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REGULATO
RY STA
BILITY
TESTI
NG
VI C
H R
EQ
UI R
ME
NT
S
VENKATA KUMAR SAHUDEVELOPMENT PROJECTS-AH
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.
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.
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.
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.
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
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
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
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
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.
STORAGE CONDITIONS
General case:
Refrigerated storage:
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
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.
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”
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
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
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
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.
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.
STORAGE CONDITION
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
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
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
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
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”
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
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