The document discusses guidelines for conducting stability studies on drug substances and drug products according to ICH guidelines. It provides details on the objectives and scope of stability testing, factors to consider like storage conditions and container closure systems, types of studies to perform, and statistical approaches to analyze the data. The goal is to establish retest periods for drug substances and shelf lives for drug products based on stability data from multiple batches in order to submit this information for product registration applications.

1. Department of Pharmaceutical Analysis and Quality Assurance
Raghavendra Institute of Pharmaceutical Education and Research (RIPER),
Ananthapuramu, Andhra Pradesh (515721)
PRESENTED BY
B. JAHNAVI
V.BHARATH NAIK
B.MOHAN REDDY

2. • ICH
• Stability
• Q1A
• Q1B
• Q1C
• Q1D
• Q1E
• Reference

4. • ICH initially involved EU, Japan and USA.
• ICH was initiated in April 1990.
ICH GUIDELINES

5. Stability studies
DRUG SUBSTANCE DRUG PRODUCT
Unformulated drug
substance that may be
formulated with
excipients to produce
the dosage form
Dosage form in the final
immediate packaging
intended for marketing

7. • Stability data package for a new drug substance or drug product that is
sufficient for a registration application with in three regions of the EC, Japan,
and United States.
Scope:
• Information to be submitted in registration applications for new molecular
entities and associated drug products.
• The purpose of stability testing is to provide evidence on how quality of drug
substance or drug product varies with time under influence of various
environmental factors to establish retest period and shelf life .
• This guideline addresses climatic zones I and II. Tripartite guidelines on
stability testing of new drug substances and products (Q1A) in 1993 has
become standard for quality evaluation in Japan, US and EU.
Objective:

8. Stress Testing
Container Closure System
Storage Conditions
Evaluation

9. Photo stability Testing
Container Closure System Evaluation
Storage Conditions

10. DRUG SUBSTANCE DRUG PRODUCT
General Systemic approach to stability
evaluation
Knowledge of behavior and
properties of drug substance
Stress testing(DS)
/photostability
testing(DP)
To identify degraded products
and to establish degradation
pathways & intrinsic pathways
Conducted on at least one
primary batch of drug
product
Selection of
batches
Data from formal stability
studies should be provided on at
least 3 primary batches of drug
substance
Two of three batches should
be at least pilot scale batches
and third one is smaller
Container Closure
System
Stability studies should be
conducted on the drug substance
packaged in a container closure
system(storage and distribution)
Conducted on dosage form
packaged in CCS proposed
for marketing
Specification List of tests, reference to
analytical procedures, proposed
acceptance criteria
Testing covers physical,
chemical, microbiological
attributes, preservative
content, functionality tests.

11. DRUG SUBSTANCE DRUG PRODUCT
Testing Frequency
For long term studies,
frequency of testing should
be sufficient to establish
stability profile.
For long term studies,
frequency of testing should
be sufficient to establish
stability profile.
Storage Conditions
Long term , Intermediate,
Accelerated storage for
general, refrigerator, freezer
Drug products packaged in
impermeable and semi
permeable containers
Stability Commitment
Commitment should be
made to continue stability
studies on primary batch to
establish a retest period.
To establish shelf life for a
drug product.
Evaluation
To establish retest period
for future batches, based on
testing of 3 batches.
To establish shelf life for
future batches, based on
testing of 3 batches.
Labeling
Retest period should be
derived from stability
information, retest date
should be displayed on
container label.
Specific instructions,
expiration date ‘’ambient
conditions "or ’’room
temperature” are avoided
on container label.

12. Study Storage condition Minimum time period
Long term* 25 ± 2°C, 60% RH ± 5% RH
OR
30 ± 2°C, 60% RH ± 5%RH
12 months
Intermediate ** 30 ± 2°C, 60% RH ± 5%RH 6 months
Accelerated 40 ± 2°C, 75% RH ± 5%RH 6 months
General case
Study Storage condition Minimum time period
Long term 5° ± 3°C 12 months
Accelerated 25 ± 2°C, 60% RH ± 5% RH 6 months
Storage in a refrigerator
For storage in a freezer, long term- -20°C ± 5°C(12 months)

14. • Systemic approach to photostability testing covers studies,
1. Tests on the drug substance.
2. Tests on exposed drug product outside the immediate pack.
3. Tests on drug product in the immediate pack.
4. Tests on the drug product in the marketing pack.
LIGHT SOURCE
Option 1
Light source that is
designed to produce
output similar to
D65/ID65 emission
standard
Option 2
1.Cool white
fluorescent lamp.
2.Near UV
fluorescent lamp.

