OVER VIEW OF STABILITY STUDIES IN

PHARMACEUTICALS INDUSTRYBy: PRABAKARAN.A

STABILITY DEFINATION

Ability of a substance to remain unchanged over time under stated or reasonably expected conditions of storage and use. Usually the conditions that may cause instability (such as humidity, shock, or temperature) are identified.

1.To provide evidence on the quality of a drug substance or drug product

2. To Define shelf life of the product

3. Permits the establishment of recommended pack, storage condition, retest periods and shelf life.

4. Development of the product.

5. Registration of application.

6. To extend current shelf life.

PURPOSE OF STABILITY TESTING

ICH – QUALITY GUIDELINES

Q1A 1993Guideline No. Year of Publication

Q1A(R2) Feb. 2003

Q1A(R) Nov. 2000

ICH – QUALITY GUIDELINES – PROGRESSIVE CHANGES

Q1A(R)Q1A Q1A(R2)

Testing Frequency

Long Term

Intermediate

Accelerated

0, 3, 6, 9, 12,18, 24, … .months

0, 3, 6, 9 & 12 months

0, 1, 2, 3 & 6 months

0, 3, 6, 9, 12,18, 24, … .months

0, 3, 6, 9 & 12 months

0, 3 & 6 months

0, 3, 6, 9, 12,18, 24, … .months

0, 3, 6, 9 & 12 months

0, 3 & 6 months

CHANGE

5 point study to 3 point study

ICH – QUALITY GUIDELINES – PROGRESSIVE CHANGES

Q1A Q1A(R) Q1A(R2)

Stability StorageCondition

Long Term 25 20C / 60 5% RH

25 20C / 60 5% RH

25 20C/ 60 5% RHor 30 20C/65 5% RH

(Decision is left to the applicant)

CHANGE

Intermediate

Accelerated

30 20C / 60 5% RH

40 20C / 75 5% RH

30 20C / 60 5% RH

40 20C / 75 5% RH

30 20C / 65 5% RH

40 20C / 75 5% RH

CHANGE

EVALUATION OF STABILITY DATA TO ESTABLISHSHELF LIFE - For Drug Products

RE-TEST DATE - For Drug Substances

If accelerated stability data for 6 months is OK.

Accelerated (6months)

x y

Accelerated (6months)Accelerated (6months)

Long Term (9 months OK)

y = 2xShelf life / re-test date is 18 months

Long Term (12 months OK)

y = 2xShelf life / re-test date is 24 months

Accelerated (6months)

Accelerated (6months)

Long Term (18 months OK)

Long Term (24 months OK)

y = x + 12Shelf life / re-test date is 30 months

y = x + 12Shelf life / re-test date is 36 months

y = xNo extrapolation beyond 36 months

Long Term (36 months OK)

EVALUATION OF STABILITY DATA TO ESTABLISHSHELF LIFE - For Drug Products

RE-TEST DATE - For Drug Substances

If accelerated stability data for 6 months is NOT OK.

Accelerated (6months)

x Y

Intermediate 12 months OK

y = 1.5xShelf life / re-test date is 18 months

Accelerated (6months)

Intermediate 9 months OK

y = 1.5xShelf life / re-test date is 13.5 months

Accelerated (6months)

Intermediate 9 months NOT OK

& if long term 9 months OK

y = x + 3Shelf life / re-test date is 12 months

LABLELING CONSIDERATION FORDRUG PRODUCTS & DRUG SUBSTANCES

25 20C / 60 5% RH (LT)30 20C / 60 5% RH (Acc)

Testing conditions where stability has been shown Required label Additional label*, where

relevant

25 20C / 60 5% RH (LT)40 20C / 75 5% RH (Acc) No labeling to be used. Do not refrigerate or

freeze.

Do not store above 30 0C.

Do not refrigerate or freeze.

25 20C / 60 5% RH (LT)

5 30C (lt)

Below zero

Store at 2 0C –8 0C.

Store in a freezer **

Do not freeze.

