Stability Testing for FPPs

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Questions and Answers

What aspect should be reported for sterile products at the beginning and end of shelf-life?

Sub-visible particulate matter

Sterility (correct)

Bacterial endotoxins

Weight loss from containers

How frequently should sub-visible particulate matter be reported for parenteral products?

At every test interval

Frequently, but not necessarily at every test interval (correct)

Only at the initial test interval

Once a year

Which factor may need to be included in a protocol for storage of certain products?

Light exposure

Orientation of the product (correct)

Size of the container

Temperature variation

What is required for photostability studies according to ICHQ1B?

Testing on at least one primary batch of the FPP Signup and view all the answers

What type of study is important if a drug product is susceptible to temperature fluctuations?

Freeze/thaw study Signup and view all the answers

What is the main purpose of stability testing for APIs and FPPs?

To provide evidence of quality variation over time due to environmental factors Signup and view all the answers

Which of the following is NOT a basic data requirement for FPP stability studies?

Stability studies on only the main strength of the FPP Signup and view all the answers

Under what condition can photostability tests be omitted?

If ‘protect from light’ is stated and the container is light-protective Signup and view all the answers

What is the minimum data requirement for long-term stability studies at registration?

12 months of testing under 30 °C ± 2 °C/65% RH ± 5% RH Signup and view all the answers

What is the minimum duration required for accelerated stability studies at registration?

6 months Signup and view all the answers

Which statement about photostability testing is true?

It should be conducted on at least one primary batch if appropriate Signup and view all the answers

Which environmental factor is NOT typically assessed during stability testing?

Atmospheric pressure Signup and view all the answers

What is the recommended approach when dealing with different strengths of an FPP?

Test each strength individually, unless using bracketing or matrixing Signup and view all the answers

What is the minimum time period covered by data for long-term stability studies at 25 °C ± 2 °C and 40% RH ± 5% RH?

12 months Signup and view all the answers

Which storage condition corresponds to accelerated stability studies?

40 °C ± 2 °C/75% RH ± 5% RH Signup and view all the answers

What factors are included in stability studies when determining attributes of the finished pharmaceutical product (FPP)?

Physical, chemical, biological, microbial attributes, and preservative content Signup and view all the answers

At what temperature and duration is the long-term stability study for products intended to be stored in a freezer conducted?

-20 °C ± 5 °C for 12 months Signup and view all the answers

Which of the following is not part of the stability protocol requirements?

Cost analysis of production Signup and view all the answers

What is the minimum time period covered by data for accelerated stability studies at 30 °C ± 2 °C and 65% RH ± 5% RH?

6 months Signup and view all the answers

Which type of tests should be included in stability studies to assess changes during storage?

Physical, chemical, biological, microbiological tests Signup and view all the answers

Which of the following is a condition for long-term stability studies for products that are not refrigerated?

25 °C ± 2 °C/40% RH ± 5% RH Signup and view all the answers

Match the following stability testing aspects with their requirements:

Sterility reports = Beginning and end of shelf-life Sub-visible particulate matter = Reported frequently Bacterial endotoxins = Only reported at initial test interval Weight loss from containers = Reported over the shelf-life Signup and view all the answers

Match the following product types with their specific testing requirements:

Parenteral products = In-use periods justified with experimental data Liquid products = Freeze/thaw study important Ophthalmic products = In-use periods justified with experimental data Creams and emulsions = Specific photostability studies required Signup and view all the answers

Match the following storage orientations with their considerations:

Upright storage = Potential contact with closure system Inverted storage = Potential contact with closure system Horizontal storage = Generally not relevant Variable orientation = Need for stability assessment Signup and view all the answers

Match the following aspects of stress testing with their focus:

Photostability studies = Conducted on at least one primary batch Freeze/thaw testing = Important for temperature-sensitive products Stability during storage = Evaluates condition impacted by orientation Temperature evaluation = Assesses risk under varying conditions Signup and view all the answers

