1. VICH Outreach Forum Stability Studies to address climatic zones III and IV Mai Huynh US FDA/Center for Veterinary Medicine October 26-27, 2015

2. US FDA - Center for Veterinary Medicine Protecting both Human and Animal Health 2

3. From the VICH Press Release Published 26 February 2015 – The Steering Committee mandated the Quality Expert Working Group to develop guidance on stability testing in the climatic zones III and IV (based on concept paper submitted by the Task Force)

4. Concept Paper Task Force: Chair: Thérèse Nugent, IFAH - Europe –Other members: JMAFF : T. Ogata US FDA: M. Huynh EU: N. Möller Senasa : A. Desuque South Africa : H. Leng JVPA : H. Yabe Thai FDA : Yaowalak Wattanapisit AHI : Rex Henry Camevet: C.Francia

5. Climate zones Current WHO definition of climatic zones: * conditions covered in current GL3 (R ) Climatic zone DefinitionStorage condition ITemperate climate21°C/45% r.h. II Subtropical and Mediterranean climates 25°C/60% r.h. IIIHot, dry climate30°C/35% r.h. IVAHot, humid climate30°C/65% r.h.* IVBHot and very humid climate 30°C/75% r.h.

6. From VICH GL3 (R) From VICH GL3 (R): –The choice of test conditions defined in this guidance is based on an analysis of the effects of climatic conditions in the three regions of the EU, Japan, and the United States. The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV. This guidance addresses climatic zones I and II.

7. GL3(R) : Stability Testing Medicinal Product General case: StudyStorage conditionMinimum 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 6 months Intermediate**30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated40°C ± 2°C/75% RH ± 5% RH 6 months

8. GL3(R) : Stability Testing Medicinal Product General case: or –*It is up to the applicant to decide whether long-term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH. –**If 30°C ± 2°C/65% RH ± 5% RH is the long- term condition, there is no intermediate condition.

9. Stability Testing If the applicant selects to test the product at: 30°C ± 2°C/65% RH ± 5% RH. Zones IVA (according to WHO guideline) is already covered in the current VICH GL3 (R)

10. Stability Testing What’s left to be considered: –Zone III: 30°C /35% RH - Hot and dry climate –Zones IVB: 30°C /75% RH – Hot and very humid climate

11. Points to consider The majority of active substances are also used for human medicinal products. Their stability is therefore widely tested in accordance with the temperature/humidity conditions used for human medicinal products. There are some veterinary medicinal products which were approved first as human medicinal products. The stability studies for these products will therefore have been carried out under the temperature/humidity conditions used for human medicinal products.

12. Points to consider Testing at elevated temperature and higher humidity conditions may result in shorter expiry –Therefore, it may not be so desirable to conduct testing at conditions for zones III and IV only –Extrapolation among the various conditions may not be found acceptable

13. Points to consider Potential problems with extrapolation (EU, US FDA): –US FDA current thinking: From the concept paper: Extrapolation from storage at higher temperatures (e.g., 30°C) and humidities (e.g., 75% RH) to existing temperatures (e.g., 25°C) and humidities (60% RH) or vice versa: –Not the conditions described in VICH GL51: Statistical Evaluation of Stability Data

14. Points to consider Potential problem with extrapolation (cont.): –Poolability, matrixing, as described in VICH GL51 are based on testing conditions described in VICH GL 3 (R) – see slide 6 Therefore, if extrapolation is to be considered in the new GL, as stipulated in the concept paper, a re-evaluation of VICH GL51 may be needed >>>not a desirable outcome

15. ICH Q1F ICH Q1F was withdrawn: –WHO survey: consensus – adopted and implemented in 2003 in non ICH countries 30 0 C/65% RH: long term storage conditions for climatic zone III/IV countries –Some countries in climatic zone IV: 30 0 C/75% RH; long term storage conditions for hot and humid conditions –ICH Q1F was withdrawn due to the divergence in global stability testing –Defer to WHO for definition of storage conditions in climatic zones III and IV

16. Moving forward Based on survey conducted by the WHO: –Majority of the results: Long term testing conditions: –30 0 C /65% RH –30 0 C/75% RH Selection of the conditions for stability testing is based on a risk analysis.