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●The ICH Q1 topic on stability testing is covered by 5 separate guidelines● The ICH Q1 series of guidelines are designed for stability programs

Q1 guidelines

• Stability Testing of New Drug Substances and Products (the parent guideline)

ICH Q1A(R2)

• Photostability Testing of New Drug Substances and Products ICH Q1B

• Stability Testing of dosage forms ICH Q1C

• Bracketing and matrixing Design for stability testing of new drug substance and products

ICH Q1D

• Evaluation of stability Data ICH Q1E

• Stability data package for registration applications in climatic zones III and IV

ICHQ1F

Definitions: Stability

USP defines the stability of a pharmaceutical product as “ extent to which a product retains , with in specified limits, and throughout its period of storage and use i.e. its shelf life, the same properties and characteristics that it possessed at the time of its manufacture”. Stability is used to determine●Quality of a drug substance or drug product ● Shelf life for the drug product ● Recommended storage conditions

Definitions cont.……● Formal stability studies: Long term and accelerated studies undertaken on commitment batches according to a prescribed stability protocol to conform re-test period of drug substance or shelf life of drug product.● Accelerated testing: Studies designed to increase the rate of chemical degradation or physical change of a drug substance or a drug product as a part of formal stability studies. ● Intermediate testing: Studies conducted at 30°C/65% RH and designed to moderately increase the rate of chemical degradation or physical changes for a drug substances or drug products.●Re-test period: the period of time during which the samples of drug substance is expected to remain within its specification and can be used in the manufacture of a given product.●Shelf life: The time period during which a drug product is expected to remain within the approved shelf life specification, provided it is stored under the conditions defined on the container label.●Climatic zones: The 4 zones in the world that are distinguished by their characteristic prevalent annual climatic conditions.

Climatic zones

Zone I: Temperate climate(21oC/45% RH)

Zone II: Subtropical and Mediterranean climate (25oC/60%

RH)

Zone III: Hot and dry climate

(30oC/35% RH)

Zone IVA: Hot and humid climate

(30oC/65% RH)Zone IVB: Hot and very humid climate

(30oC/75% RH)

Definitions cont.….Significant change:Where “Significant change" occurs during accelerated testing, additional testing at an intermediate condition e.g. 30º ± 2ºC and 65% ± 5 % RH shall be conducted for a period of 12months. “Significant change” at the accelerated condition is defined as:

● A 5% change in assay from its initial value or failure to meet the acceptance criteria for potency when using biological or immunological procedures.● Any degradation product’s exceeding its acceptance criteria.● Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g. dose delivery per actuation). ●Failure to meet the acceptance criterion for pH.● Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Guidelines for drug substance and drug product

Drug substance Drug productStress testing PhotostabilitySelection of batches Selection of batchesContainer closure system

Container closure system

Testing frequency Testing frequencyStorage condition Storage conditionStability commitment Stability commitmentEvaluation EvaluationStatement and labelling Statement and labelling

Drug substance

Drug Substances: stress testing

●To identify potential degradants of the API which helps establish the degradation pathways and intrinsic stability of the molecule.

● To validate the stability indicating power of the analytical procedures.

● To identify stability-affecting factors such as ambient temperature, humidity and light and to select packing materials, which protect the drug product against such effects.

● Stress testing (forced degradation) is usually carried on a single batch

Stress testing conditions

Degradation factor ConditionsThermal 10 oC increment from

accelerated conditionHumidity ≥ 75% RH

Acid 0.1N HClBase 0.1N NaOH

Oxidative Oxygen gas, or 3% H2O2

Photolytic As per ICH Q1B

Selection of batches and container closure system for drug substances

●Formal stability studies to be carried out on at least 3 primary batches.(Primary batch is a batch of drug substance or a drug product used in formal stability studies from which data will be submitted in registration of application).● Stability studies should be conducted on drug substance packaged in a container closure system that is same or simulates packaging proposed for storage and distribution.

Specification for drug substances

●Specification is a list of test, references to analytical procedures and proposed acceptance criteria addressed in ICH Q6A and Q6B. ● Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. The attributes should include:

♦ physical aspect♦ chemical aspect♦ biological aspect♦ microbiological aspect

Testing frequency for drug substance

Storage conditions Months

3 6 9 12 18 24 36Long term storage condition

+ + + + + + +

Accelerated storage condition

+ +

Intermediate storage condition

- + + + + + +

Storage condition: drug substances (general case)

Study

Storage condition

Minimum time period covered by data at submission

Long term 25°C ± 2°C / 60% ± 5% RH or30°C ± 2°C / 65% ± 5% RH

12 months

Intermediate 30°C ± 2°C / 65% ± 5% RH

6 months

Accelerated 40°C ± 2°C / 75% ± 5% RH

6 months

Drug substances intended for storage in a refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C / 60% ± 5% RH

6 months

Study Storage condition Minimum time period covered by data at submission

Long term -20°C ± 5°C 12 months

Drug substances intended for storage in a freezer

Drug substances intended for storage below - 20°CIt is treated on case -by- case basis.