Match the following product types with their specific characteristics during stability testing:

Aqueous liquid products = Need specific photostability testing Metered dose inhalers = Specific testing required Dry products = Less susceptible to photostability concerns Semi-solids = Consider orientation during stability assessment Signup and view all the answers

Match the following types of stability studies with their respective storage conditions:

Long-term study = 30 °C ± 2 °C/65% RH ± 5% RH Accelerated study = 40 °C ± 2 °C/75% RH ± 5% RH Photostability study = Secondary batch under light exposure Minimum data requirement = 6 months for stability data Signup and view all the answers

Match the following terms related to stability testing with their definitions:

API = Active Pharmaceutical Ingredient FPP = Finished Pharmaceutical Product Bracketing = Testing of selected strength or size Matrixing = Testing of a subset of samples Signup and view all the answers

Match the following data requirements with their respective conditions:

Photostability testing = On at least one FPP batch Stability studies = Perform on each individual strength Exceptions = Justification required for smaller batches Pilot batches = At least 2 for conventional dosage forms Signup and view all the answers

Match the following stability-related concepts with their purposes:

Stability testing = Determine acceptable quality over time Photostability labeling = Protect against light exposure Stress testing = Evaluate dosage forms under additional conditions Long-term stability = Assess product quality over extended period Signup and view all the answers

Match the storage condition with its corresponding temperature and humidity for long-term stability of FPPs:

25 °C ± 2 °C/40% RH ± 5% RH = 12 months 5 °C ± 3 °C = 12 months -20 °C ± 5 °C = 12 months 30 °C ± 2 °C/65% RH ± 5% RH = 6 months Signup and view all the answers

Match the following terms with their corresponding time requirements:

Long-term data at registration = 12 months Accelerated data at registration = 6 months Minimum storage for long-term study = 6 months Stability testing for photostability = One primary batch if appropriate Signup and view all the answers

Match the following stability factors with their influence:

Temperature = Affect API quality Humidity = Impact on FPP stability Light = Criteria for photostability testing Time = Determines retest period or shelf-life Signup and view all the answers

Match the type of stability study with its duration:

Long-term study = 12 months Accelerated study = 6 months Intermediate study = 6 months In-use stability study = Varies Signup and view all the answers

Match the following stability study aspects with their key components:

Environmental factors = Temperature, humidity, light Minimum data for FPP = Three batches for testing Batch size = Smaller if justified Light protection = When container-closure is light-protective Signup and view all the answers

Match the stability testing requirements with their corresponding details:

Stability protocol = Container closure system(s) Stability studies = Testing of physical, chemical, biological attributes Stress testing = Conditions beyond normal storage Proposed shelf-life = Commitment batches Signup and view all the answers

Match the FPP storage condition with its storage duration:

Storage in refrigerator = 12 months Storage in freezer = 12 months Accelerated at 40 °C = 6 months Intermediate at 30 °C = 6 months Signup and view all the answers

Match the following testing protocols with their applications:

Protect from light = Labeling requirement if applicable Individual strength testing = Necessary for stability studies Pilot scale testing = Required unless justified Bracketing and matrixing = Alternate testing strategy for batches Signup and view all the answers

Match the stability attributes with their categories:

Physical attributes = Appearance, pH Chemical attributes = Active ingredient content Microbiological attributes = Presence of contaminants Functionality tests = Efficacy during shelf-life Signup and view all the answers

Match the stability study type with its conditions:

Long-term conditions = 5 °C ± 3 °C Accelerated conditions = 30 °C ± 2 °C/65% RH ± 5% RH Storage in freezer = -20 °C ± 5 °C Intermediate conditions = 30 °C ± 2 °C/65% RH ± 5% RH Signup and view all the answers

Match the condition to the study covered:

