STABILITY STUDIES

STABILITY

• the extent to which a product retains, within specified limits, and throughout its shelf-life, the same properties and characteristics that it possessed at the time of its manufacture.

Signs of instability or expiry in a drug product:

• physical changes

• color change, tablets breaking easily, precipitate in solutions, sugar crystallization in syrups.

Signs of instability or expiry in a drug product:

• chemical changes 

• degradation reactions that reduce effectiveness.

Drugs are usually considered expired or chemically degraded when

~10% (NOT ALWAYS the case) of the active ingredient is lost.

T 0.90 or T 90% (shelf-life)

 time it takes for the drug to degrade to 90% of its original potency

TYPES OF STABILITY

• chemical 

Each active ingredient retains its chemical integrity and labeled potency, within the specified limits.

TYPES OF STABILITY

• physical 

The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability, are retained.

TYPES OF STABILITY

• microbiological 

• Sterility or resistance to microbial growth is retained according to the specified requirements. 

• Antimicrobial agents that are present retain effectiveness within the specified limits.

TYPES OF STABILITY

• therapeutic

The therapeutic effect remains unchanged.

TYPES OF STABILITY

• toxicological 

No significant increase in toxicity occurs.

Toxicity risk:

if a drug product degrades by 10% of its active ingredient

STABILITY STUDIES

Series of tests in order to obtain an assurance of the stability of a drug product

STABILITY STUDIES

• provide

 evidence that the strength, quality, purity of drug substance are suitable for its intended purpose or its entire expiry period or retest period at labeled storage conditions

STABILITY STUDIES

• covers 

• physical, chemical, microbiological, therapeutic, and toxicological attributes

stability studies

• SHALL BE PERFORMED UNDER THE FOLLOWING SITUATIONS:

• New products

• New packages

• Change in formula, processing method or source of raw materials

• Batches released by exception

• Marketed products to confirm assigned shelf-life

• Changing primary packaging

Shelf-Life Determination

• The period of stability of the product

• The time from the date of manufacture of the formulation until its chemical or biological activity is not less than 90%of the labeled potency or the lower limit as indicated in the specific guideline or monograph

Expiration Date Determination

It is the time in terms of month and year calculated from shelf-life + date of the last processing stage prior to packaging

ASEAN GUIDELINE ON STABILITY STUDY OF DRUG PRODUCT

• objective 

• To provide recommendations on the core stability study package required for drug products

• To propose shelf-life based on the stability data generated from the study package

ASEAN GUIDELINE ON STABILITY STUDY OF DRUG PRODUCT

• scope

• Addresses information to be submitted during application or marketing authorization or registration and variations of drug products in ASEAN Member States

ASEAN GUIDELINE ON STABILITY STUDY OF DRUG PRODUCT

• scope: The drug products covered in this guideline include

new chemical entity (NCE), generics and variation

ASEAN GUIDELINE ON STABILITY STUDY OF DRUG PRODUCT

• scope: The drug products covered in this guideline exclude 

• drug products containing vitamin and mineral preparations

Stability is an essential factor of

• quality,

• safety, and

• efficacy of a drug product.

Stability testing should be biased towards

more stressful rather than less stressful conditions i.e., stricter than lenient

The objective of a stability study is to

determine the shelf life

The stability study consists of a series of tests including

maintenance of the specifications of the drug product packed in its specified packaging material and stored at the established storage condition within the determined time period.

 LONG-TERM (OR REAL TIME) STABILITY TESTING

• Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.

• Can be used to determine shelf-life/ when a drug product is viable

LONG-TERM (OR REAL TIME) STABILITY TESTING

schedule 

• Every 3 months on the 1^st year;

• Every 6 months on the 2^nd year;

• And every year thereafter until expiration

LONG-TERM (OR REAL TIME) STABILITY TESTING

Testing Frequency

0, 3, 6, 9, 12, 18, 24, 36

ACCELERATED (OR SHORT-TERM) STABILITY TESTING

• Studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies

ACCELERATED (OR SHORT-TERM) STABILITY TESTING

conditions 

• At high temperature (40°C) and high humidity (75% RH), degradation

ACCELERATED (OR SHORT-TERM) STABILITY TESTING

schedule 

Every 3 months for 6 months

ACCELERATED (OR SHORT-TERM) STABILITY TESTING

testing frequency 

0, 3, 6

The storage conditions and the lengths of studies chosen should be

sufficient to cover storage, shipment, and subsequent use

Required storage conditions would depend on the

type of container and the type of testing that would be performed.

Long term (for products in primary containers semi-permeable to water)

• 30°C ± 2°C

• 75% RH ± 5% RH

Long term (for products in primary containers impermeable to water vapor)

30°C ± 2°C / RH not specified

Accelerated

• 40°C ± 2°C

• 75% RH ± 5% RH

Stress testing*

40°C ± 2°C / 75% RH ± 5% RH or at more stressful conditions

STRESS TESTING is necessary for

•  analytical method validation

• pharmaceutical formulation

• identifying & monitoring potential degradants during stability testing.