Stability commitment

●If the submission includes data from at least 3 batches a commitment is made to continue these studies through the proposed re test period.● If the submission includes data from on fewer than 3 batches a commitment is made to continue these studies and place additional batches to a total of at least 3 on long term stability studies through the proposed re test period. ● If the submission does not include data from on any batches a commitment is made to place first 3 batches on long term stability studies through the proposed re-test period.

Statements/labelling for drug substances

● Labelling is done in accordance with relevant national/regional requirements.● Wherever applicable specific instructions should be provided particularly for drug substances that cannot tolerate freezing.● “Ambient conditions/room temperature” terminology to be avoided.

Drug product

Photostability testing for drug product

● It should be conducted on at least 1 primary batch.

● The standard conditions for photostability testing are as described in

ICH Q1B.

Selection of batches and container closure system for drug product

● Formal stability studies to be carried out on at least 3 primary

batches, 2of the 3 batches should be at least pilot scale batches and

the third can be a smaller one.

● Stability studies should be conducted on drug product packaged in

a container closure system that is same or simulates packaging

proposed for marketing.

Specification for drug product

● Specification is a list of test, references to analytical procedures and

proposed acceptance criteria addressed in ICH Q6A and Q6B.

● Stability studies should include testing of those attributes of the

FPP that are susceptible to change during storage and are likely to

influence quality, safety and/or efficacy. Some attributes are as follows:

♦ physical

♦ chemical

♦ microbiological

♦ functionality test

Testing frequency of drug product

Storage conditions Months

3 6 9 12 18 24 36

Long term storage condition + + + + + + +

Accelerated storage condition + +

Intermediate storage condition - + + + + + +

Storage condition: drug products (general case)

Study

Storage condition

Minimum time period covered by data at submission

Long term 25°C ± 2°C / 60% ± 5% RH or30°C ± 2°C / 65% ± 5% RH

12 months

Intermediate 30°C ± 2°C / 65% ± 5% RH

6 months

Accelerated 40°C ± 2°C / 75% ± 5% RH

6 months

Drug product packed in impermeable containers● For such cases sensitivity to moisture or potential for solvent loss is not a concern hence stability studies for such products can be carried out under controlled or ambient humidity condition.

Drug products packed in semipermeable containersStudy Storage

conditionMinimum time period covered by data at submission

Long term 25°C ± 2°C / 40% ± 5% RH or30°C ± 2°C / 35% ± 5% RH

12 months

Intermediate 30°C ± 2°C / 65% ± 5% RH

6 months

Accelerated 40°C ± 2°C / NMT 25% RH

6 months

Drug product intended for storage in a refrigerator

Study Storage condition Minimum time period covered by data at submission

Long term 5°C ± 3°C 12 months

Accelerated 25°C ± 2°C / 60% ± 5% RH

6 months

Study Storage condition Minimum time period covered by data at submission

Long term -20°C ± 5°C 12 months

Drug product intended for storage in a freezer

Drug substances intended for storage below - 20°C It is treated on case -by- case basis.

Stability commitment

●If the submission includes data from at least 3 batches a commitment is made to continue these studies through the proposed re test period and accelerated studies for 6 months.● If the submission includes data from on fewer than 3 batches a commitment is made to continue these studies and place additional batches to a total of at least 3 batches on long term stability studies through the proposed re test period and accelerated studies for 6 months. ● If the submission does not include data from on batches a commitment is made place first 3 on long term stability studies through the proposed re test period and accelerated studies for 6 months.

Evaluation of data of drug substances and drug product

Best case ●Tabulate and plot stability data on all attributes at all

storage conditions and evaluate each attribute separately.

● No significant change at accelerated conditions within six (6) months.

● Long-term data show little or no variability and little or no change over time. Accelerated data show little or no variability and little or no change over time.

Evaluation of data of drug substances and drug product

● Statistical analysis is normally unnecessary and providing a justification for the omission should be sufficient

Data showing variability

● A formal statistical analysis is done. ● In case the batch to batch variability is less it is advantageous to combine the data into an overall estimate.

● Limited extrapolation of real time stability data is done but should always be verified by additional long-term stability data.

Statements/labelling for drug products

● Labelling is done in accordance with relevant national/regional requirements.● Wherever applicable specific instructions should be provided particularly for drug substances/products that cannot tolerate freezing.● “Ambient conditions/room temperature” terminology to be avoided.● An expiration date should be displayed on the container label.

Thank you!