Drug stability
Ahmed Vandy
9454
B.Pharm YR1
DRUG STABILITY
Is the capacity of a drug to remain within established
specifications of identity, quality, purity in a specific
period of time.
 USP defines stability of pharmaceutical products as
“the extent to which a product retains with in
specified limit and throughout it period of storage and
use ( shelf life).
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TYPES OF STABILITY
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Chemical stability: each active ingredient retains its chemical
integrity and labelled potency within the specified limits.
Physical stability: the physical stability properties includes
appearance, palatability, uniformity, dissolution and
suspendabilty are retained.
Therapeutical stability: the theurapeut activity remains
unchanged
Toxicologic stability: no significant increase in toxicity occurs.
Factors that influence stability include
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stability of the active ingredient
Interaction between active ingredients and recipients
Manufacturing procedure followed
Type of dosage form
Container/closure system used for packing
Light, heat, and moisture conditions encountered
Degradation reactions such as oxidation-reduction,
hydrolysis etc
STABILITY TESTING OF PHARMACEUTICAL
PRODUCTS
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Stability testing evaluates the effect of
environmental factors on the quality of the a
drug substance or a formulated product
which is utilized for prediction of its shelf
life, determine proper storage conditions and
suggest labelling instructions.
Guideline for stability testing
To assure that optimally stable molecules and products are
manufactured, distributed and given to the patient, the
regulatory authorities in several countries have made
provision in the drug regulation for the submission of
stability data by the manufacturers. These guideline includes
basic issues related to stability, the stability data requirement
dossier and the steps for their execution. Such guideline were
initially issued in 1980 and were later made uniform in the
international conference on harmonization (ICH).
Codes and title used in ICH guidelines
ICH CODE
GUIDELINE TITLE
Q1A
- stability testing of new drug substance and product (second revision)
Q1B
- photostability testing of new drug substance and product.
Q1C
- Stability testing of new dosage form
Q1D
- Bracketing
Q1E
Q1F
and matrixing design
- Evaluation of stability data
- Stability data package for registration application in climatic zone III & IV
Types of shelf life study
Real time stability study
Accelerated stability study
Real time stability study
In real time stability testing, a product is stored at
recommended storage conditions and monitored until it
fails the specification
Real time testing is normally performed for longer
duration of the test period in order to allow significant
product degradation under recommended storage
conditions.
Method
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In real time stability tests, a product is stored at recommend storage
conditions and monitored for a period of time (Ttest)
Product will degrade below its specification at some time, denoted as (ts)
and we must also assure that ts is less than or equal to Ttest. The
estimated value of its ts can be obtained by modelling the degradation
pattern
Good experimental design and practices are needed to minimise the risk
of biases and reduce the amount of random error during data collection
Testing should be performed at time intervals that encompass the target shelf
life and must be continued for a period after degrades below specification.
Its is also required that at least three lots of materials be used in stability
testing to capture lot-to-lot variation, an important source of product
variability.
CLIMATIC ZONES FOR STABILITY TESTING
For the purpose of stability testing, the whole world has
been divided into four zones (I - IV) depending upon the
environmental conditions the pharmaceutical products are likely to
be subjected to during their storage. These conditions have been
derived on the basis of the mean annual temperature and relative
humidity data in these regions. Based upon this data, long-term or
real-time stability testing conditions and accelerated stability
testing conditions have been derived. The standard climatic zones
for use in pharmaceutical product stability studies have been
presented in the Table below.
ICH Climatic zones and long term
stability conditions.
Climatic
zone
Climatic
definition
Major countries
Mean average temp/
Mean annual partial
Water vapor
Long term testing
condition
I
Temperate
UK, Northern
Europe, Russia
≤ 15˚c/ ≤11 hpa
21˚c/ 45% RH
II
Subtropical
&
Mediterran
ean
Japan, southern
europe, usa
≤15-22˚c/>11-18 hpa 25˚c/60% RH
III
Hot & dry
Iraq, india
>22˚c/≤15 hpa
30˚c/30% RH
Protocol for stability testing
The protocol for stability testing is pre-requistie for certain stability testing and is
necessarily a written document that describes the key components of a regulated
and well controlled stability studies. Because the testing conditions is based on
inherent stability of the compounds, the type of dosage formed and the proposed
container closur4e system, the protocol depends on the type of drug substance or
the product. In addition, the protocol can depend on whether the drug is new or is
already in the market. The product should also reflects the region where the
product is proposed to be marketed. Example if the product is planned to be
used in climatic zones I-III, IVa and IVb, the stability program must include all this
zones. A well designed stability protocol should contain the following information.
a. Batches
Stability studies at developmental stages are generally
carried out on a single batch while studies intended for
registration of new product or unstable established product
are done on first three production batches, while for stable
and well-established batches, even two are allowed. If the
initial data is not on a fullscale production batch, first three
batches of drug product manufactured post-approval
should be placed on long-term studies using the same
protocol as in approved drug application.
b. Containers and closures
The testing is done on the product in immediate container and closure
proposed for marketing. The packing materials inlude aluminium
strip packs, blister packs, Alu-Alu packs, HDDPE bottles etc. This
may also include secondary packs , but not shippers . Product in all
different containers/closure, whether meant for distribution or for
physician and promotional samples, are to be tested separately.
However, for bulk containers testing in prototype containers is
allowed, if it stimulate the actual packaging.
C. Orientation of storage of container
Samples of the solution, is disperse system and semui solid
drugs product for stability studies must be kept upright
and position either inverted or on the side to allow for full
interaction of the product with the container/closure. This
orientation helps to determine whether the contact
between the drug product or solvent and the closure results
in the extraction of chemical substance for the closure
component or absorption of product component into the
container-closure.
D. Sampling time points
Frequency of testing should be such that it is sufficient to
establish the stability profile of the new drug substance. For
products with a proposed shelf life of at least 12 months, the
testing frequency at the long-term storage condition should be
every 3 months over the first year, every 6 months over the second
year and annually thereafter throughout the proposed shelf life
expiration date. In the case of accelerated storage conditions, a
minimum of three time points, including the initial and end points, for example, 0, 3,
and 6 months is recommended. When testing at the intermediate storage
condition is necessary as a result of significant change at the accelerated storage
condition, a minimum of four test points, including the initial and final time points, is
recommended, for example, 0, 6, 9 and 12 months. The test schedule for stability
testing of a new product has been presented in the table .
Environment
Sampling time points(months)
Method and climate zone
25˚c/ 60% RH
3,6,9,12,18,24,36
Long term for zones I and IV
30˚c /35% RH
3,6,9,12,18,24,36
Long term for zones III
30˚c/65% RH
3,6,9,12,18,24,36
Long term for zone IVa
30˚c/75% RH
3,6,9,12,18,24,36
Long term for zone IVa
40c/75% RH
3,6
Accelerated conditions for all
zones
Test Storage condition
The storage conditions to be selected are based on
the climatic zone in which the product is intended to
be marketed . General recommendations on the
storage conditions have been given by ICH,CPMP,
and WHO. The abridge ICH and WHO storage
condition for the drug product have been given in
the table.
integrated storage
Condition
Stability test method
ICH Test temperature
and humidity(period
in months)
WHO temperature
and humidtiy (period
in months )
Room temperature
Long term
25±2˚C/60±5% RH
(12months)
25±2˚C/60±˚5%RH
(12months)
Refrigerated
Long term
5˚C/ambient
(12 months)
25±2˚C/ 60±5%
Freezer
Long term
-20˚C/ambient
(12months)
-20˚C±5˚C
THE END