Long-term stability = 12 months at 25 °C Accelerated stability = 6 months at 40 °C Intermediate stability = 6 months at varying RH Stress testing = Extreme temperature and humidity tests Signup and view all the answers

Match each storage condition with its described usage:

25 °C ± 2 °C/40% RH ± 5% RH = Normal conditions in controlled climate 40 °C ± 2 °C/75% RH ± 5% RH = Stress testing conditions 5 °C ± 3 °C = Refrigerated storage -20 °C ± 5 °C = Freezer storage Signup and view all the answers

Study Notes

Stability Testing Purpose

Stability testing assesses how API or FPP quality changes over time due to environmental factors like temperature, humidity, and light.
It determines the retest period (API) or shelf-life (FPP) for acceptable quality (meeting specifications).

Basic Data Requirements (FPP)

Photostability testing is required on one FPP batch (exceptions apply).
Data from three FPP batches is needed. At least two of these batches should be pilot scale; the third can be smaller if justified. For conventional dosage forms, two pilot batches are sufficient.
Stability studies must be conducted for each individual strength, dosage form, container type, and size of the FPP (unless bracketing or matrixing is applied).

Photostability

Follow the WHO stability guideline, conducting photostability testing on at least one primary batch of the FPP if appropriate.
If the official pharmacopoeia states "protect from light" for the API or FPP, it's sufficient to label the product "protect from light" if the container/closure system is light-protective.
Additional stress testing might be needed for specific dosage forms.

Minimum Data Requirements (FPP)

Study	Storage Condition	Minimum Time Period (Submission)	Minimum Data (Registration)
Long-term	30°C ± 2°C/65% RH ± 5% RH	6 months	12 months
Accelerated	40 °C ± 2 °C/75% RH ± 5% RH	6 months	6 months

FPPs Packaged in Semi-Permeable Containers

Study	Storage Condition	Minimum Time Period (Submission)
Long-term	25 °C ± 2 °C/40% RH ± 5% RH or 30 °C ± 2 °C/35% RH ± 5% RH	12 months
Intermediate	30 °C ± 2 °C/65% RH ± 5% RH	6 months
Accelerated	40 °C ± 2 °C/75% RH ± 5% RH	6 months

FPPs Intended for Storage in a Refrigerator/Freezer

Study	Storage Condition	Minimum Time Period (Submission)
Long-term	5 °C ± 3 °C	12 months
Accelerated	25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH	6 months
Storage in a Freezer	-20 °C ± 5 °C	12 months

Stability Testing CTD File Requirements

Stability protocol
Stability specifications
Stress testing
Long-term conditions
Accelerated conditions
Stability studies
In-use stability data (if applicable)
Proposed shelf-life for FPP and commitment batches

Stability Protocol

Number of batches and their sizes
Container closure systems
Tests and acceptance criteria (references to testing methods)
Storage conditions
Testing frequency

Specification

Stability studies should test FPP attributes susceptible to change during storage and affecting quality, safety, or efficacy.
Testing should cover physical, chemical, biological, and microbiological attributes.
Preservative content (e.g., antioxidant or antimicrobial preservative).
Functionality tests (e.g., for a dose delivery system).
Specific tests should be conducted for various dosage forms, such as tablets (dissolution, water content, hardness/friability), capsules (dissolution, hardness/brittle-ness, water content, microbial contamination, pH), and soft capsules (pH, leakage).
For oral suspensions and solutions, formation of precipitate, clarity, pH, viscosity, extractables, dispersibility, rheological properties, and particle size distribution should be monitored.
Parenteral products should consider color, clarity, particulate matter, pH, sterility, pyrogens/endotoxins, and reconstitution time and water content.

Stability-Indicating Parameters

Parameter	Included in Studies?
Description, Assay	Yes
Dissolution	Yes
Water	Yes
Impurities (including enantiomers unless justified)	Yes
MLT	Yes
Identity	No
Content uniformity	No
Diameter/thickness	No
Average weight	No
Residual solvents	No

Release & Shelf Limits

Manufacturers typically set separate release and expiry limits for tests with quantitative results.
This allows for potential deterioration during stability studies.
It ensures batches are less likely to be recalled during regulatory testing, and maintains a positive product image.
Expiry limits apply after a batch release.