17. Moving Forward Testing at a more severe long term condition can be an alternative to storage testing at 25 0 C /60% RH or 30 0 C /65% RH, as long as data generated can support the proposed expiry. Caution: Such selection may yield a shorter expiry than the standard testing conditions outlined in GL3 (R) Extrapolation, if considered, should be discussed with regulators prior to implementation

18. Proposed Testing Scheme for climate zone IVA From ICH Q1F: General case: Study Storage condition Minimum time period covered by data at submission Long Term 30 0 C + 2 o C/65% RH + 5% RH 12 months Accelerated 40 0 C + 2 o C/75% RH + 5% RH 6 months

19. Proposed Testing Scheme for climate zone IVB Study Storage condition Minimum time period covered by data at submission Long Term 30 0 C + 2 o C/75% RH + 5% RH 12 months Accelerated40 0 C + 2 o C/75% RH + 5% RH 6 months

20. Proposed Testing Scheme No intermediate storage condition for stability studies is recommended for Climatic Zones III and IV.

21. Proposed Testing Scheme Sections from GL3 (R ) that can be considered common to any country in any of the climatic zones: –Stress testing –Selection of batches –Container/closure –Specification –Testing frequency

22. Proposed Testing Scheme Sections from GL3 (R ) that can be considered common to any country in any of the climatic zones (cont.): Storage conditions for drug substance or product in a refrigerator Storage conditions for drug substance or product in a freezer Stability commitment Evaluation Statement/labeling

23. Questions If we concur on the common sections, they will not be repeated in the new GL: Refer to VICH GL3 (R ) as the parent guideline

24. Questions Will there be a need to revise GL51? –Not necessarily if we do not extrapolate data among various temperatures –Extrapolation may still be applied to the same data sets generated within the same testing scheme

25. Questions Should 80% RH be the testing humidity condition, instead of 75% RH? –For example, solid dosage forms in water- vapor permeable packaging, e.g., tablets in PVC/aluminumm blisters, intended to be marketed in zones IVB? How should studies be designed to account for extremely hot and humid conditions (e.g. during transport)?

26. Questions Should there be a testing scheme developed for climate zone III? –Only 1 country among 203 is identified in the WHO report with stability conditions listed for zone III –Or can zone III adopt the testing scheme outlined for Zone IVA? 26

27. Why do we need stability studies? Data collected from stability testing is used: –To support product expiry –To support label storage conditions Product expiry: VICH GL3 (R) & VICH GL51 Label storage conditions: In the US: US Pharmacopeia: Chapter : Packaging and Storage Requirements659>: Packaging and Storage Requirements

28. Recommended labeling statements Recommended labeling statements for finished pharmaceutical products (FPPs) in the US Testing conditions under which the stability of the FPP has been demonstrated Recommended labeling statements 25 o C/60% RH (long term) 40 o C /75% RH (accelerated) Do not store above 25 o C* 25 o C/60% RH (long term) 30 o C /65% RH (intermediate, failure of accelerated) Do not store above 25 o C* Or Store at 20-25ºC with excursions permitted between 15-30ºC

29. Recommended labeling statements Recommended labeling statements for finished pharmaceutical products (FPPs) in the US Testing conditions under which the stability of the FPP has been demonstrated Recommended labeling statements 30 o C/65% RH (long term) 40 o C /75% RH (accelerated) Store at or below 30  C Or Do not store above 30 o C* Or Stored at controlled room temperature (15 o C - 30 o C), with excursions up to 40 o C 25 o C/60% RH (long term) 30 o C /65% RH (intermediate, failure of accelerated) Do not store above 25 o C* Or Store at 20-25ºC with excursions between 15-30ºC

