Post Approval Stability Studies

1. Post Approval Stability Studies

2. LEARNING OBJECTIVES • Awareness of ICH / EMA / other Stability Guidelines • Understand minimum requirements for Routine Stability study of marketed products (for API, Drug Product and Medical Device) • Understand necessary studies/changes that impact marketed product stability

3. ICH Guidelines - Stability • Q1A(R2) - Stability Testing of New Drug Substances and Products (Revision 2) (August 2003) = CPMP/ICH/2736/99 : Zones I and II • Q1B – Photostability Testing of New Active Substances and Medicinal Products (January 1998) = CPMP/ICH/279/95 • Q1C – Requirements for New Dosage Forms (January 1998) = CPMP/ICH/280/95 • Q1D – Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products (August 2002) = CPMP/ICH/4104/00 • Q1E – Evaluation of Stability Data (August 2003) = CPMP/ICH/420/02) • Q1F – Stability Data Package for Registration Applications in Climatic Zones III and IV (August 2003) = CPMP/ICH/421/02 : Withdrawn on June 1st 2006. • Q5C – Stability Testing of Biotechnological/Biological Products (July 1996) = CPMP/ICH/138/95

4. EMA Guidelines - Stability • Stability Testing of Existing Active Substances and Related Finished Products : CPMP/QWP/122/02, rev 1 (March 2004) • Declaration of Storage Conditions : • A : In the Product Information of Medicinal Products • B : For Active Substances : CPMP/QWP/609/96/Rev 1 (October 2003) (Annex to ICH Q1 A (R2) and to CPMP/QWP/122/02, rev 1) • Stability Testing for Applications for Variations to a Marketing Autorisation: CPMP/QWP/576/96 Rev 1 (01 December 2005) • DRAFT : Stability Testing for Active Substances and Medicinal Products manufactured in Climatic Zones III and IV to be marketed in the EU : CPMP/QWP/6142/03 – Consultation (August 2004)

5. Additional Guidelines (1) • EMA Guidelines • Start of shelf-life of the finished dosage form (Annex to NFG on the manufacture of the finished dosage form): CPMP/QWP/072/96 (December 2001) • EU Commissions Guidelines • Notice to applicants: Dossier requirements for Type 1A and type 1B notifications – Volume 2C (June 2006) • US FDA CDER 21 CFR Part 211.166 • Current Good Manufacturing Practice for Finished Pharmaceuticals-Stability Testing • US FDA CDER Guidance for Industry • Changes to an Approved NDA or ANDA April 2004

6. Additional Guidelines (2) • ASEAN Guideline on stability study of drug product, updated version February 22, 2005 : Drug products : NCE, Generics and Variations • WHO Technical Report Series N° 863, 1996, Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms, revised by technical Report Series N° 908, p 13, 2003 and N° 937, p 12, 2006.

7. Additional Guidelines (3) • WHO Working document QAS/06.179/Rev.2 August-September 2007 : Stability testing of active pharmaceutical ingredients and pharmaceutical products. • Close to ICH Q1A(R2) and EMA CPMP/QWP/122/02, rev 1 • New Chemical Entities and existing APIs and their related pharmaceutical products, not applicable for biologicals • Specific items : In-use stability, variations, ongoingstability studies • Climatic Zones : I, II, III, IVA, IVB • Climatic Zones defined for some countries (less WHO Eastern Mediterranean Draft regional compared to Rev 1 April 2007) • WHO Eastern Mediterranean Draft regional guidelines on stability testing of active substances and pharmaceutical products, August 2006 : NCE, existing active substances and related pharmaceutical products.

