VICH Guidelines Stability Testing of New Veterinary Drug

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

Content • Overview of Quality Section • Stability Guidelines: general overview of currently available VICH guidelines • Overview of GL 3 • Drug Substance Information • Drug Product Information • Overview of GL 51 (new)

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

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

VICH Stability Guidelines • Currently available and posted on the CVM website: • VICH GL 3 (R) – Stability Testing of New Veterinary Drug Substances and Medicinal Products: November 2007 • VICH GL 4 - Stability Testing of New Veterinary Dosage Forms: May 1999 • VICH GL 5 – Stability Testing – Photostability Testing of New Veterinary Drug Substances and Medicinal Products: May 1999

VICH Stability Guidelines (cont. ) • VICH GL 8 – Harmonization of Technical Requirements for Approval of Veterinary Medicinal Products on Stability for Medicated Premixes: March 2000 • VICH GL 17 – Stability Testing of New Biotechnological/Biological Products: March 2002 • VICH GL 51: Statistical Evaluation of Stability Data: – Draft published for public comment: April 2012 – Reach Step 6 (? )- VICH meeting February 2013

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.

Background – VICH GL 3 (R) – Stability Testing of New Veterinary Drug Substances and Medicinal Products: – GL 3: Stability Testing of New Veterinary Drug Substances and Medicinal Products (original VICH implementation date, May 2000) – GL 3 based on ICH’s Q 1 A – ICH Q 1 A revised several times to ICH Q 1 A(R 2): (last revision implemented 2003) – Revision of GL 3, i. e. , GL 3(R), based on ICH Q 1 A(R 2): (last revision implemented 2007)

Background (continued) • GL 3(R) Scope: Similar to GL 3’s Scope -Addresses new molecular entities and associated drug products -Does not address abbreviated or abridged applications, variations, or clinical trial applications -References GL 4, GL 8 and GL 17 for further stability guidance on new dosage forms, medicated premixes, and biotechnological/biological products, respectively.

GL 3(R) : Stability Testing 1. Drug Substance 2. Medicinal Product

GL 3(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.

GL 3(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. , 600 C, > accelerated conditions) Humidity (e. g. , 75%), as applicable Oxidation Photolysis (see VICH GL 5) Hydrolysis over a wide range of p. H

GL 3(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

GL 3(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

GL 3(R) : Stability Testing Drug Substance • Specifications: – More specific information: VICH GL 39, 40, &10(R) – GL 10 Impurities in New Veterinary Drug Substances – GL 39 Specifications: Test Procedures and Acceptance Criteria for New Veterinary Drug Substances and New Medicinal Products: Chemical Substances – GL 40 Test Procedures and Acceptance Criteria for New Biotechnological/Biological Medicinal Products

GL 3(R) : Stability Testing Drug Substance – Specifications (continued): • Testing should cover, as appropriate: –Physical –Chemical –Biological and –Microbiological attributes • Testing should be done using stabilityindicating methods

GL 3(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.

GL 3(R) : Stability Testing Drug Substance • Testing frequency and storage conditions: General case: Study Long term* Storage condition Minimum time period covered by data at submission 25°C ± 2°C/60% RH ± 5% RH 12 months or 30°C ± 2°C/65% RH ± 5% RH Intermediate** 30°C ± 2°C/65% RH ± 5% RH 6 months Accelerated 40°C ± 2°C/75% RH ± 5% RH 6 months

GL 3(R) : Stability Testing Drug Substance • Testing frequency and storage conditions: Refrigerated storage: Study Long term Accelerated Storage condition Minimum time period covered by data at submission 5°C ± 3°C 12 months 25°C ± 2°C/60% RH ± 5% RH 6 months

GL 3(R) : Stability Testing Drug Substance • Testing frequency and storage conditions: Storage in a freezer: Study Storage condition Long term -20°C ± 5°C Minimum time period covered by data at submission 12 months

GL 3(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.

GL 3(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

GL 3(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”

GL 3(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”

GL 3(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

GL 3(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 m. L, 100 m. L, 500 m. L) unless otherwise justified

GL 3(R) : Stability Testing Medicinal Product • Specifications: – More specific information: VICH GL 39, 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

GL 3(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 <51> – Preservative effectiveness (in addition to preservative content) at the proposed shelf life should also be conducted for verification purposes, regardless.

GL 3(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 inuse 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.

GL 3(R) : Stability Testing Medicinal Product • General case: Study Storage condition Long-term* 25°C ± 2°C/60% RH 6 months ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH 30°C ± 2°C/65% RH 6 months ± 5% RH 40°C ± 2°C/75% RH 6 months ± 5% RH Intermediate** Accelerated Minimum time period covered by data at submission

GL 3(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

GL 3(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

GL 3(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

VICH GL 51 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 Swiss. Medic, 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

VICH GL 51 Statistical Evaluation of Stability Data • In general: – Guideline provides further recommendation on the evaluation section of GL 3(R) – Statistical evaluation should be done with the help of a statistician – Application of this guideline is entirely “optional” – Principles are similar to ICH Q 1 E – References to VICH GL 39 and GL 40: • Recommendations on the setting and justification of acceptance criteria – References to VICH GL 45: • Recommendations of the use of full versus reduced design studies

References • • • http: //www. fda. gov/Regulatory. Information/Guidances/ucm 122050. htm VICH GL 4 Stability Testing of New Veterinary Dosage Forms VICH GL 5 Photostability Testing of New Veterinary Drug Substances and Medicinal Products VICH GL 8 Stability Testing for Medicated Premixes VICH GL 10(R) Impurities in New Veterinary Drug Substances VICH GL 11(R) Impurities in New Veterinary Medicinal Products VICH GL 17 Stability Testing of Biotechnological/Biological Veterinary Medicinal Products VICH GL 39 Specifications: Test Procedures and Acceptance Criteria for New Veterinary Drug Substances and New Medicinal Products: Chemical Substances VICH GL 40 Specifications: Test Procedures and Acceptance Criteria for New Biotechnological/Biological Veterinary Medicinal Products

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