Understanding and predicting

product shelf-life

Dr. Mathias Kramer

Purpose of Stability Testing

What affects Stability?
Evaluation of Stability Data
Reasonable Stability Testing
Conclusion

Understanding and predicting product shelf-life

Purpose of Stability Testing

Gather knowledge about the product and degradation
Find interactions between excipients and API
Investigate different package dresses
Enables a product to be registered
Establish expiration dating period
Establish storage conditions, label claims
Establish regulatory specifications
derived from a consideration of available stability data
Delivers medicines of proven quality, safety and efficacy

Purpose of Stability Testing

What affects Stability?
Evaluation of Stability Data
Reasonable Stability Testing
Conclusion

Understanding and predicting product shelf-life

What affects Stability?

(1)

Storage Time
Storage Condition (Temperature, Humidity, Light, Oxygen)
Dosage Form (Tablet, Capsule, Vial)
Manufacturing Procedure
Packaging
Formulation (Composition, Quantity, Quality of excipients and API)

Understanding and predicting product shelf-life

What affects Stability?

(2)

Temperature
- the kinetic of a degradation can be described by the Arrhenius equation
- for evaluation you need the accelerated condition
k=A*exp(-Ea/R*T)
k: is the rate coefficient; A: is a constant; Ea: is the activation energy
R: is the universal gas constant; T: is the temperature (in Kelvin)
A historically useful generalization supported by the Arrhenius equation is that,
for many common chemical reactions at room temperature, the reaction rate
doubles for every 10 degree Celsius increase in temperature

Understanding and predicting product shelf-life

What affects Stability?

(3)

Humidity
- may influence degradation; hydrolysis
- for evaluation you need different humidity, packaging configuration
Light
- may influence degradation; photoreaction
- for evaluation you need photo stability testing
Oxygen
- may influence degradation; oxidation
- for evaluation you need different packaging configuration

Understanding and predicting product shelf-life

What affects Stability?

Packaging configuration
- no temperature protection
- light protection
- humidity protection
humidity protection (water vapour permeability) of blisters
PVC- < Duplex- / Triplex- < Alu- blisters
humidity protection (water vapour permeability) of bottles
HDPE- bottles < Glass- bottles

(4)

Understanding and predicting product shelf-life

What affects Stability?

(5)

Formulation
Fixed dose combination finished pharmaceutical product (FDC-FPP)
Def.: A finished pharmaceutical product that contains two or more actives
- May have an impact on the stability, the APIs may react with each other
- The most sensible API will trigger the shelf-life
- Testing has to take all APIs into account (assay, degradation, dissolution)

Purpose of Stability Testing

What affects Stability?
Evaluation of Stability Data
Reasonable Stability Testing
Conclusion

Understanding and predicting product shelf-life

Evaluation of Stability Data

(1)

Defined in the ICH Q1E and WHO-Guideline

A systematic evaluation should be performed. Stability data for each attribute
should be assessed sequentially
The assessment should begin with any significant change at the accelerated
condition
Extrapolation to extend the shelf life beyond the period covered by long-term data
can be proposed if no significant change is observed at the accelerated condition

Understanding and predicting product shelf-life

Evaluation of Stability Data

(2)

Provisional shelf-life may be established without statistical analysis if

The API is known to be stable (not easily degradable)
6 month accelerated and 12 month long term data are available
The accelerated and long-term data show no or little changes or variability
The manufacturer will continue the long-term studies up to the proposed shelflife
Results will be submitted to the health authorities

Understanding and predicting product shelf-life

Evaluation of Stability Data

(3)

Significant change
5% change in assay from its initial value
Any degradation product exceeding its acceptance criteria
Failure to meet the acceptance criteria for appearance, physical attributes and
functionality test (e.g. color, phase separation, caking, hardness)
Also, as appropriate for the dosage form;
- failure to meet the acceptance criteria for pH
- failure to meet acceptance criteria for dissolution for 12 dosage units

Understanding and predicting product shelf-life

Evaluation of Stability Data

(4)

Statistical Approach
- Regression analysis (linear, non-linear)

An appropriate approach to shelf life estimation is to analyze

- assay
- degradation products
Determine the earliest time at which the 95% confidence limit intersects the
proposed acceptance criterion

Understanding and predicting product shelf-life

Evaluation of Stability Data

Proposed shelf life for
Room temperature
Storage
Y= 2 * X
but not more than X + 12
(24 month)
(30 month)
Y= 2 * X
but not more than X + 12
(24 month)
(30 month)
depending on the
statistical evaluation

(5)

Available
long-term
data [X]

Change or
variability over
time

Available
accelerated
data

Change or
variability over
time

little or no

6 month

little or no

Showing change
and / or
variability over
time

6 month

Showing change
and / or
variability over
time

(12 month)
(18 month)
X
(12 month)
(18 month)

statistical
analysis

Purpose of Stability Testing

What affects Stability?
Evaluation of Stability Data
Reasonable Stability Testing
Conclusion

Understanding and predicting product shelf-life

Reasonable Stability Testing

(1)

What has to be tested?

Basis Q1A (R2)

Stability studies should include testing of those attributes of the drug
product that are susceptible to change during the storage and are
likely to influence quality, safety and / or efficacy.

Understanding and predicting product shelf-life

Reasonable Stability Testing

(2)

Galenical Formulation

Parameter unlikely to change during storage

which could be omitted

Solid dosage forms (e.g.

tablets, capsules)

Identity, Shape und Imprint etc., Uniformity of

mass/fill mass/content

Ampoules

Identity, extractable volume, sterility, endotoxine test,

density

Vials

Identity, extractable volume, density

Powder, oral suspensions

Identity, Uniformity of mass/content

Understanding and predicting product shelf-life

Reasonable Stability Testing

Quality Attribute

Strength
Appearance
Color
Odor
Clarity
Moisture
Dissolution
pH
Viscosity
Resuspendability/redispersiblity
Separation
Weightloss
Homogeneity
Particulate/matter/size
Extractables
Pyrogenicity
Sterility/microbial limit
Preservatives
Container closure integrity
Other recommendations

Emulsions

+
+
+
+

+
+

+
+

c). d)

Oral
Solution
and
suspensions
+
+
+
+
+

+
+

+
+

d)

Aerosols

+
+
+

e)

(3)
Topical
SmallLargeand
volume
volume
ophthalmic parenterals parenterals
+
+
+
+
+

+
+
+
+
+
+
+

+
+

f)

+
+
+
+a
+
+a

+ a)

+
+ b)
+
+
+
+
d)

+
+
+

+b)

+
+b)
+
+
+

d)

+ May be required or required

Not required.
a)

Required for reconstituted

products.

b)

Required for products in

plastic containers

c)

Heating/cooling cycle 4C
45C

d)

Storage on side or inverted

e)

Number of metered doses,

delivered dose per activation,
propellant pressure, valve
corrosion, spray pattern, If
more than 3.5 g, sample at
surface, middle, bottom of
container, sample tubes near
crimp.
[Van den Akker, C. R.; Pharm. md.
53, 483 (1991)]

Purpose of Stability Testing

What affects Stability?
Evaluation of Stability Data
Reasonable Stability Testing
Conclusion

Understanding and predicting product shelf-life

Conclusion

You have to take many parameters into account

Quality is designed and built into a product and not tested in!
Stability has to be planned during lifecycle of the product with standardized
conditions

Thanks for your attention!

Dr. Mathias Kramer

We Innovate Healthcare