8. Additional Guidelines (4) • Brazil : Guide for the Undertaking of Stability Studies : Federative Republic of Brazil ; National Press, Official Gazette of the Union Supplement to N°. 146 - Section 1 Brasilia - DF, Monday, August 1st, 2005. • Ministry of Health, National Agency of Health Surveillance, Resolution - RE N°. 1, of July 29, 2005 • Guide for undertaking the stability tests of pharmaceutical products so as to predict, determine or follow-up their validity term • Long-term conditions : Zone IVB : general case 30°C ± 2°C 75% RH ± 5% RH

9. Purpose – Stability Studies • A marketed product stability program fulfils registration commitments and ensures that marketed product is stable (potent) until expiry date stamped on product label • Post-approval stability testing is to verify that Active Pharmaceutical Ingredients (API), Pharmaceutical Products and Medical Devices comply during their retest period or shelf life with the specifications defined in the Marketing authorisation

10. Stability Study…. • Provides evidence on how the quality of an active pharmaceutical product, medical device, or pharmaceutical product (i.e. drug product) varies with the time under the influence of a variety of environmental factors such as temperature, humidity and light and enables recommended storage conditions, retest date/periods or shelf life to be established.

11. Common Terminology (1) • Long-term testing : • Stability studies under the recommended storage condition for the retest period or shelf-life approved for labelling • Accelerated testing : • Studies designed to increase the rate of chemical degradation or physical change of active pharmaceutical product, medical device or pharmaceutical product (I.e. drug product) by using exaggerated storage conditions as part of the formal defined storage program • Climatic Zone : • Zones into which the world is divided based on the prevailing annual climate conditions. Zone I is temperate. Zone II is subtropical and Mediterranean with possible high humidity. Zone III is hot and dry. Zone IVa is hot and humid. Zone IVb is hot and very humid.

12. Common Terminology (2) • Date of Manufacturing : • The first day of compounding for pharmaceutical products. It is the date of the final production step for chemical substances • Retest Date : • The date after which samples of the API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given pharmaceutical product • Shelf life : • The time interval that a pharmaceutical product (i.e. drug product) or medical device is expected to remain within the approved specification provided that it is stored under the conditions defined on the label in the proposed containers and closure

13. Common Terminology (3) • Expiry date/Expiration date : • The date placed on the container label of an API / pharmaceutical product designating the time during which a batch of the API / product is expected to remain within the established/approved shelf-life specification, if stored under defined conditions, and after which it must not be used • Bracketing : • The design of stability schedule such that only samples on the extremes of certain designs factors (e. g. strength, container size and/or fill) are tested at all time points as in the full design. The design assumes that the stability of any intermediate levels is represented by the facility of the extremes tested • Matrixing : • The design of a stability schedule that a selected subset of the total number of possible samples for all factor combinations would be tested at a specified time point • T0 : • Initiation of the stability study (i.e. samples put in the climatic chambers)

14. Routine Post Approval Stability Testing • Routine stability monitoring is performed to confirm stability characteristics of tested materials during the routine production : • Verify the retest date/expiry date established for active substances and shelf life/expiry date for drug products and medical devices, demonstrating current product and process is under control • Stability studies on routine annual batch

15. Changes and Variations (1) • Whenever a change to product, pack, process or site is made, that may affect product stability (assessed by Change Control system or stability failure investigation) stability testing is initiated to : • Verify the established expiry period, including first 3 production batches • Support change in the source of active substance/excipient for existing product • Support change to product, package, process for existing product • Justify a bulk holding time • Support site transfer for existing product • Support a process/product deviation investigation • Support reworking/reprocessing • Support a change of storage conditions (for example to ICH conditions) • Support extension of the initially established expiry period

16. Changes and Variations (2) • The decision regarding the classification of any change as a minor (Type IA and IB) or major (Type II) change should be made on a scientific basis and based upon the EC Notice to Applicants Guideline • With respect to the existing registered formula of known stability profile.

