HPE Drug stability: What do we need to know? | Page 14
It is essential to
use validated
stability-indicating
assay methods
that are able to
separate
degradation
products being
formed in the
practical use of
the drug
salt effects, oxygen, shaking and shearing, and
concentration.
When studying chemical, physical and
microbiological stabilities, the main aspects to be
evaluated are:
1 Stability of the solution over time using one or
more appropriate analytical techniques (HPLC (more
commonly), mass spectrometry)
2 Identification of any degradation products and
purity of product (Diode Array more commonly)
3 Simulation of the operating conditions of use and
conservation
4 Compatibility with the primary packaging
5 Bibliographic references.
A useful summary of the guidelines for the
development of stability analysis methods has been
presented by Bakshi and Singh, 18 who defined the
fundamental steps for conducting these studies as:
• Critical study of drug structure to define
degradation patterns
• Collection of information on chemical
and physical properties
• Forced degradation studies
• Final development and optimisation of the method
• Identification and characterisation of degradation
products and standard preparations
• Method validation.
For in-use stability, the conditions of use cannot
always be well standardised owing to the variability
of the situations that the user might require. The
EMA’s recommendations 4,5 for assessing in-use
stability with the methods and limits of the tests to
be performed detail important conditions, including:
• Necessity to analyse at least two different
production batches, of which at least one is
numerically representative (pilot scale batches),
based on the specific production
• Desirable that one of the two lots be near the end
of its shelf-life
• That in the extraction of the samples for analysis,
the conditions of use should be simulated, in
terms of dilution for the administration of the
product, and for the dose intervals, and suggested
environmental and conservation conditions.
14 | 2019 | hospitalpharmacyeurope.com
In practical stability studies, one batch might be
acceptable but determinations should be performed
in triplicate.
The methods used by the pharmaceutical industry
for analysing stability of a product are called
‘stability-indicating assays’. The ICH guidelines 6
recommend conducting forced degradation studies
under a variety of conditions, such as pH, light,
oxidation, dry heat, etc, and the separation of
the drug from its degradation products; it is then
recommended that the method allows the analysis
of the individual degradation products.
It is essential to use validated stability-indicating
assay methods that are able to distinguish
degradation products being formed in the practical
use of the drug.
A stability-indicating assay must therefore be
able to identify drug substance and its degradation
products; this usually occurs by stress testing/forced
degradation, by varying:
• pH: NaOH, HCl
• temperature
• heat: starting from 50°C
• oxidative conditions: H 2 O 2 from 3% up to 30%.
It is essential to degrade only a part of the drug
present (ICH recommends no more than 40%);
passing from mild conditions to conditions that
become increasingly aggressive, in the eventuality
of identifying different routes of degradation of the
substance.
A stability-indicating assay is a validated
quantitative analytical method that can detect
changes in the chemical, physical or microbiological
properties of a drug substance over time, and which
is specific enough to allow the active ingredients,
degradation products and other components of
interest to be separated, detected and quantified
accurately.
The practical stability study should first involve
simplified stress assays performed in glass vials,
testing for the intrinsic stability of the solution
and to determine the relevant stability conditions
to be used. After that, the drug should be tested
in the solvent and the container used in clinical