STORAGE CONDITIONS FOR CLIMATIC ZONES

zone I 

• Temperate

• 21°C / 45% RH

STORAGE CONDITIONS FOR CLIMATIC ZONES

zone II

• Mediterranean / Subtropical

• 25°C / 60% RH

STORAGE CONDITIONS FOR CLIMATIC ZONES

zone III

• Hot, Dry

• 30°C / 35% RH

STORAGE CONDITIONS FOR CLIMATIC ZONES

zone IVa

• Hot Humid / Tropical

• 30°C / 65% RH

STORAGE CONDITIONS FOR CLIMATIC ZONES

zone IVb 

• Hot / Higher Humidity

• 30°C / 75% RH

SEMI-PERMEABLE / SELECTIVELY PERMEABLE

• Containers that allow the passage of solvent, usually water, while preventing solute loss.

SEMI-PERMEABLE / SELECTIVELY PERMEABLE

• The mechanism for solvent transport occurs by:

• adsorption into one container surface

• diffusion through the bulk of the container material

• desorption from the other surface

SEMI-PERMEABLE / SELECTIVELY PERMEABLE

• examples

• plastic bags

• semi-rigid LDPE pouches

• LDPE ampoules, bottles, vials

IMPERMEABLE CONTAINER

Containers that provide a permanent barrier to the passage of gases or solvents

IMPERMEABLE CONTAINER

• examples include 

• sealed aluminum tubes

• sealed glass ampoules

• aluminum/ aluminum blisters

semi-rigid, LDPE pouches

• LDPE: low-density polyethylene

• for large volume parenterals (LVPs)

Sealed Aluminum tubes

semisolids

Sealed Glass Ampoules

solutions

Aluminum/Aluminum blisters

solid dosage forms

SPECIFICATIONS (TESTING PARAMETERS)

• Testing should cover, as appropriate,

• the physical,

• chemical,

• biological,

• and microbiological attributes,

• preservative content,

• and functionality tests

physical

pH, color, friability test, tablet hardness, chemical assay test, biological test

preservative content

antioxidant, antimicrobial preservative

functionality tests

for a dose delivery system

The analytical procedure should be

• fully validated and stability indicating

• tested for precision, accuracy, linearity robustness

SIGNIFICANT CHANGE

If there is a “significant change” noted between 3 and 6 months testing at the accelerated storage condition,

the proposed shelf-life should be based on long-term (real time) data only—not on accelerated data.

When evaluating stability results (especially accelerated stability at 40°C/75% RH), regulatory agencies check for 

“significant change”.

SIGNIFICANT CHANGE

• occurs if ANY of the following happen at accelerated conditions:

1. A 5% change in assay from its initial value (not from label claim), or failure to meet the acceptance criteria/specification; 

2. Any degradation product exceeding the acceptance criterion 

3. Failure to meet the acceptance criteria for pH; 

4. Failure to meet the acceptance criteria for dissolution for 12 dosage units (capsule or tablet)

5. Failure to meet acceptance criteria for: appearance, physical attributes, functionality test.

5% decrease in assay from INITIAL value

• NOT from label claim

• From the initial tested assay 

• e.g., 101% → 95% = significant

Any degradation product exceeds its acceptance criteria

• Monographs indicate specified limits for impurities.

• e.g., If p-aminophenol (Paracetamol impurity) exceeds its limit → significant change

Failure to meet pH specification

For solutions, syrups, suspensions, etc.

Failure of dissolution in 12 units

• For tablets/capsules: Dissolution of all 12 units must meet the spec.

• Failure = significant change

 Failure to meet acceptance criteria for: appearance, physical attributes, functionality test

However, some changes in physical attributes (e.g. softening of suppositories, melting of creams) may be expected under accelerated conditions; and as appropriate for the dosage form.

TWO POSSIBLE RESULTS OF ACCELERATED & LONG-TERM DATA

1. Show little or no change over time and little or no variability between batches

2. Show change over time and/or variability within a factor or among factors

  LITTLE OR NO CHANGE OVER TIME

• If results show:

• Minimal degradation

• Minimal variation among batches

• Then, statistical analysis is not needed

  LITTLE OR NO CHANGE OVER TIME

• Shelf-life assignment rule: (asean rule) 

• Shelf-life (Y) = 2x, but NOT exceeding x+12 months. 

• X = duration of long-term date

 CHANGE OVER TIME / VARIABILITY AMONG BATCHES

• if data shows:

• Downward assay trend

• Increasing impurities

• Variability among lots

• Differences among strengths

Then, statistical analysis is required

STATISTICAL APPROACHES TO STABILITY DATA ANALYSIS

• , Statistical analysis of the long-term data can be useful in establishing:

• a retest period

• shelf-life within the factor (e.g. different strengths

LINEAR REGRESSION

• Determining the earliest time at which 95 percent confidence limit for the mean intersects the proposed acceptance criterion/specification

• Plot assay vs time

• Look for slope

• Determine when 95% CI intersects acceptance limit (= earliest failure time)

When the regression predicts an unreasonably long shelf-life and R² is very low (little change, low variability), we don't use the 95% intersection. Instead, 

we use the ASEAN rule for "little or no change."

POOLABILITY TESTS BETWEEN BATCHES

• Determine if batches:

• Behave similarly, or

• Need separate shelf-life assignments

STATISTICAL MODELING

Multi-Factor, Full-Design Studies

ANALYSIS OF COVARIANCE (ANCOVA)

Used when:

• Multiple strengths

• Multiple batch factors

• Need to compare degradation behavior across factors