15. For drug substances, photostability testing should consists of 2 parts
Forced Degradation Testing
• To evaluate overall photosensitivity of material for method development
purposes/degradation pathway elucidation.
• This involves drug substance alone/sample solution/suspensions.
• Samples- chemically inert , transparent containers.
• Variety of exposure conditions may be used depends on photosensitivity of drug
substance and intensity of light source.
• Information may be useful in developing and validating suitable analytical
methods.

16. Confirmatory Testing
• This should be undertaken to provide information necessary for handling,
packaging and labeling.
• Normally one batch of drug substance is tested during development phase
and then photostability characteristics should be confirmed on a single
batch as described in parent guideline.
• Quinine chemical actinometry.

17. START
DIRECTLY EXPOSED
ACCEPTABLE
CHANGE?
IMMEDIATE PACK
ACCEPTABLE
CHANGE?
MARKETING PACK
ACCEPTABLE
CHANGE?
REDESIGN PACKAGE OR
REFORMULATION
TEST
END
TEST
END
TEST
END
FORMULATION
CHANGE?
IMMEDIATE
PACK
CHANGE?
MARKETING
PACK
CHANGE?
NO
NO
NO
YES
YES
YES
YES
NO
NO
For a drug product:

18. • New dosage form is a drug product which is a different pharmaceutical
drug product but contains same active substance as in the already
existing drug product approved by regulatory authority.
• Such pharmaceutical product types include
1. Route of administration.
2. Delivery systems.
3. Same route of administration with different dosage forms.

19. • Full study design is one
in which samples for
every combination are
tested at all time points.
• Reduced design is one in
which samples for every
combination are not tested
at all points.
.

20. Strength 50 mg 75 mg 100 mg
Batch 1 2 3 1 2 3 1 2 3
Container
Size
15 ml T T T T T T
100 ml
500 ml T T T T T T

21. Time point
(months)
0 3 6 9 12 18 24 36
S
t
r
e
n
g
t
h
S1 Batch 1 T T T T T T
Batch 2 T T T T T T
Batch 3 T T T T T
S2 Batch 1 T T T T T
Batch 2 T T T T T T
Batch 3 T T T T T
One – Half Reduction

22. Time point
( months)
0 3 6 9 12 18 24 36
S
t
r
e
n
g
t
h
S1 Batch 1 T T T T T T
Batch 2 T T T T T T
Batch 3 T T T T T T T
S2 Batch 1 T T T T T T T
Batch 2 T T T T T T
Batch 3 T T T T T T
One – Third Reduction

23. • Intended on how to use stability data generated in accordance with principles
mentioned in the ICH guideline Q1A to propose a retest period or shelf life in
registration application.
• Describes when and how extrapolation can be considered when proposing a
retest period or shelf life for a drug product that extends beyond the period
covered by “available data from the stability study under the long term storage
condition.”
• This guideline addresses evaluation of stability data that should be submitted in
registration applications for new molecular entities and associated drug products.

24. • Extrapolation is the practice of using a known data set to infer information about
future data.
• Extrapolation to extend the retest period or shelf life beyond the period covered
by long term data can be proposed in the application, particularly if no change is
observe at accelerated condition.
• Extrapolation of stability data assumes that the same change pattern will continue
to apply beyond the period covered by long term data.

25. Statistical Approaches:
• Appropriate statistical method should be employed to analyze long term stability
data .
• The purpose of analysis is to provide high degree of confidence, retest period or
shelf life during which quantitative attribute will remain within acceptance criteria
for all future batches .
• Regression analysis is considered to evaluate the stability data for quantitative
attribute.
Examples:
1.Data analysis of a single batch.
2. Data analysis for One-Factor, Full Design Studies.
3. Evaluating whether all batches support the proposed retest period or shelf life.
4. Testing for poolability of batches(Analysis of covariance)

26. 1. Chen, J.J., Ahn, H., and Tsong, Y., “Shelf – life Estimation for Multifactor Stability
Studies” Drug Inf. Journal, 31:573-587, 1997.
2. Carstensen, J.T., and Rhodes, C.T., “Drug Stability Principles & Practices”, Third
Edition.
3. Yoshioka S. et al., Drug Development and Industrial Pharmacy,20 (13), 2049-2062
(1994).
4. Ruberg, S.J. and Hsu, J.C., “Multiple Comparison Procedures for Pooling Batches in
Stability Studies” Technometrics, 34:465-472,1992

27. Any
Queries?

28. Thank you