GL3 ( R): Stability Testing of New Veterinary Drug Substances and Medicinal Products

1. VENKATA KUMAR SAHU
DEVELOPMENT PROJECTS-
AH

2. WHAT IS STABILITY?
“the state or quality of being stable” or “continuance without
change; permanence”
- By Dictionary.com
The term “stability,” with respect to a drug dosage form, refers to
the chemical and physical integrity of the dosage unit and,
when appropriate, the ability of the dosage unit to maintain
protection against microbiological contamination.
- By United States Pharmacopoeia
Shelf life
time lapse from initial preparation to the specified expiration date.

3. 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.
Stability Testing is a must for Regulatory submissions for approval of
dosage form.

4. HOW DO YOU DO STABILITY TESTING?
For veterinary products
- GL3 ( R): Stability Testing of New Veterinary Drug Substances and Medicinal
Products
Stability studies on active substances and packaged dosage forms are conducted
by means of “realtime,” longterm tests at specific temperatures and relative
humidities representing storage conditions experienced in the distribution
chain of the climatic zone(s) of the country or region of the world concerned.

5. CLIMATIC ZONES
For convenience in planning for packaging and storage, and for stability studies,
international practice identifies four climatic zones
Classification based on mean kinetic temperatures (MKT) and average
humidity values
India is in IVb zone.

6. STABILITY TESTING – DRUG SUBSTANCE
will discuss following
- Stress Testing
- Selection of Batches
- Container Closure system
- Specifications
- Testing frequency
- Storage conditions
- Stability commitment
- Evaluation
- Statement/Labeling

7. 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

8. 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
- quality of the batches of drug substance placed on formal stability studies
should be representative of the quality of the material to be made on a
production scale

9. 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
- attributes of the drug substance that are susceptible to change during storage
and are likely to influence quality, safety, and/or efficacy.
- physical, chemical, biological, and microbiological attributes.
- Validated stability-indicating analytical procedures must be used.
SPECIFICATIONS

10. TESTING FREQUENCY
- long-term storage condition should normally be every 3 months over the first
year, every 6 months over the second year, and annually thereafter through
the proposed re-test period.
- For 4 year self life testing frequency should be 0, 3, 6, 9, 12, 18, 24, 36, 48
months
- accelerated storage condition, a minimum of three time points, including the
initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study
- When testing at the intermediate storage condition is called for as a result of
significant change at the accelerated storage condition, a minimum of four
time points, including the initial and final time points (e.g., 0, 6, 9, 12 months),
from a 12-month study is recommended.

11. STORAGE CONDITIONS
General case:
Refrigerated storage:

12. STORAGE CONDITIONS (CONT..)
Storage in a freezer:
- In absence of an accelerated storage condition for drug substances intended
to be stored in a freezer, testing on a single batch at an elevated temperature
(e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be
conducted to address the effect of short term excursions outside the
proposed label storage condition, e.g., during shipping or handling

13. 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.
- If submission does not include stability data on production batches, a
commitment to place first three production batches on long term stability.

14. 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
- Any evaluation should cover not only the assay, but also the levels of
degradation products and other appropriate attributes.
STATEMENTS/LABELING
- Information should be in accordance with relevant regional/national
requirements
- Avoid using terms such as “room temperature” or “ambient conditions”

15. STABILITY TESTING – DRUG PRODUCT
Will discuss only subjects different from Drug substance
- Photostability Testing
- Selection of batches
- Specifications (e.g. preservative)
- Storage conditions (e.g., in use study, minimum data,
excursion)
- Evaluation: expansion on “significant change”
- Containers (impermeable vs. semi-permeable)
- Stability Commitment
- Labeling

16. 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

17. SPECIFICATIONS
 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

18. SPECIFICATIONS (CONT..)
 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.

19. SPECIFICATIONS (CONT..)
 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) how ever is not covered within GL3 (R )
guidance.

20. STORAGE CONDITION

21. 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
 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

22. 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
STATEMENTS/LABELING
- Information to be displayed on the container label
Storage conditions
Expiration date (for India, both expiration and manufacturing dates are
required)
Both pieces should be supported by stability data provided at the time
of registration

23. BRACKETING & MATRIXING
 Bracketing
- A design in which only the extremes are tested at all time
points, eg strength, pack size, container fill
 Matrixing
- Designs in which a selected subset of samples is tested, eg
different strengths, container/closure systems, batches

24. EXAMPLE OF A BRACKETING DESIGN
Strength 50mg 75mg 100mg
Batch 1 2 3 1 2 3 1 2 3
Container
size
15ml T T T T T T
100ml
500ml T T T T T T
T = Sample is tested

25. EXAMPLE OF A MATRIXING DESIGN
Time point (months) 0 3 6 9 12 18 24 36
Strength
S1
Batch
1
T T T T T T
Batch
2
T T T T T T
Batch
3
T T T T T
S2
Batch
1
T T T T T
Batch
2
T T T T T T
Batch
3
T T T T T
“One half reduction”

26. THE RISK ASSOCIATED WITH BRACKETING &
MATRIXING
- If the results are not what you expected, you may have
insufficient to propose an intermediate shelf life
- Would be risky to use bracketing & matrixing if you did not
have a good idea as to what the product’s stability will be
- Consequently: Bracketing & matrixing designs are used
mainly for confirmatory studies