major cities around the world & proposed division of the world into 4 climatic zone. ZONE ZONE 1 (Temperate) ZONE 2 (Mediterranean) ZONE 3 (Hot/ Dry) ZONE 4 (Very hot/ Moist) Kinetic Average temperature 21 °C 25 °C 30°C 30°C Yearly Average RH 45 % RH 60% RH 35% RH 70% RH

13. REGIONS ZONE 1& 2 COUNTRIES ZONE 3& 4 COUNTRIES EUROPE All countries - AMERICA Argentina, Bolivia, Canada, USA Brazil, Columbia, Cuba ASIA Afghanistan, China, Iran, Israel, Japan, Nepal Bangladesh, India, Indonesia, Iraq, Srilanka AFRICA Egypt, Algeria, South Africa Ethiopia, Ghana, Kenya, Nigeria AUSTRALIAN/OCEANIC Australia, New Zealand Fiji, Society Island, New Guinea. DISTRIBUTION OF WORLD NATIONS INTO DIFFERENT ZONES

14. ICH GUIDELINES FOR STA BILITY TESTING OF NEW DRUG SUBSTANCES & PRODUCTS Q1A(R2)

15. OBJECTIVES OF A GUIDELINE This guideline is a revised of the ICHQ1A – stability data package for new drug substance / DRUG PRODUCT . To define stability data package that sufficient for a registration application within the 3 regions of EU ,JAPAN & USA To maintain the quality of drug products, in relation to safety , efficacy & acceptability throughout the propose shelf life.

16. O utline the changes made in Q1A(R) The intermediate storage condition has been changed from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH in the following sections: Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - General Case Drug products packaged in semi-permeable containers 30°C ± 2°C/65% RH ± 5% RH can be a suitable alternative long-term storage condition to 25°C ± 2°C/60% RH ± 5% in the following sections: Drug Substance - Storage Conditions - General Case Drug Product - Storage Conditions - General Case 30°C ± 2°C/35% RH ± 5% RH has been added as a suitable alternative long-term storage condition to 25°C ± 2°C/40% RH ± 5% and the corresponding example for the ratio of water-loss rates has been included in the following section: Drug products packaged in semi-permeable containers

17. GENERAL PRINCIPLES The purpose of stability testing are: 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. To estimate the self life of the drug product and its degradation pathway. To recommend storage conditions. To established a re-test period of the drug substance/product for stability testing To fulfill the relevant legal requirements concerned with the purity, safety & efficacy of the drugs. To prevent the economical consequences of marketing the unstable products.

18. GUIDELINES DRUG PRODUCT DRUG SUBSTANCES General Stress testing Selection of Batches Container Closure system Specification Testing Frequency Storage Condition Stability Commitment Evaluation Statements/Labeling General Photo stability testing Selection of Batches Container Closure System Specification Testing Frequency Storage Conditions Stability Commitment Evaluation Drug substance Excipient Expiration date

19. Formal stability studies Impermeable containers Intermediate testing Long term testing Mass balance Matrixing Mean kinetic temperature New molecular entity Pilot scale batch Primary batch Production batch Re-test date Re- test period Pull times

20. GUIDELINES 1. Drug substance General Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation. Stress testing Stress testing of drug substance help to determine degradation product, established the degradation pathway and validate the stability indicating power of analytical procedures. This include the effect of: Temperature Humidity(75%RH or greater). Oxidation ,& photolysis on the drug substance. Hydrolysis across a wide range of pH Values when in solution or suspension.

21. . Selection of batches Data from formal stability studies should be provide on at least 3 primary batches of the drug substances. Batches should be manufactured to a minimum of pilot scale by the same synthetic routes & using a method of manufacturing procedure that simulates the final process to be used for final production batches. The overall quality of drug substance placed on formal stability study should be representative of quality of material to be made on a production scale.

22. Container closure system The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution. Specification It’s a list of test ,reference to analytical procedures , and proposed acceptance criteria ,is addressed in ICH Q6A &Q6B .in addition, specification for degradation products in a drug substance is discussed in Q3A. Stability study should cover the attributes which likely to change during storage and influence the quality, safety and efficacy of drug products i.e, physical, chemical, biological and microbiological attributes.

23. Testing frequency For drug substances with a proposed re-test period of at least 12 months, the frequency of testing at the long term storage condition is 3 months over the first year, every 6 months over the second year ,and annually thereafter through the proposed retest period. At accelerated storage condition , a minimum three time points 0, 3, 6 months the testing should performed. For intermediate study minimum four time points 0, 6, 9 &12 months ,from 12 month study is recommended.

24. Storage conditions In general ,a drug substance should be evaluated under storage conditions with appropriate tolerance that test it’s thermal stability and sensitivity to moisture. T he storage conditions & the length of studies chosen should be sufficient to cover storage, shipment & subsequent use.

25. General case STUDY Storage Conditions Minimum time period covered by data at submission Long term 25° C + 2°C/60% RH + 5 % or 30°C ± 2°C/65% RH ± 5% RH 12 months Intermediate 30° C + 2°C/65% RH + 5% 6 months Accelerated 40° C + 2°C/75% RH + 5% 6 months If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

26. Drug substances intended for storage in a refrigerator STUDY STORAGE CONDITION MINIMUM TIME PERIOD Long term 5°C + 3°C 12 months Accelerated 25°C± 2°C/60%RH±5%RH 6 months

27. Drug substance intended for storage in a freezer STUDY STORAGE CONDITION MINIMUM TIME PERIOD Long term -20°C±5”C 12 months

28. Stability commitment When available long term stability data on primary batches do not cover the proposed re –test period granted at a time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the re test period. If the submission includes data from stability study on fewer then the three production batches, a commitment should be made to continue the study on more then three future production batches. If the submission does not include stability data on production batches, a commitment should be made to do this.

29. Evaluation The evaluation of stability information is a systemic approach which include the evaluation of results from the physical, chemical, biological and microbiological tests. The purpose of the stability study is to establish shelf life (based on testing a minimum of three batches of the drug substances) and label storage conditions applicable to all future batches. Any evaluation should consider not only the assay but also degradation product so stability indicating methods used for evaluation .

30. Statements/ Labeling A storage statement should be established for the labeling in accordance with relevant national/regional requirements. The statement should be based on stability evaluation of the drug substance, where applicable specific instructions should be provided ,particularly for drug substances that cannot tolerate freezing. Terms such as ‘‘ambient conditions ’’ or “room temperature” should be avoided A re- test period should be derived from the stability information ,and a retest date should be displayed on the container label if appropriate. Expiration date should be mention on container label.

31. 2. Drug Product The design of the formal stability studies of drug product based on behavior & properties of drug substance and from stability studies on drug substance . Photo stability testing- Standard conditions for photo stability testing are described in ICHQ1B. Other guidelines are similar to guidelines used for drug substance .

32. Reference Samalti Ajay & samalti Mona “Essentials of pharmaceutical technology”PharmaMed pess,page no.300 www.ich.org/products/.../stability-testing-of-new-drug-substances-and-products.html

33. Thank you