1. VICH Guidelines: Stability Testing of New Veterinary Drug Substances and Medicinal Products Mai Huynh U.S. FDA Center for Veterinary Medicine Washington D.C, February 20, 2013

2. Content Overview of Quality Section Stability Guidelines: general overview of currently available VICH guidelines Overview of GL3 Drug Substance Information Drug Product Information Overview of GL51 (new)

3. New Animal Drug Application Quality Section Information to be included in the Quality Section (for US registration): – Components and Composition – Facilities/Equipment – New Drug Substance – Raw Materials Controls – Manufacturing Operations

4. New Animal Drug Application Quality Section – Information to be included in the Quality Section:(for US registration): Analytical Controls* Analytical Controls* Container/Closure System Stability* Stability* Sterile Process Validation GMP status of the facility – 21 CFR 514, 21 CFR 211 * VICH Guidelines are available

5. VICH Stability Guidelines Currently available and posted on the CVM website: VICH GL3 (R) – Stability Testing of New Veterinary Drug Substances and Medicinal Products: November 2007 VICH GL4- Stability Testing of New Veterinary Dosage Forms: May 1999 VICH GL5 – Stability Testing – Photostability Testing of New Veterinary Drug Substances and Medicinal Products: May 1999

6. VICH Stability Guidelines (cont.) VICH GL8 – Harmonization of Technical Requirements for Approval of Veterinary Medicinal Products on Stability for Medicated Premixes: March 2000 VICH GL17 – Stability Testing of New Biotechnological/Biological Products: March 2002 VICH GL51: Statistical Evaluation of Stability Data: – Draft published for public comment: April 2012 – Reach Step 6 (?)- VICH meeting February 2013

7. VICH Stability Guidelines (cont.) Why stability? – The purpose of stability testing is to provide evidence on how the quality of a drug substance or medicinal product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the medicinal product and recommended storage conditions.

8. Background – VICH GL3 (R) – Stability Testing of New Veterinary Drug Substances and Medicinal Products: – GL3: Stability Testing of New Veterinary Drug Substances and Medicinal Products (original VICH implementation date, May 2000) – GL3 based on ICH’s Q1A – ICH Q1A revised several times to ICH Q1A(R2): (last revision implemented 2003) – Revision of GL3, i.e., GL3(R), based on ICH Q1A(R2): (last revision implemented 2007)

9. Background (continued) GL3(R) Scope: Similar to GL3’s Scope -Addresses new molecular entities and associated drug products -Does not address abbreviated or abridged applications, variations, or clinical trial applications -References GL4, GL8 and GL17 for further stability guidance on new dosage forms, medicated premixes, and biotechnological/biological products, respectively.

10. GL3(R) : Stability Testing 1. Drug Substance 2. Medicinal Product

11. GL3(R) : Stability Testing 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.

12. GL3(R) : Stability Testing Drug Substance Stress Testing: – Help identify the likely degradation products – Can be carried out on a single batch – Include effects of: Temperature (e.g., 60 0 C, > accelerated conditions) Humidity (e.g., 75%), as applicable Oxidation Photolysis (see VICH GL5) Hydrolysis over a wide range of pH

13. GL3(R) : Stability Testing Drug Substance Selection of batches: – Data from at least 3 primary batches – Batch size = minimum pilot batch size (10% of production scale) – Manufacturing process/equipment should be the same or equivalent

14. GL3(R) : Stability Testing Drug Substance Container/closure system: – Stability batches should be packaged in the same container/closure as proposed for the marketed product – Stability batches should be stored under the same conditions as proposed on the labels

15. GL3(R) : Stability Testing Drug Substance Specifications: – More specific information: VICH GL39, 40, &10(R) – GL10 Impurities in New Veterinary Drug Substances – GL39 Specifications: Test Procedures and Acceptance Criteria for New Veterinary Drug Substances and New Medicinal Products: Chemical Substances – GL40 Test Procedures and Acceptance Criteria for New Biotechnological/Biological Medicinal Products

16. GL3(R) : Stability Testing Drug Substance – Specifications (continued): Testing should cover, as appropriate: – Physical – Chemical – Biological and – Microbiological attributes Testing should be done using stability- indicating methods

17. GL3(R) : Stability Testing Drug Substance Testing frequency and storage conditions: – Elaboration on use of intermediate storage conditions. – Relative humidity at Intermediate storage condition changed from 60% RH to 65% RH. – Storage conditions in refrigerator, freezer and below -20 ◦ C.

18. GL3(R) : Stability Testing Drug Substance Testing frequency and storage conditions: 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 12 months Intermediate**30°C ± 2°C/65% RH ± 5% RH6 months Accelerated40°C ± 2°C/75% RH ± 5% RH6 months

19. GL3(R) : Stability Testing Drug Substance Testing frequency and storage conditions: Refrigerated storage: StudyStorage conditionMinimum time period covered by data at submission Long term5°C ± 3°C12 months Accelerated25°C ± 2°C/60% RH ± 5% RH6 months

20. GL3(R) : Stability Testing Drug Substance Testing frequency and storage conditions: Storage in a freezer: StudyStorage conditionMinimum time period covered by data at submission Long term-20°C ± 5°C12 months

21. GL3(R) : Stability Testing Drug Substance Stability commitment: – Commitment for reporting long-term stability data on primary batches that did not cover the re-test period at the time of approval. – Commitment to place or continue reporting stability data on at least three production batches on long-term post approval stability studies through the re-test period.