30. Recommended labeling statements *Statements suggested on slide 28/29 are based on the assumption that the product has been found acceptable under freeze thaw conditions- otherwise additional statement can also be added: –“Do not freeze” –“Do not refrigerate or freeze” Statement such as “Room temperature” or “ambient conditions” is not acceptable (in the US) 30

31. Additional considerations If it cannot be demonstrated that the drug substance or drug product will remain within its acceptance criteria, when stored at the proposed testing scheme for the duration of the proposed retest period or shelf life: –Reduce the retest period or shelf life –Consider a more protective container closure system –Additional cautionary statements in the labeling

32. Additional considerations For products marketed in the US: –US FDA/CVM will accept any testing conditions (i.e. temperature and humidity) proposed by the applicant –Selection of the conditions for stability testing is based on a risk analysis. Testing at a more severe long-term condition can be an alternative to storage testing at 25 o C/60% RH or 30 o C/65% RH 32

33. Timeline 6 months – 1 year for completion of draft 33

34. New members to Quality EWG According to the mandate, the new members from South Africa and VOF countries/regions (China, CAMEVET and Morocco) were nominated as QEWG experts (October 2015)

35. Quality Expert Working Group Chair: JMAFF ORGANISATIONNAME TELEPHONE FAXE-MAIL US FDAM. HUYNH+ 1 240-402-0669 mai.huynh@fda.hhs.gov AHI (BAYER)R. HENRY rex.henry@bayer.com JMAFF T. OGATA (Chair) + 81 423 21 1849+ 81 423 21 1769tomokot@nval.maff.go.jp CANADA VDDJ. BENOLIEL+ 1 613 957 6841+ 1 613 946 4589Joseph.Benoliel@hc-sc.gc.ca EU (BVL) N. MÖLLER (expert) + 49 30 18444 30200 + 49 30 18444 30009 norbert.moeller@bvl.bund.de USDA A. MORGAN (advisor) + 1 301 734 8245+ 1 301 734 4314albert.p.morgan@usda.gov JVPA (Nippon Zenyaku Kogyo Co) A. YOSHITA (expert) + 81 24 945 2361+ 81 24 945 2421yoshita-akihiro@zenoaq.jp ANZ (MPI)W. HUGHES+64 4 8942560+64 4 8942566warren.hughes@mpi.govt.nz Chair: JMAFF

36. Quality Expert Working group IFAH-EU (Merial)Th. NUGENT+1 678 638 3811+1 678 638 3732therese.nugent@merial.com IFAH-EU (Vetoquinol) V. NERON DE SURGY (climatic zone III and IV) +33 3 84 62 55 86 viviane.nerondesurgy@vetoquinol.co m SOUTH AFRICAH. LENG+27 21 855 4159 hmjleng@gmail.com ANZ P. COGHLAN (Advisor - climatic zone III and IV) phil.coghlan@apvma.gov.au CHINA (CIVDC) X. LIANG (climatic zone III and IV) +8610 621 03557+8610 621 03562lxm990@163.com CAMEVET M. AGUIRRE (climatic zone III and IV) milenaaguirre@over.com.ar MOROCCO A. ELGHAFKI (climatic zone III and IV) amina.elghafki@gmail.com

37. References 1. World Health Organization: Who Technical Report, Annex 2: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products 2. VICH GL 3 ( R): Stability of New Veterinary Drug Substances 3. VICH GL 4: Stability of New Veterinary Dosage Forms 4. VICH GL 51: Statistical Evaluation of Stability Data 5. ICH Q1A (R2): Stability Testing of New Drug Substances and Products 6. ICH Q1F: withdrawn 7. US Pharmacopeia 37

38. 38 Questions/Comments/Suggestions? Contact: Mai.Huynh@fda.hhs.gov

39. 39 Thank You