REGULATO

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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