stability testing of formulations

1. Stability Testing
Presented by : Presented to:
Ayushi Goyal(22003) Dr. Gurpal
Singh
M. Pharm-1(Pharmaceutics)

2. CONTENTS-
• Introduction
• Variables affecting the stability
• Adverse effects of instability of drugs
• Stability Testing Terminologies
ICH Q1A(R2)
ICH Q1B
ICH Q1C
ICH Q1D
ICH Q1E

3. INTRODUCTION-
DRUG STABILITY-
“A measure of how pharmaceutical products
maintains its quality attribute over a time.”
STABILITY TESTING-
A process which 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, and enables
recommended storage conditions, to establish
a shelf life for the drug.

4. Variables affecting the stability-
• Formulation
• Packaging
• Site and method of manufacture
API
Finished product
• Batch size
• Batch to batch variability
Process validation
Quality risk management
• Container labeling
• Changes to product

5. ADVERSE EFFECTS OF INSTABILITY
OF DRUGS-
• 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 degradation)

6. TYPES OF STABILITY
I AM
STABLE
MICROBIOLOGICAL
STABILITY
CHEMICAL
STABILITY
PHYSICAL
STABILTY TOXICOLOGIC
STABILITY
THERAPEUTICA
L STABILITY

7. 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 .
• TOXICOLOGIC : No significant increase in
toxicity occurs.

8. STABILITY TESTING
Development studies-
• Characterize compatibility with common
excipients.
• Characterize stability profile of API (E.g.
susceptibility to acid, base, light, oxygen etc)
• Characterize stability profile of early
formulations (Especially susceptibility to heat,
humidity & light)
Confirmatory studies-
• Long term & accelerated studies on the
product as it is to be registered

9. 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 dosage 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 Registration
Applications in Climatic Zones III and IV

10. Q1A : Stability Testing of New Drug
Substances and Products-
• General
• Stress Testing
• Selection of Batches
• Container Closure System
• Testing Frequency
• Storage Conditions
• Stability Commitment
• Evaluation
• Statements/Labelling

11. GENERAL-
Information on the stability of the drug substance is
an integral part of the systematic approach to
stability evaluation.
STRESS TESTING-
• Main tool that predict the stability problems.
• Foundation for developing and validating
analytical methods. For an API the following
approaches may be used.
• When available, it is acceptable to provide
relevant data published in the scientific
literature to support the identified
degradation pathways and products.

12. ROLL OF STRESS TESTING-
Stress testing of the active substance can help in.
• Identification of degradants .
• Identification of degradation pathways
• Determination of which type(s) of stress affect
the molecule:
1.Oxidation-
• Typically done by placing the drug substance
in aqueous solution of hydrogen peroxide.
• Goal is significant degradation (typically 10-
30% of API)
Can identify degradants
Determine whether protective packaging is
required.
Determine if an antioxidant should be
considered for the drug product formulation.

13. Ph-
• Typically done by adding drug substance
to buffered aqueous solutions at pH
values from 1-10
• Decide if the molecule will survive
passage through the stomach
• Is enteric coating necessary?
• the drug be given by injection?

14. TYPICAL STRESS CONDITION
STRESS
FACTOR
Conditions
HEAT 10°C increments
HUMIDITY 75%RH or greater
ACID 0.1N Hcl
BASE 0.1N NaOH
OXIDATIVE 3%H2O2
PHOTOLYTIC Xenon Metal halide lamp or Near UV White
florescent lamp

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

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

17. TESTING FREQUENCY
• For long term studies:
Year 1: every 3 months
Year 2: every 6 months
Subsequent years: annually
• At accelerated storage conditions: (6 month
study) Minimum three points including t 0 and t
final,
e.g. 0 3 6
(initial) (final)
• At intermediate storage conditions: (12
month study) Four points including t 0 and t
final,
e.g. 0 6 9 12

18. STORAGE CONDITION
A drug substance should be evaluated
• To test its thermal stability
• Its sensitivity to moisture(if applicable)
• The long-term testing (minimum of 12
months) on at least 3 primary batches
at the time of submission and
• Should be continued for a period of
time sufficient to cover the proposed
re-test period.

