Transcript Stability Testing of New Veterinary Drug Substances and Medicinal

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 GL3
• Drug Substance Information
• Drug Product Information
• Overview of GL51 (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 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
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
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 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)
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.
GL3(R) : Stability Testing
1. Drug Substance
2. Medicinal Product
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.
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., 600 C, > accelerated conditions)
Humidity (e.g., 75%), as applicable
Oxidation
Photolysis (see VICH GL5)
Hydrolysis over a wide range of pH
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
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
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
GL3(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
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.
GL3(R) : Stability Testing
Drug Substance
• Testing frequency and storage conditions:
General case:
Study
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
Long term*
GL3(R) : Stability Testing
Drug Substance
• Testing frequency and storage conditions:
Refrigerated storage:
Study
Long term
Accelerated
Minimum time
period covered
by data at
submission
5°C ± 3°C
12 months
25°C ± 2°C/60% RH ± 5% RH 6 months
Storage condition
GL3(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
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.
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
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”
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”
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
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
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
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 <51>
– Preservative effectiveness (in addition to preservative content)
at the proposed shelf life should also be conducted for
verification purposes, regardless.
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 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.
GL3(R) : Stability Testing
Medicinal Product
• General case:
Minimum time
period covered by
data at submission
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
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
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
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
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
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
References
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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
Questions?
Thank You
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