Stability testing protocols

ADVANCED PHARMACEUTICAL ANALYSIS
STABILITY TESTING
PROTOCOLS
LIKITHA BOGA
M. Pharmacy I-I
Pharmaceutical Analysis

DRUG STABILITY
 DEFINITION:
A measure of how pharmaceutical products maintains its quality attribute over a
time period.

TYPES OF STABILITY
 CHEMICAL: Each active ingredient retains its chemical integrity and
labeled potency within the specified limit.
 PHYSICAL: The physical stability properties includes appearance,
palatability, uniformity, dissolution and suspend ability are retained.
 MICROBIOLOGICAL: Sterility or resistance to microbial growth is
retained according to specified requirement.
 THERAPEUTIC: Therapeutic activity remains unchanged.
 TOXCOLOGICAL: No significant increase in toxicity occurs.

ICH GUIDELINES
ICH GUIDELINES TITLE
Q1 A Stability testing of new drug substances
and products
Q1 B Stability testing: photo stability testing
of new drug substance and products
Q1 C Stability testing for new dsage forms
Q1 D Bracketing and matrixing designs for
stability testing of drug substances and
products
Q1 E Evaluation of stability data
Q1 F Stability data package for registation
application in climatic zones Ш and IV

What is meant by stability testing?
 Stability testing is utilized to determine if the quality of a drug substance or drug
product is altered over time by various environmental factors, such as light, temperature
and humidity.

INTRODUCTION
 This guidance is the second revision of Q1A Stability Testing of New Drug Substances
and Products, which was first published in September 1994 and revised in August
2001.
 The purpose of this revision is to harmonize the intermediate storage condition for
zones I and II with the long-term condition for zones III and IV recommended in the
ICH guidance.

Objectives of the Stability testing
 Stability testing is 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, and light.

STABILITY TESTING OF API’S
1. General
2. Stress testing
3. Selection of batches
4. Container closure system
5. Specifications
6. Testing frequency
7. Storage conditions
8. Stability commitment
9. Evaluation
10. Statements/labeling

1. GENERAL
 Information on the stability of the drug substance is an integral part of the systematic
approach to stability evaluation.

2. STRESS TESTING
 Stress testing of the drug substance can help identify the likely degradation products,
which can in turn help establish the degradation pathways.
 validate the stability indicating power of the analytical procedures used.
 Stress testing is likely to be carried out on a single batch of the drug substance.
 The testing should include the effect of temperatures (in 10°C increments (e.g., 50°C,
60°C) above that for accelerated testing), humidity (e.g.,75 percent relative humidity or
greater) where appropriate, oxidation, and photolysis on the drug substance.

3. SELECTION OF BATCHES
 Data from formal stability studies should be
provided on at least three primary batches of the
drug substance.
 The batches should be manufactured to a minimum
of pilot scale by the same synthetic route as
production batches and using a method of
manufacture and procedure that simulates the final
process to be used for production batches.

4. CONTAINER CLOSURE SYSTEM
 The stability studies should be conducted on the drug substance
packaged in a container closure system that is the same as or
simulates the packaging proposed for storage and distribution.

5. SPECIFICATION
 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
efficacy.
 The testing should cover as appropriate the physical, chemical, biological and
microbiological attributes.
 Eg. Appearance, assay, degradation.

6. TESTING FREQUENCY
 For long term stability studies:
year 1: every 3 months
year 2: every 6 months
subsequent years: annually
 At accelerated storage conditions: (6 months study)
minimum three points including t0 and t final
Eg. 0(initial) 3 6(final)
 At intermediate storage conditions: (12 months study)
four points including t0 to t final
Eg. 0(initial) 6 9 12(final)

7. STORAGE CONDITIONS
 In general, a drug substance should be evaluated under storage conditions (with
appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity
to moisture.
 GENERAL CASE:
GENERAL CASE:
STUDY STORAGE CONDITIONS MINIMUM TIME PERIOD
COVERED BY DATAAT
SUBMISSSION
LONG TERM
(AMBIENT)
250 C ± 20C
60% RH ± 5% RH
12 MONTHS
INTERMEDIATE
(CONTROLLED)
300 C ± 20C
65% RH ± 5%
6 MONTHS
ACCELERATED 400 C ± 20C
75% RH ± 5%
6 MONTHS

 STORAGE IN REFRIGERATOR:
 STORAGE IN FREEZER:
COVERED BY DATAAT
SUBMISSION
LONG TERM 50C ± 30C 12 MONTHS
ACCELERATED 250C ± 20C
60% RH ± 5%
6 MONTHS
COVERED BY DATAAT
SUBMISSION
LONG TERM -200C±50C 12 MONTHS

8. STABILITY COMMITMENT
 When available long-term stability data on primary batches do not cover the proposed
retest period granted at the time of approval, a commitment should be made to continue
the stability studies post approval to firmly establish the retest period.
 If the submission includes data from stability studies on at least three production
batches, a commitment should be made to continue these studies through the proposed
retest period.
 If the submission includes data from stability studies on fewer than three production
batches, a commitment should be made to continue these studies through the proposed
retest period and to place additional production batches, to a total of at least three, on
long-term stability studies through the proposed retest period.
 If the submission does not include stability data on production batches, a commitment
should be made to place the first three production batches on long term stability studies
through the proposed retest period.

9. EVALUATION
 Based on testing a minimum of three batches of the drug substance.
 Evaluating the stability information (including, as appropriate, results of the physical,
chemical, biological, and microbiological tests).
 The degree of variability of individual batches affects the confidence that a future
production batch will remain within specification throughout the assigned retest period.
 If analysis shows that the batch-to-batch variability is small, it is advantageous to
combine the data into one overall estimate.
 Any evaluation should cover not only the assay, but also the levels of degradation
products and other appropriate attributes.

10. STATEMENT /LABELING
 A storage statement should be established for the labeling in accordance with relevant
national/regional requirements.
 The statement should be based on the stability evaluation of the drug substance.
 Where applicable, specific instructions should be provided, particularly for drug
substances that cannot tolerate freezing.
 A retest period should be derived from the stability information, and a retest date should
be displayed on the container label if appropriate.

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