19. STORAGE CONDITIONS
Study Storage condition Minimum time period
covered by data at
submission
In general
Long Term* (Ambient) 25º C ± 2º C
60%RH ± 5%
12 months
Intermediate**
(controlled)
30º C ± 2º C
65%RH ± 5%
6 months
Accelerated 40º C ± 2º C
75%RH ± 5%
6 months
Refrigerator
Long Term 5º C ± 3º C 12 months
Accelerate 25º C ± 2º C 60%RH ±
5%
6 months
Freezer
Long Term -20º C ± 5º C 12 months

20. EVALUATION-
• Minimum of 3 batches of drug substance is
tested.
• The degree of variability of individual batches
affects the confidence that a future production
batch will remain within specification throughout
the assigned re-test period.
STATEMENT/LABELING-
• A storage statement should be established for
the labeling based on the stability evaluation
of the active substance.
• Where applicable, specific instructions should
be provided, particularly for active substances
that cannot tolerate freezing. Terms such as
“ambient conditions” or “room temperature”
must be avoided

21. Q2B: PHOTOSTABILITY TESTING OF
NEW DRUG SUBSTANCES AND
PRODUCTS
Photo-stability testing studies include:
(Single batch)
• Test on drug substance.
• Test on exposed drug product outside the
immediate pack.
• Test on drug product in the immediate pack.
• Test on drug product in the marketing pack.
Light source-
• Option 1: Artificial daylight lamp combining
both visible & UV output similar.
• Option 2: Cool white fluorescent & near UV
lamp(320-400nm

22. Q1C: Stability Testing for New Dosage
Forms-
• This document is an annex to the ICH parent
stability guideline and addresses the
recommendations on what should be submitted
regarding stability of new dosage forms by the
owner of the original application, after the
original submission for new drug substances
and products.
• A new dosage form is defined as a drug product
which is a different pharmaceutical product
type, but contains the same active substance
as included in the existing drug product
approved by the pertinent regulatory

23. Q1d:(Bracketing and Matrixing Designs
for Stability Testing of New Drug
Substances and Products)-
BRACKETING-
• It is the design of a stability schedule such
that only samples on the extremes of
certain design factors, e.g., strength,
package size, are tested at all time points
as in a full design.
• The design assumes that the stability of
any intermediate levels is represented by
the stability of the extremes tested. Where
a range of strengths is to be tested,
bracketing is applicable if the strengths are
identical or very closely related in

24. BRACKETING DESIGN

25. MATRIXING-
• It is the design of a stability schedule
such that a selected subset of the total
number of possible samples for all factor
combinations is tested at a specified
time point.
• At a subsequent time point, another
subset of samples for all factor
combinations is tested.
• The design assumes that the stability of
each subset of samples tested
represents the stability of all samples at
a given time point

26. MATRIXING DESIGN

27. Q1E: EVALUATION OF STABILITY
DATA
Data Presentation-
• Data for all attributes should be presented
in an appropriate format (e.g., tabular,
graphical, narrative) and an evaluation of
such data should be included in the
application.
• The values of quantitative attributes at all
time points should be reported as
measured (e.g., assay as percent of label
claim).
• If a statistical analysis is performed, the
procedure used and the assumptions
underlying the model should be stated and
justified.

28. Q1F: Stability Data Package for
Registration Applications in Climatic
Zones III and IV
• Describes harmonized global stability testing
requirements in order to facilitate access to
medicines by reducing the number of
different storage conditions.
• WHO conducted a survey amongst their
member states to find consensus on
30°C/65% RH as the long term storage
conditions for hot-dry and hot-humid regions.

29. ICH Stability Zones
ZONE TYPE OF CLIMATE
Zone 1 Temperate zone
Zone 11 Subtropical/ Medititerranean Zone
Zone 111 Hot dry zone
Zone 1Va Hot humid/ Tropical zone
Zone 1Vb Hot/ Higher humidity

30. Drug Recalls
DATE BRAND NAME PRODUCT NAME
11/07/2022 Adam’s Polishes Hand Sanitizer due to potential
contamination of Methanol
10/25/2022 Aurobindo Pharma
USA, Inc.
Quinapril (20 mg) and
Hydrochlorothiazide (12.5 mg)Tablets
USP due to N-nitroso impurity
10/25/2022 Mylan Institutional LLC Octreotide Acetate Injection (500
mcg/ml) due to glass Particulates in a
Syringe
8/22/2022 Hospira Propofol Injecable Emulsiom
(Containing Benzyl Alcohol) due to
presence of Visible Particulates
4/22/2022 Pfizer ACCUPRIL(Quinapril HCL) due to N-
nitroso- quinapril content