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VICH Guidelines: Stability Testing of New Veterinary Drug Substances and Medicinal Products

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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 ... – PowerPoint PPT presentation

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Title: VICH Guidelines: Stability Testing of New Veterinary Drug Substances and Medicinal Products


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 ApplicationQuality 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 ApplicationQuality 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

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 ICHs 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 GL3s 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/biologi
    cal 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 TestingDrug 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, gt accelerated
    conditions)
  • Humidity (e.g., 75), as applicable
  • Oxidation
  • Photolysis (see VICH GL5)
  • Hydrolysis over a wide range of pH

13
GL3(R) Stability TestingDrug 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 TestingDrug 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 TestingDrug 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 TestingDrug 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 TestingDrug 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 TestingDrug Substance
  • Testing frequency and storage conditions
  • General case

Study Storage condition Minimum time period covered by data at submission
Long term 25C 2C/60 RH 5 RH or 30C 2C/65 RH 5 RH 12 months
Intermediate 30C 2C/65 RH 5 RH 6 months
Accelerated 40C 2C/75 RH 5 RH 6 months
19
GL3(R) Stability TestingDrug Substance
  • Testing frequency and storage conditions
  • Refrigerated storage

Study Storage condition Minimum time period covered by data at submission
Long term 5C 3C 12 months
Accelerated 25C 2C/60 RH 5 RH 6 months
20
GL3(R) Stability TestingDrug Substance
  • Testing frequency and storage conditions
  • Storage in a freezer

Study Storage condition Minimum time period covered by data at submission
Long term -20C 5C 12 months
21
GL3(R) Stability TestingDrug 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 TestingDrug 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 TestingDrug 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 TestingMedicinal 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 TestingMedicinal 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 TestingMedicinal 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 TestingMedicinal 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 TestingMedicinal 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 lt51gt
  • Preservative effectiveness (in addition to
    preservative content) at the proposed shelf life
    should also be conducted for verification
    purposes, regardless.

29
GL3(R) Stability TestingMedicinal 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 TestingMedicinal Product
  • General case

Study Storage condition Minimum time period covered by data at submission
Long-term 25C 2C/60 RH 5 RH or 30C 2C/65 RH 5 RH 6 months
Intermediate 30C 2C/65 RH 5 RH 6 months
Accelerated 40C 2C/75 RH 5 RH 6 months
31
GL3(R) Stability TestingMedicinal 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 TestingMedicinal 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 TestingMedicinal 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 GL51Statistical 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 GL51Statistical 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/Bi
    ological 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/Biolo
    gical Veterinary Medicinal Products

37
Questions?Thank Youmai.huynh_at_fda.hhs.gov
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