STABILITY TESTING

API
Ajmal Nasir
Ph.D.
Q1A (R2)
This Guideline provides recommendations on
stability testing protocols including temperature,
humidity and trial duration for climatic Zone I and
II.
Furthermore, the revised document takes into
account the requirements for stability testing in
Climatic Zones III and IV in order to minimise the
different storage conditions for submission of a
global dossier.
DRUG STABILITY

A measure of how pharmaceutical

products maintains its quality attribute
over a time.

To provide evidence on how the quality of a drug

substance or drug product varies with time under
the influence of a variety of environmental factors
such as Temperature , Humidity & light,
DRUG STABILITY
Provide Evidence As To How The Quality Of The

Drug Product Varies With Time.

Establish Shelf Life For The Drug Product.

Re-test Periods & To Establish Shelf Lives

Determine Recommended Storage Conditions.

Determine Container Closure System Suitability.

WHY DRUG STABILITY ???

Chemical Degradation Of The Product Leads

To Lowering Of The Concentration Of The

Drug In The Dosage Form.

Toxic products may be formed , due to

chemical degradation of the active ingredient.

BENEFITS OF STABILITY

STABILITY STUDY PROVIDES :

Assurance to the patient

Economic controls

Legal Compliance
VARIABLES EFFECTING STABILITY
Formulation Batch To Batch Variability

Packaging Process Validation

Site And Method Of Quality Risk Management

Manufacture Container Labelling

API Changes To Product

Finished Product Batch Size

ADVERSE EFFECTS OF INSTABILITY
Loss of active drug (e.g. aspirin hydrolysis, oxidation of adrenaline)

Loss of vehicle (e.g. evaporation of water from o/w creams, evaporation of

alcohol from alcoholic mixtures)

Loss of content uniformity (e.g. creaming of emulsions, impaction of

suspensions)

Loss of elegance (e.g. fading of tablets and colored solutions)

Reduction in bioavailability (e.g. ageing of tablets resulting in a change in

dissolution profile)

Production of potential toxic materials (e.g. breakdown products from drug

STABILITY CATEGORIES
THERA
PEUTI
C
STABI
LITY
TOXIC
PHYSI
OLOGI
CAL
CAL
STABI
LITY STA STABI
LITY
BLE
PRO
DUC MICRO
PHYSI
CAL T BIOLO
GICAL
STABI
STABI
LITY
LITY
CHEMI
CAL
STABI
LITY
STAGES OF STABILITY
STAGE 1- Early stage stress and accelerated testing with
drug substances.

STAGE 2- Stability on pre-formulation batches.

STAGE 3- Stress testing on scale-up batches.

STAGE 4- Accelerated and long term testing for

registration purposes.

STAGE 5- On-going stability testing

STAGE 6- Follow-up stabilities

DEFINITIONS
Re-test date The date after which samples of the drug substance

should be examined to ensure that the material is still in compliance with the

specification and thus suitable for use in the manufacture of a given drug

product.

Re-test period- The period of time during which the drug substance is

expected to remain within its specification and, therefore, can be used in the

manufacture of a given drug product, provided that the drug substance has been

stored under the defined conditions. After this period, a batch of drug substance

destined for use in the manufacture of a drug product should be re-tested for

compliance with the specification and then used immediately.

DEFINITIONS
Shelf life (also referred to as expiration dating period)-

The time period during which a drug product is expected to

remain within the approved shelf life specification, provided

that it is stored under the conditions defined on the

container label.
API Stress Testing

Stress Testing Is An Important Part Of

Developmental Studies Used To Establish:

Degradation pathway and intrinsic stability

Validate stability indicating power of

analytical method
API Stress Testing
The stress stability condition is more severe than normal

accelerated condition Temperature

10 o increment above accelerated (i.e. 50 o , 60 o , 70 o )

Humidity (75% or greater)

Oxidation

Photolysis

Hydrolysis across justified range of pH

API Stress Testing

Requirement : One API batch

Photo stability testing-generally as per ICHQ1B Literature

data is also acceptable

If the monograph (USP, IP,BP/EP) states protect from light for

API or FPP there is no need to request photo stability data or

testing
API Stress Testing

From Q1B API photo stability studies-This is part of

stress testing (forced degradation) and is not designed

to establish qualitative or quantitative limits for change

Because of harsher condition compounds from stress

testing may not be observed under accelerated study

However, this approach serves to generate degradation

products that can be used as a worse case to assess

the analytical method performance.