17. Examples of Minor Changes – Little or no impact on product stability (1) • Minor changes in synthesis of drug substances where there is no change in qualitative and quantitative impurity profile or in physico-chemical properties i.e. particle size, apparent volume. The active substance is not a biological substance and the synthetic route remains the same • Change in specification of an excipient. The change does not concern adjuvant for vaccines or a biological excipient • Change in test procedure for an excipient. The substance is not a biological excipient • Change in the specifications of the primary packaging of the finished product • Change in batch size of the finished product : up/down by a factor of 10 times the size of the original approved batch. Normally stability studies are requested when batch size is up/down scaled more than 10 times (biological active substances excluded).

18. Examples of Minor Changes – Little or no impact on product stability (2) • Change to alternative equipment of the same design and operating principles (a minor change in the manufacturing process of the finished product requires stability studies). • Change in test procedures of drug product with no change in specification (i.e., optimisation of methods). • Change in the dimensions of tablets, capsules, suppositories or pessaries; without change in the quantitative composition and mean mass.

19. Examples of Major Changes – Likely to impact on product stability (1) • Any quantitative or qualitative excipient changes • Change in the technical grade of an excipient i.e. particle size • Change in manufacturer for drug substance • Major changes in synthesis of drug substance (change in qualitative or quantitative impurity profile) • Changes in the excipient ranges of low solubility or low permeability drugs.

20. Examples of Major Changes – Likely to impact on product stability (2) • Change of storage conditions • Change in specifications of the drug product or API • Change in test procedures linked with a change in specification • Change in dimensions of a sustained release formulation • Major changes in manufacture of the drug product • Change from wet granulation to direct compression of dry powder • Site change to a contiguous facility on the same campus or change of the manufacturing site to a different campus • Change in batch size beyond 10 times the size of the original batch • Change to equipment of different design and different operating principles.

21. Responsibilities – Site Management (1) • Ensure procedures and systems for Stability Programs including review and approval of stability protocols and reports • Ensure adequate storage, utilities, equipment, security and personnel to perform stability programs • With Manufacturing representative, select batches to be put under stability including campaign production.

22. Responsibilities – Site Quality (2) • To optimise resources select batches to be put in stability in the event of multiple changes instead of putting all batches on stability • Rapidly react and initiate follow-up actions (with Quality Control) in case of unusual observations : OOS or OOT during testing • Ensure SOPs for Stability Programs are in place and are consistent with company policies and other regulatory requirements • Ensure pharmaceutical products manufactured, packaged or distributed by (or for) the given site are put under stability • Involved in the review and approval of potential changes to product, manufacturing process or packaging that may impact on product’s stability profile and shelf-life.

23. Responsibilities – Site Quality Control (3) • Written procedures for • initiating/conducting stability programs • Labelling samples for stability studies in an adequate manner • reporting/trending/archiving data • maintenance/calibration of storage/testing equipment • Organise periodical review of data and reporting trends that may result in product failing to meet specifications during retest period or shelf-life

24. Responsibilities – Laboratory Manager/Analyst (4) • Laboratory • complete review of laboratory actions leading to stability result and approve laboratory investigations reports, retest plans, re-sampling justification and plans, conclusion from failure investigations • Analyst • identify OOS/atypical results (OOT) – report them to laboratory management

25. General Points To Consider (1) • Approved protocols for each study (Routine or post-approval variations) in compliance with the zone in which the product is marketed • In the event the Manufacturing and Packaging operations are performed at different sites, a decision must be taken as to which site is responsible for routine post-approval stability study • Site Management/Quality must be immediately informed in case of result failure : OOS/OOT.

26. General Points To Consider – Storage Facility Control and Maintenance (2) • Use Robust systems where possible, for example continuous power supply : back-up generator, alarm, back-up climatic chambers • Prior to use, Storage Facilities mapped for temperature & humidity with typical load pattern. Re-map when significant changes to area or controls • Storage Facilities calibrated regularly : temperature and humidity • Procedures to continuously monitor temperature and humidity • What actions in event of storage condition failure ? • Record failures : Review and assess by senior stability person • Deviations must be documented and require investigation(s) • Keep Durable Records of storage conditions • Archive 1 year minimum beyond expiration date of any products stored.