Testing Frequency

Long-term: Year 1: every 3 months, Year 2: every 6 months, Subsequent years: annually
Accelerated: Minimum three points, including initial and final times
Intermediate: Four points including initial and final times (consider matrixing/bracketing).

Out Of Trend

A request to the applicant to verify an unusual trend, explain, and correct errors and take measures to prevent repeat failures in the future.
High variability in the analytical method could denote an issue with assay method accuracy/precision and needs confirmation.
Possible reasons can include analytical method errors, uniformity problems in the manufactured product, and packaging issues.
Examine other issues that could affect product quality.

"Significant Change"

Changes from the initial API content by 5% or more by assay or potency failures identified when using biological or immunological procedures.
Any degradation products exceeding their acceptance criteria.
Failure of the appearance, physical attributes, and functional data of testing. Specific tests may be observed, such as softening of suppositories, melting of creams, and partial loss of adhesion of transdermal products.
Acceptable failure standards determined by the dosage form (e.g., failure of pH standards for solubility or failure of dissolution standards for 12 or more dosage units).

In-use Studies

This testing is used to provide information for labeling the preparation. It covers storage conditions and utilization period for multi-dose products after opening and reconstituted or diluted products. Additionally, testing should incorporate specific conditions for powder/granules for solutions/suspensions (multidose), oral solution/suspension, and sterile products.

In-use Study Details

Require at least two batches (preferably pilot) for testing.
Select batches towards the end of the shelf-life.
Design testing to match practical usage.
Testing parameters should match regulatory and initial testing standards.
In general, retesting is not necessary for commitment batches.

Stability Commitments

Primary stability data might not cover the proposed shelf-life period.
Data might not be available for all three production batches.
Ongoing stability commitment is required. It ensures that the FPP will remain within specifications throughout its shelf-life for all new batches.

Ongoing Stability Commitment

Applicants must provide a commitment letter for ongoing product stability studies.
Each year, one batch of every strength and packaging type should be included for testing, unless otherwise justified.
The protocol must adhere to the pre-approved standards for preliminary batches.
Significant atypical findings or Out-of-spec (OOS) results must be reported immediately to FDA.

Reduced Testing with Bracketing and Matrixing

Reduce stability program costs and increase efficiency to meet regulatory requirements.
Bracketing, Matrixing are two methods for efficient testing of products of varied parameters.
Tools like ICH Q1A (R2) and ICH Q1D may help in reduced testing strategies for new chemical entities (NCEs).

Bracketing

Extreme variable tests, such as different strengths, container sizes, or fills
Assume that extreme levels (highest vs. lowest strength, largest vs. smallest packages) encompass all intermediate levels.
Eliminate testing at intermediate levels.

Matrixing

A statistical design to check stability at particular time intervals.
A selected group of samples is tested at a specific point in time.
A specific group of batches is tested at each time interval.
The stability data of the selected group will represent the stability of the entire study.
Optionally, use fractions of the total batches to shorten the testing schedule.

Summarizing Impurities/Degradants

Summarize impurities qualitatively or quantitatively.
Important to note trends and which impurities are degradants.
Include a mass balance.

Quality Parameters

Monitor parameters susceptible to change, including physical (description, moisture), chemical (assay, degradants), preservative content, microbiological testing, and functional tests (e.g., for dose delivery systems) for each of the dosage forms.

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Description

This quiz covers the principles and requirements of stability testing for Finished Pharmaceutical Products (FPPs). Understand the importance of environmental factors, photostability testing, and data requirements for maintaining quality over time. Test your knowledge on guidelines and necessary conditions involved in stability studies.