API Stress Studies Assessment
Do the following
Check if this data is required, e.g. compendial statement protect from light
Check if the data provided is either generated by supplier or from literature
Check the condition is adequate (stress condition and extent of degradation)
Check the extent of degradation (no degradation after 10 days=stable, or 10-30%=adequate
degradation)
Confirm the stability-indication of methods where intended (i.e. mass balance, peak homogeneity)

Do not spend excessive time with degradants generated in stress studies

Impurities/degradants that must be closely investigated

are those appearing in API/FPP when stored at long
term or accelerated conditions at greater than (or
approaching) the identification threshold, (the limit of
individual unknowns,
API Stability
Selection of batches:
Primary batches-API batches used in stability studies to establish retest

[ICHQ1A]

Three pilot scale batches

Pilot batches must be of the same synthesis route, and with method of

manufacture and procedure which simulates the final process for production

batches .

Container closure system Should be the same or simulate the container

proposed for storage/distribution unless justification provided, i.e.

API Stability Specification
Specification:
Attributes susceptible to change must be tested-physical, chemical, and
microbiological attributes [appearance, assay, degradation plus others
susceptible to change]
Methods:

If the same as API specs, cross reference

If different, methodology and validation data for impurity and assay

methods needs to be provided

Method should be stability indicating If API is low soluble and micronized, and the

FPP is low dose, PSD is critical for this API due to potential of settling on storage

If low soluble API and there is evidence of polymorph stability issue, polymorphic

form should be monitored during stability studies

API Stability Testing Frequency

LONG TERM:

Initial, 3 month, 6 month, 9 month, 12 month, 18 mont, 24

month, 36 month, 48 month, etc.

ACCELERATED:

Minimum three points (0,3,6 month)

INTERMEDIATE :

Four points including initial and final (e.g. 0,6,9, 12)

API Stability Storage Condition
 Appendix to TRS953

Long term storage conditions are determined by the climatic

condition under which the API is intended to be stored

Climatic area Condition

Zone I Temperate 21 o C/45%RH
Zone II Subtropical/Mediterranean 25 o C/60%RH
Zone III Hot/Dry 30 o C/35%RH
Zone IVa Hot/Humid 30 o C/65%RH
Zone IVb Hot/Very Humid 30 o C/75%RH
API Stability Storage Condition

WHO requirement as of January, 2011 particularly for PQ

application data on long term is required at 30 0 C2/755%

unless justified
The storage condition on the label should be as described for
the storage condition of long term study Example.

Dont store above 30 0, protected from humidity if the study is

conducted at 30 0 C/65%

Dont store above 30 0C, if the study is conducted at 300/75%

Stability Evaluation

Stability commitment is required Data did not cover the

proposed re-test period

Data was not provided on three batches

When the proposed re-test/shelf life is not covered by

the stability data, 24month tentative re-test/shelf life is
granted based on the commitment that the remaining
data shall be submitted when available
API Stability Evaluation(contd,)
Establish re-test

Establish storage conditions If little variability, statistical analysis is

unnecessary

Extrapolation of data

General condition Assume data provided for 6 month acc/x month LT is

within specification, then tentative re-test is double the long term x, but
NMT x+12 (up to 24 month)

In WHO, extension beyond 24 month is not accepted without real-time

long term data
Tips for API Stability Assessment

Batch size

Packaging used in the trial and proposed recommendation

Accumulated stability data on the required lots

Study condition: temperature and humidity

Test methods for analysis

Validation of analytical method

Test results expression for quantitative figure

Mass balance

Extrapolation of shelf life/retest date

API manufacturer and FPP manufacturer: retest dates