22. GL3(R) : Stability Testing Drug Substance Evaluation: – Should not be limited to just assay; other quality attributes should also be considered – May use some statistical analysis to evaluate the variation over time - VICH GL 51 (new) Extrapolation of real time data to predict expiry or retest date can be proposed

23. GL3(R) : Stability Testing Drug Substance Statements/Labeling: – Information should be in accordance with relevant regional/national requirements – In the US, guideline for definition of storage conditions can be found in the United Sates Pharmacopeia – Re-test period should be on the label, as appropriate – Avoid using terms such as “room temperature” or “ambient conditions”

24. GL3(R) : Stability Testing Medicinal Product In general, information is similar to Drug Substance Presentation will focus on areas where additional information is to be considered: – Selection of batches – Specifications (e.g. preservative) – Storage conditions (e.g., in use study, minimum data, excursion) – Evaluation: expansion on “significant change”

25. GL3(R) : Stability Testing Medicinal Product Presentation will focus on areas where additional information is to be considered: – Containers (impermeable vs. semi-permeable) – Stability Commitment – Labeling

26. GL3(R) : Stability Testing Medicinal Product Selection of batches: – 3 batches (2 at least at pilot scale) – Studies should be conducted: On each strength (e.g. 10 mg tablet vs. 200 mg tablet)and container size (unless otherwise justified) On each container size (50 mL, 100 mL, 500 mL) unless otherwise justified

27. GL3(R) : Stability Testing Medicinal Product Specifications: – More specific information: VICH GL39, 40, &11(R) – Testing should cover: Physical, chemical, biological, and microbiological attributes Preservative content Functional tests (dose delivery system) – Shelf life specifications can be different than release specifications (difference should be justified) – Analytical methods should be stability indicating

28. GL3(R) : Stability Testing Medicinal Product Specifications (continued): – Example: Difference in shelf life vs. release: Preservative content: – Release= 90 – 100 % label claim – Shelf life = 80 – 100% label claim » 80% is permitted if data are available to demonstrate that when product is formulated with 80% content of the preservative, it meets preservative effectiveness testing: e.g. USP – Preservative effectiveness (in addition to preservative content) at the proposed shelf life should also be conducted for verification purposes, regardless.

29. GL3(R) : Stability Testing Medicinal Product Specifications (continued): – Testing frequency & Storage conditions: – In general, length of studies and storage conditions should be sufficient to cover storage, shipment, and subsequent use Special consideration: if the product is to be constituted or diluted at the time of use – Stability of the product is also to be determined for in- use period of the constituted or diluted product Stability testing following first use of the product (e.g., first broaching of a vial) is not covered within this guidance.

30. 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

31. GL3(R) : Stability Testing Medicinal Product Evaluation: – Should not be limited to just assay; other quality attributes should also be considered – May use some statistical analysis to evaluate the variation over time - VICH GL 51 (new) Extrapolation of real time data to predict expiry or retest date can be proposed – Elaborate on definition of “significant change”: For example, a 5% in assay from its initial value is considered significant

32. GL3(R) : Stability Testing Medicinal Product Stability commitment: – Information for drug product is similar to drug substance except reference to expiry in lieu of re-test – Commitment is not needed if stability data from production batches are available through expiry at the time of approval: Example: Product may have been approved in the EU – Stability data from production batches can be submitted in US application

33. GL3(R) : Stability Testing Medicinal Product Statements/Labeling: – Information to be displayed on the container label Storage conditions Expiration date - Both pieces should be supported by stability data provided at the time of registration

34. VICH GL51 Statistical Evaluation of Stability Data Timeline: – Draft guideline: Step 3: Adopted by VICH Steering Committee: November 2011 Step 4: Draft published for public consultation: – November 2011- May 2012 – In the US: April 2012 (comments were submitted by Animal Health Institute) – Non VICH members: Comments were submitted by SwissMedic, Canadian Animal Health Institute, Canadian Food Inspection Agency, Republic of Senegal and Nigeria All comments were considered and discussed among members of QEWG Step 5: sign off by QEWG – January 2013

35. VICH GL51 Statistical Evaluation of Stability Data In general: – Guideline provides further recommendation on the evaluation section of GL3(R) – Statistical evaluation should be done with the help of a statistician – Application of this guideline is entirely “optional” – Principles are similar to ICH Q1E – References to VICH GL39 and GL40: Recommendations on the setting and justification of acceptance criteria – References to VICH GL45: Recommendations of the use of full versus reduced design studies

36. References http://www.fda.gov/RegulatoryInformation/Guidances/ucm122050.htm VICH GL4 Stability Testing of New Veterinary Dosage Forms VICH GL5 Photostability Testing of New Veterinary Drug Substances and Medicinal Products VICH GL8 Stability Testing for Medicated Premixes VICH GL10(R) Impurities in New Veterinary Drug Substances VICH GL11(R) Impurities in New Veterinary Medicinal Products VICH GL17 Stability Testing of Biotechnological/Biological Veterinary Medicinal Products VICH GL39 Specifications: Test Procedures and Acceptance Criteria for New Veterinary Drug Substances and New Medicinal Products: Chemical Substances VICH GL40 Specifications: Test Procedures and Acceptance Criteria for New Biotechnological/Biological Veterinary Medicinal Products

37. Questions? Thank You mai.huynh@fda.hhs.gov