Stability

Q1(R2)

Role Of Stability
Safety and efficacy of drug product are established during
development via clinical studies
Quality is established for identify, strength, quality and purity
If drug product stability changes beyond established acceptance
criteria, established safety and efficacy are no longer applicable.
Change of Drug Stability would risk patient safety
Quality of finished products decrease
Potential sub-potent or over-dose products
Potential toxic unknown impurities
Uncontrolled process product investigation product recalls
cGMP violations consent decree criminal prosecution

DRUG DEVELLOPMENTT PROCESS

Factors affecting Drug Stability

Stability of the Active Pharmaceutical Ingredient (API) from storage
Interaction between the API and excipient
Formulation Development
Selection of dosage form
Manufacturing process of drug product
Selection of container closure packaging system
Effect of storage (temperature, humidity and light)
Selection of marketing image
Handling of the finished products

Purpose of Stability Testing

The purpose of 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 permits the establishment of
recommended storage conditions, retest periods, and
shelf-lives.

Drug Product Stability

Stability characteristics of API or Drug Product is a critical
quality attribute of pharmaceutical product
Stability Studies are used to:
Establish how product changes over time under critical
environmental factors (temperature, heat and light)
Determine appropriate product specifications
Select marketing container closure system
Determine appropriate storage conditions
Justification of expiry of commercial product
Provide necessary medical supplies

Stability Protocol
Stability program must be written and followed:
Used in determining appropriate storage
conditions and expiration date.
Written program must include: Sample size and
test
intervals, Storage conditions for samples,
Reliable, meaningful, and specific test methods,
Testing of drug product in marketed container,
Testing of drug product for reconstitution at
dispensing time and reconstituted time.

Stability Protocol
An adequate number of batches must be tested to
determine an appropriate expiration date. A record of
such data must be maintained.
Accelerated studies, combined with basic stability
information on the components, drug products, and
container-closure system, may be used to support
tentative expiration dates.
Full shelf-life studies, if not available, are being
conducted.

Stability Q1(R2)

ICH condition contributing 80% of pharmaceutical market

Outlines minimum stability data package for new drug application.
It is not intended for INDs, ANDAs or sNDAs.
Harmonizes stability requirement for marketing application in EU,
Japan and US. Other countries adopt with some modifications.
Must use Validated Stability-Indicating analytical methods
Methods must cover physical, chemical, biological and
microbiological attributes
.

Stability Q1(R2)

Studies evaluated under thermal and elevated

humidity to cover storage, shipment and
subsequent use
Accelerated and intermediate used to evaluate
impact of short-term excursions.
Acceptance criteria should include individual
and total upper limits for impurities and
degradation products
No formal statistical analysis is needed if data
show little degradation or variability.

API
Significant change is defined as failure to meet the
specification.

Drug Product
- 5 percent potency change from the initial assay value;
-Any specified degradant exceeding its acceptance criteria
-Failure to meet acceptance criteria for appearance and
physical properties (e.g., color, phase separation,
resuspendibility, delivery per actuation, caking,
hardness); and as appropriate to the product type;
-The pH exceeding its acceptance criteria; and Dissolution
exceeding the acceptance criteria for 12 dosage units.

Photostability:
Two types of studies, exposure is cumulative from the light sources
Forced degradation study to generate potential degradation products
2 X exposure to UV and fluorescent sources
Confirmatory study to confirm product and package performance
NLT 1.2 million lux hours + 200 watts/hrs per sq. meter

Light Sources:
Option 1
Dual output light sources, such as D65/ID65
Simulates artificial day light fluorescent lamp
Use Xenon or Metal Halide
Option 2
Tandem exposure to single light source types
Cool white fluorescent lamp + near UV fluorescent lamp (320-400 nm)
Accumulate exposure under one, then the other

Bracketing:

Used for packaging extremes

Assume that the intermediates are represented by the
extremes
For a range of strengths, strengths must be identical or
very closely related in composition
Can be applied to different container sizes or fills of
same packaging system
Bracketing design is NOT appropriate if extremes are
not demonstrated.

Matrixing:
Define full design and reduced design (with
examples)
Assume that the stability of each subset of
samples tested represent
the stability of all samples at a given time point
Define what is needed for justification
Covering different batches, different strengths,
different sizes of the
same container and closure, and, possibly, in some
cases, different
container/closure systems.

Design Program by Phase

Stability Program varies depending on the phase
and
clinical study it supports
Stability Study Goals...
Identify problems early
Know your product
Minimize repeat study
Identify critical control attributes i.e., Particle size
Develop a stable commercial product
Maintain database--stability informatics
Establish systems to cycle back learning
Develop stability strategies to expedite product
development

Phase II & III

Stability profile of clinical materials must be monitored
Test stations
25 C/60%RH
30 C/75%RH (if trial conducted in zone III and IV)
40 C/75%RH (Open Dish 1M)
40 C/75%RH
ICH Photostability
What packaging will be required
Is your product moisture, light or heat sensitive
Desiccant needed/filler

