Drug stability in dosage forms
(2102)
Howida Kamal Ibrahim, Ph.D
Rehab Shamma, Ph.D
Master degree in pharmaceutical sciences (Pharmaceutics)
Master degree in pharmaceutical sciences (Industrial Pharmacy)
Diploma of industrial pharmacy
Drug stability in dosage forms
Drug substance
Chemical degradation
Physical degradation
•Hydrolysis
•Oxidation
•Dehydration
•Photodegradation
•Transitions in crystalline states
•Formation & growth of crystals
•Moisture adsorption
•Sublimation
Drug stability in dosage forms
Drug substance
Dosage form
Drug substance
Excepients
Physical
degradation
Drug/Excepient interaction
Biological
degradation
Packaging
Drug stability in dosage forms
•Introductory overview
•Reaction orders
•Factors affecting reaction rate
•Accelerated stability testing
•Pre formulation
•Kinetics of physical degradation
•Physical testing of dosage forms
•Packaging
•Stability guidelines
Drug Stability, Principles and Practices
By:
J.T. Carestensen
C.T. Rhodes
Introductory Overview
1. Stability is an essential quality attribute for drug
products
2. Conformance period, shelf life and expiration date.
3. Modes of degradation
4. Potential adverse effects of instability in pharmaceutical
products
5. The scope of stability concerns
6. Reasons for stability testing
7. The essential elements of a high-quality and cost effective
stability program
8. Some possible strategies to improve shelf life
Stability is an essential property
of drug products and the
assignment of a shelf life is a
routine regulatory requirement.
Stability is an essential property
of drug products and the
assignment of a shelf life is a
routine regulatory requirement.
Conformance period, shelf life
and expiration date
Conformance period: is defined by the most vulnerable timedependant quality attribute.
Shelf life is = or < the conformance period and is usually a
convenient round number.
Expiration date on a product label is the date at which the shelf
life ends for this batch (on storage at the recommended storage
conditions).
It is given only the month and the year (April’ 09)
For 5-year shelf life, the practice is to give expiration dates for
months of January or July.
Potential adverse effects of instability in
pharmaceutical products
Modes of degradation
1. Chemical
2. Physical
3. Biological (especially microbiological)
Potential adverse effects of Instability in
pharmaceutical products
1. Loss of active
2. Increase in active concentration
3. Formation of toxic degradation products
4. Loss of content uniformity
5. Alteration in bioavailability
6. Decline of microbiological status
7. Loss of package integrity
8. Loss of pharmaceutical elegance and patient acceptability
9. Reduction of label quality
10.Modification of any factor of functional relevance
Potential adverse effects of Instability in
pharmaceutical products
Loss of active
% of labeled claim
110
100
90
6
12
18
Time (months)
24
Potential adverse effects of Instability in
pharmaceutical products
Loss of active
% of labeled claim
110
Linear regression
100
90% confidence zone
90
95% one-sided lower
confidence limit for the mean
6
12
18
Time (months)
24
Least squares regression analysis
Order of the reaction
Potential adverse effects of Instability in
pharmaceutical products
Loss of active
Shelf life values are assigned to a
product rather than a batch
?
Potential adverse effects of Instability in
pharmaceutical products
Increase in active concentration
95% one-sided upper
confidence limit for the mean
% of labeled claim
110
Linear regression
100
90
6
12
18
Time (months)
24
Least squares regression analysis
Potential adverse effects of Instability in
pharmaceutical products
Formation of toxic degradation products
If a drug degrades to a molecular species that is toxic
Ex. 4-Epianhydrotetracycline from tetracycline
4-Epianhydrotetracycline exhibit
a 250-fold higher toxicity
Potential levels of toxic degradation products are of
considerable importance for the approval of stability
overages for new products
Potential adverse effects of Instability in
pharmaceutical products
Loss of content uniformity
Suspensions are the drug delivery systems that most
likely to show a loss of content uniformity as a
function of time
Stability study should include physical such as:
1. Ease of re-dispersion
2. Sedimentation volume
Potential adverse effects of Instability in
pharmaceutical products
Alteration in bioavailability
Bioavailability and bioequivalence are of great
importance to evaluate the drug product quality
Bioavailability (rate and extent of drug absorption)
In vitro dissolution is an appropriate test to predict any
possible clinically relevant modification of
bioavailability or bioequivalence
Examples of bioavailability alterations
problems:
Hardening of the
surface of
tablets
Pellicle formation
with hard gelatin
capsules
a skin-like film on the gelatin capsules
Potential adverse effects of Instability in
pharmaceutical products
Decline of microbiological status
The microbial status of all pharmaceutical
products should be evaluated with time
Sterile products
Non-sterile products
Should be free from all forms
of life (vegetative & sporing)
Extent of total
bioburden
Exclusion of
pathogens
Potential adverse effects of Instability in
pharmaceutical products
Decline of microbiological status
Change of microbial status with time
↑ of present m.o by reproduction
> maximum permitted bioburden
Ingress of m.o due to loss
of package integrity
Package
integrity tests
Quality of raw
materials
Manufacturing
facility
Manufacturing
operation
Potential adverse effects of Instability in
pharmaceutical products
Decline of microbiological status
In some parts of the world, Biological
problems are not limited to the microbial one
but rats, roaches, ants and other nonmicrobiological organisms can be responsible
for stability problems
Potential adverse effects of Instability in
pharmaceutical products
Loss of package integrity
Example: loss of back-off-torque for a plastic screw cap
Potential adverse effects of Instability in
pharmaceutical products
Loss of pharmaceutical elegance
and patient acceptability
Loss of pharmaceutical elegance includes any aspect of
the product that might suggest that the product is
somehow substandard or variable
Potential adverse effects of Instability in
pharmaceutical products
Loss of pharmaceutical elegance
and patient acceptability
speckling on
tablet surface
ease of use
loss of label Batch to batch variations
adhesion
in appearance, taste or
smell
Potential adverse effects of Instability in
pharmaceutical products
Reduction of label quality
Any legibility problem
Potential adverse effects of Instability in
pharmaceutical products
Modification of any factor of functional relevance
Any time dependant change of any functionally relevant
attribute of a drug product that adversely affects safety,
efficacy, patient acceptability or ease of use
Example: adhesion aging of a transdermal patch
The scope of stability concerns
1. Bulk drug substance and excepients
2. Research and development formulation
3. Clinical trials materials
4. Marketed product
5. Product in the channel of distribution
6. Product under the control of the patient
7. In vivo stability
8. Reformulation, change of manufacturing site,
troubleshooting, complaints
The scope of stability concerns
(Raw materials)
Bulk drug substance and excepients
Just-in-time
method
In-house testing by
the manufacturer
Drug
Pharmacopeias
excepients
No standards
Handbook of pharmaceutical excepients
Comprehensive data
due to manufacturers’
competitions
The scope of stability concerns
Research and development formulation
No universally accepted procedures of evaluating
stability of R&D formulae
Accelerated
testing
Comparison with
similar market products
The scope of stability concerns
Clinical trials materials
• FDA has issued specific requirements during clinical trials
• All efforts are devoted to produce data that will convince a
regulatory authority that a particular formulation, process
and shelf life for a new or reformulated product are
acceptable
The scope of stability concerns
Marketed product
The manufacturer continues stability studies by
storing samples in stability storage areas and
testing them to generate reliable stability data to
assure that the marketed product continues to
justify the assigned shelf life.