27. General Points To Consider – Stability Protocol (3) • Each approved protocol must contain : • Purpose: objective of study • Specifications: tests and associated acceptance limits/criteria • Storage Conditions/Test Schedules: correlate condition with test interval and test performed at that interval • Sample Requirements: number of samples for each time point and for the study as a whole • Follow regulatory and product license requirements • Approved protocols are binding • Changes are discouraged - if necessary through approved change control procedure • Use stability indicating methods, in case of method change: new method must be validated, and approved. Analytical results from new methods should be proven through comparison to previous results.

28. General Points To Consider – Stability Protocol (4) • Studies conducted on samples manufactured at the site; in the event manufacturing, packaging or distribution performed at different sites >> decision must be taken which site is responsible for follow-up stability testing • Studies on at least one lot per year • High volume products (e.g. >50 batches per year) requires studies on more than one batch per year • All marketed products included in a stability program: strength/packaging.

29. General Points To Consider – Stability Protocol (5) • Not every primary packaging presentation but the most sensitive/vulnerable • The use of « Bracketing » and/or « Matrixing» permitted but must be justified • Consideration must be given to storage conditions between the time the sample is taken and the analysis is performed: minimise degradation process • Bulk storage, holding-times, time out of refrigeration or freezing, storage of intermediates, in-use and transportation stability, as appropriate must be studied.

30. General Points To Consider – Stability Protocol (6) • For initiation of stability study (T0) after date of manufacturing: within 3 months • For withdraw from storage : between 2 weeks of planned time point and at the same time samples must be retrieved just prior to analysis. If time point not met, samples kept in climatic chambers and report bears actual retrieval and testing dates • For finishing analysis after having retrieved samples : within 30 calendars days (unless test duration is > 30 days), if additional time is required, the original retrieved samples must be stored at conditions that minimise the degradation process.

31. General Points To Consider – Criteria's to be Monitored (7) • Change in Colour, Appearance of Product/Package (including labelling) • Potency and Purity at each time point – Impurity Profile / Degradation impurities: Any new observed impurities ?* • Pharmaceutical Properties, some examples : • Disintegration/Dissolution for solids • Dose Delivery/Unit Spray Content for Aerosols *Refer to ICH NFG: Q3 A(R) • Impurities in New Drug Substances (August 2002) = CPMP/ICH/2737/99; Q3 B ( R ) • Impurities in New Drug Products (August 2003) = CPMP/ICH/2738/99 and European Pharmacopoeia Monograph: “Substances for Pharmaceutical Use” 01/2005

32. General Points To Consider – Criteria's to be Monitored (8) • Microbial contamination • Parenterals : Sterility test, Pyrogens, Endotoxins (tested at least at expiry date) • Products normally stored upright • consider additional orientations, for example change to container/closure • Photo-stability & Freeze-Thaw studies. These are usually not performed for Follow-up or after variations Note: Programs conducted in Final Market Primary Package for DP, API or Bulk DP sold in large drums may be placed in smaller/equivalent containers for stability studies, based on a justified rational.

33. General Points To Consider – Contract Laboratories and Transfers (9) • Satisfactory audit prior to any start of testing • Analytical procedure (method) transfer successfully concluded • In case of production transfer, routine post marketing stability testing transferred to receiving site • Stability program must be established as part of product transfer process • If manufacture is in the situation of terminating, stability program must be continued to end of shelf life • If a solid dosage form is produced at one site and packaged at another, stability program may be reduced at one site if stability is not critical and packaging materials and processes are equivalent.

34. General Points To Consider – Data Review and Reporting (10) • Quality management must review stability results at least annually • Trend analysis of data must be undertaken. Trends that would predict a failure for product/medical device to meet shelf life specifications is to be managed through a quality alert reporting procedure • OOS and OOT must be investigated according to the corresponding procedure • In case of a confirmed OOS, local requirements must be considered for reporting to regulatory authorities.