Special storage conditions

For liquids in semi-permeable package
Long term: 25 oC/40%RH (Zone I/II)
Or 30 oC/35%RH (all zones)
Intermediate: 30 oC/65%RH
Accelerated: 40 oC/<25%RH and 40 C/75%RH
To support adverse shipping and unusual storage of samples
(liquid)
Freeze Thaw Cycling (-10 C to -20 C four days, 25 C or
25 C/60%RH for three days)
Thermal Cycling (40 C four days, equilibrate to 25 C and
then 5 C for three days)

Analytical Methods
Analytical methods must be validated for its
intended purpose.
Analytical methods are needed for active ingredient,
degradation products and other component of interest
(211.166)
Stability methods must be stability indicating

ICH Guidelines
Q1AR2The testing should cover, as appropriate, the
physical, chemical, biological and microbiological
attributes, preservative content, and functionality tests
(e.g for a dose delivery system). Analytical procedures
should be fully validated and stability indicating.

Q2A Validated analytical procedures should be

used, irrespective of whether they are for in-process,
release, acceptance, or stability testing.

ICH Guidelines
Q3B: Analytical methods should be
validated to demonstrate that impurities
unique to the new drug substance do not
interfere with or are separated from
specified and unspecified degradation
products in the drug product.

ICH Guidelines
Q2A
Stress studies (e.g. products of acid and base hydrolysis,
thermal degradation, photolysis, oxidation) for the drug substance and
for the active ingredient in the drug product should be provided to
demonstrate the specificity of the assay and analytical procedures for
impurities.

Goals
Generate typical degradation products which may be expected on
stability at sufficient levels to allow identification
Avoid secondary degradation
Target range is 5-20 % loss of active as judged by assay relative to
an undegraded sample
Look for purity and mass balance

Storage Conditions

Global storage conditions :

Selection of batches :

Q1A R2 -- API Stress Testing

Stress testing is required
To understand the drug substance stability
To establish degradation pathways
To validate the stability indicating power of the analytical procedures
used.
To support the severe conditions that may be encountered during
distribution.
Use single batch of material
at temperature above the accelerated temperature (50 C, 60 C)
humidity (e.g., 75 %RH or greater),
oxidation and photolysis on the drug substance across a wide range
of pH values
when in solution or suspension.
Photostability testing should be an integral part of stress testing (ICH
Q1B)

Q1A R2 -- API Stress Testing

Study depend on the individual drug substance and type
of drug product. Some degradation pathways can be
complex and that, under forcing
conditions,decomposition products may be observed that
are unlikely to be formed under accelerated or long-term
testing.
Useful in developing and validating suitable analytical
methods, but it may not always be necessary to examine
specifically for all degradation products if it has been
demonstrated that in practice these are not formed.
Results from these studies are part of regulatory
submission.

Typical Forced Degradation Design

Drug Substance
Solid State:
Heat: 60 C for up to 1 month
Photostability: twice ICH requirements
Solution State: depending on solubility
Acid: 0.1-1N HCl to 2 weeks and to 60 C
Base: 0.1-1N NaOH to 2 weeks and to 60 C
Peroxide: 3% of H2O2 to 24 hours and to 40 C
Photostability: twice ICH requirements

Typical Forced Degradation Design

Drug Product
Drug Product:
Heat: 60 C for up to 1 month
Photostability: twice ICH requirements
Using placebo as control

For combination product (multiple active ingredients)

Stress should be done for API individually and also in the
presence of the other API (s).

Potential Impurities
Impurities for APIs and Excipients:
synthesis precursors
synthesis bi-products
residual solvents
catalysts
decomposition
and other impurities
Impurities for Drug Products:
degradations products
extractables
residual solvents
unknown substances

Conclusion
Stability is a critical quality attribute of the API and the
Drug Product
Stability profile needs to be established for drug product
to assure safety, efficacy and quality.
Understand key concepts to develop stability indicating
methods.
Understand the Regulatory Requirements versus
Scientific Knowledge.
Understand regional versus global concerns to develop
stability program
Design strategy for stability study based on data of
development batches
Review cGMPs violations and regulatory observations
Develop stability program and maximize efficiency

DEFINITION
STABILITY
The capacity off a drug product/substance to remain within
specifications established to ensure its system, identity,
strength, purity & quality
The purpose off stability testing is to provide evidence on
how the quality off a drug substance or product varies with
time under the influence off a variety off environment factor.
Temperature, humidity, light and to set up retest period
for the drug substance or a shelf-life for the drug product
and recommended storage conditions.

ICH Drug Stability Test Drug Stability Test

Requirements
Scientific in approach
Provide clear mandate to users
Call for good infrastructure and investment in stability
testing

HOW TO GO ABOUT STABILITY STUDY

ICH
International Conference on
Harmonization of Technical
Requirements for Registration of Pharmaceuticals for
Human use.

ICH - A TRIPARTITE AGREEMENT

17 countries in three regions
The world biggest pool for production and
consumption of pharmaceuticals

Legal status of guidelines

Most of the guidelines have
become part of the local
regulations in US , Europe and
Japan

THE ZONE CONCEPT

Distribution of world into
Four different zones

FOUR ZONES