The scope of stability concerns
Product in the channel of distribution
Products could be subjected to instability issues
during distribution
Dropping off a
truck back
Staying in direct sun or
freezing cold
Regulations
?
The scope of stability concerns
Product under the control of the patient
Patient counseling
Stress stability testing
The scope of stability concerns
In vivo stability
pH sensitive drugs (in the GIT)
The scope of stability concerns
Reformulation, change of manufacturing site,
troubleshooting, complaints
An intermittent new study after marketing for a
variety of reasons
Change
Change
formulation process
Change site of
manufacturing
Unexpected
stability
problems
Complains of
patients and
health
professionals
Stability testing
Stability testing aims to ensure the quality,
safety and efficacy of drug products up to their
expiration date.
This means that all organoleptic, physiochemical,
chemical and microbial test results must be
within the shelf life tolerance ranges up to the
end of the shelf life.
Stability testing accompanies the development
of a medicinal product from the first preliminary
trials with the drug substance up to continuous
production.
Reasons for stability testing
1.Our concern for patients’ welfare
2.To protect the reputation of the producer
3.Requirements of regulatory agencies
4.To provide a database that may be of value in
the formulation of other products
Reasons for stability testing
patients’ welfare
Toxic
Inconvenience
Sub-potent
degradation
levels
products
Discomfort Cost associated
problems
The over all stability programme can be divided into six steps:
Step 1 •Stress and acceleration tests with the drug substance
Step 2 •Pre-formulation and formulation finding for toxicological
test samples, clinical samples, and final dosage form.
Step 3 •Stress and acceleration tests with selected formulations
toxicological test samples, clinical samples, final dosage
form, and selection of primary packaging materials.
Step 4 •Acceleration and long-term tests on drug substance and
drug products up to marketing authorization
Step 5 •Ongoing stability testing of drug substance, drug products
marketing authorization batches, and production batches
Step 6 •Follow-up stability tests on drug substance, drug products
continuous production, and modifications during
continuous production.
Each stage covers 11 basic principles:
•Selection of batches and samples
•Test criteria
•Analytical procedures
•Specifications
•Storage conditions
•Testing frequency
•Storage period
•Number of batches
•Packaging materials
•Evaluation
•Stability information
The essential elements of a high-quality
and cost effective stability program
1. Commitment of the organization to quality
2. Firm grasp of underlying scientific theory
3. Up- to- date knowledge of all relevant policies of
regulatory agencies and applicable pharmacopoeial
standards
4. Effective communication between R&D, production, QC/
QA, complaints, and regulatory affairs
5. A general understanding of the limitations of the
analytical methods used in the stability testing program
6. Careful monitoring of the stability budget
7. Managerial skills to coordinate and optimize the
program
Some possible strategies to improve
shelf life
1.Formulation
2.Process
3.Sampling and analytical
4.Statistical
Some possible strategies to improve
shelf life
1.Formulation
2.Process
3.Sampling and analytical
4.Statistical
Some possible strategies to improve
shelf life
1.Formulation
The overage
% Labeled Claim
110%
100%
90%
80%
0
100
200
Time (days)
300
400
Example
Calculate the overage required to extend the shelf life
of this product from ….. to ….. months.
% Labeled Claim
110%
100%
90%
80%
0
5
10
15
20
25
Time (months)
30
35
Some possible strategies to improve
shelf life
1.Formulation
2.Process
3.Sampling and analytical
4.Statistical
Some possible strategies to improve
shelf life
3. Sampling and analytical
% of labeled claim
110
100
90% confidence zone
90
6
12
18
Time (months)
24
Least squares regression analysis
Some possible strategies to improve
shelf life
3. Sampling and analytical
% of labeled claim
110
100
90% confidence zone
90
6
12
18
Time (months)
24
Least squares regression analysis
Some possible strategies to improve
shelf life
4. Statistical
% of labeled claim
110
100
90
6
12
18
Time (months)
24
Least squares regression analysis
Some possible strategies to improve
shelf life
4. Statistical
% of labeled claim
110
100
90
6
12
18
Time (months)
24
Least squares regression analysis