35. General Points To Consider – Data Review and Reporting (11) • All results presented in stability reports • Must be approved by senior stability personnel • Suitable quality for submission to regulatory authorities • Issued at each significant milestone of study • Contain conclusions and shelf-life recommendation • Based upon full review of data and statistical analysis, as appropriate. • See Guidance from ICH Q1E (Evaluation of Stability Data) • Several statistical treatments possible - not specified here • End with Stability Report Design

36. Example Stability Report Format (1) • I Cover & Approvals signatures • IIIntroduction Purpose of study, products, packages, site and any other information • IIIReferences Protocol number, approval date and indication as to whether the protocol is included in the corresponding (A)NDA. • IVResults should be tabulated by lot/study • VAnalysis A. Statistical Analysis Regression Analysis (with tests for similarity of slopes by strength, package and lot), as appropriate any other Analysis. B. Protocol Deviations* *Note: all deviations from the protocol or acceptance criteria must provide justification for accepting the deviation or out of specification result where applicable.

37. Example Stability Report Format (2) • VIConclusions, Study meets/fails acceptance criteria, references to other supportive data/studies • VII Recommendations, Study support and expiration date (of xx months) and any other Recommendations.

38. Example Stability Report Format (2) • VIConclusions, Study meets/fails acceptance criteria, references to other supportive data/studies • VII Recommendations, Study support and expiration date (of xx months) and any other Recommendations.

39. Long Term Stability Storage Conditions (1) • Storage conditions • Zone I 25°C +/- 2°C / 45% RH +/- 5% RH • Zone II 25°C +/- 2°C / 60% RH +/- 5% RH • Zone III 30°C +/- 2°C / 35% RH +/- 5% RH • Zone IVa 30°C +/- 2°C / 65% RH +/- 5% RH • Zone IVb 30°C +/-2°C / 75% RH +/- 5% RH • Temperature sensitive products (intended for storage in a refrigerator) 5°C +/- 3°C • Temperature sensitive products (intended for storage in a freezer) - 20 °C +/- 5°C • Products in semi permeable containers 25 °C +/- 2 °C / 40 % RH +/- 5 % RH or 30 ° C +/- 2 °C / 35 % RH +/- 5 % RH

40. Long Term Stability Storage Conditions (2) • Relaxing measures: • To keep the number of storage chambers for the respective manufacturing site at a minimum necessary, studies planned for Zone I might also be performed at Zone II conditions (25 °C +/- 2 °C /60 % RH +/- 5 % RH) • For products in impermeable containers, relative humidity is not a relevant parameter.

41. Long Term Stability Storage Conditions – Post Variation Studies (3) • Accelerated Storage Conditions • + 40° C ± 2ºC/ 75% RH ± 5 % RH • For products intended for storage in a refrigerator: 25°C +/- 2°C / 60 % RH +/- 5 % RH • For products packaged in semi-permeable containers: 40 °C +/- 2 °C RH max 25 % • See next slide for summary table on routine stability monitoring and sampling and testing requirements for qualifying changes.

43. Table A – Sampling and Testing Frequency = release or shelf life specification X= mandatory time point with reduced risk based testing permitted = optional additional time point depending on earlier time point stability results

44. Table B – Sampling and Testing Frequency = release or shelf life specification X= mandatory time point with reduced risk based testing permitted = optional additional time point depending on earlier time point stability results

45. Conclusion – Stability Studies (1) • If a risk-based approach to stability is followed during development, then the stability characteristics of an API and drug product would be properly understood and mapped • Although the resource and cost requirements of this approach may be greater initially, it should ensure that product failures due to unexpected stability results are avoided further in the product life cycle. • Adopting a science and risk-based approach, combined with an accelerated predictive model leads to >>Less routine, non value added studies during development and commercial phases • Facilitates in the continuous improvement of processes without the need to wait for unnecessary long-term data before changes could be implemented.

46. Thank You Any Questions