over view of stability studies
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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!
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