HPE Drug stability: What do we need to know? | Page 24

it is unsatisfactory that provision of information
on ingredients not having a pharmacological
effect is optional. In view of increasingly improved
drug safety measures, an obligation to declare
full information on the ingredients, including
quantities, is urgently required.
Incompatibility and compatibility data
When interpreting compatibility data, it is
important to consider the preparations themselves,
bearing in mind that similar products from different
manufacturers might have different formulations
that affect the results. Therefore, the preparations
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and other materials used for the study, including
source, quantities, and concentrations, must be
evaluated. Also, a combination might be stable
and compatible at low concentrations but not
at higher concentrations, and vice versa. Due to
possible differences between different batches of a
product (for example, changes in the formulation),
the batch number of the drug used to carry out
the tests must be documented. The temperature at
which the test takes place must also be specified.
The term ‘room temperature’, according to the
European Pharmacopoeia (15–25°C; 59–77°F), might
be sufficient for defining storage conditions but
is unsuitable for defining the test temperature,
because significantly different build-up rates
might occur at 25°C compared with 15°C. In
addition, lighting conditions must be described
(light protection or illuminance, irradiance, type
and spectrum of the light source) in photostability
studies. Because active ingredients can interact with
the container used, its type and material must also
be reported. Finally, the analytical methods should
be described in detail; for previously published
method, a reference to the source is usually
sufficient.
The pH of a mixture immediately after
preparation must lie between the starting pH values
of the injection and infusion solutions. If outside of
this range, it is an indication of a chemical change
which, unintentionally and undesirably, can render
the mixture of such components incompatible.
When the pH of the mixture subsequently
changes over time also indicates the (albeit slower)
occurrence of chemical reactions, and whether they
can be tolerated or not depends on the extent to
which the components are perishing. Therefore,
pH changes serve as an indicator of compatibility.
No shifts are allowed with buffered solutions, but
a deviation of up to 0.2 units (or deviation by more
than 0.5 units, according to other authors) from
the starting point indicates incompatibility with
unbuffered solutions. 5 This difference in assessment
for the two types of solutions is based on the fact
that small amounts of acid or alkali are sufficient
for a shift in pH of an unbuffered solution, whereas
considerably larger amounts are needed to trigger
an equally strong effect in a buffered solution. 5
Knowledge of the buffering capacity of a solution is
also important for another reason. Any deviations
in pH for parenteral preparations will equalise in
buffered carrier solutions, whereas their pH will
only slightly increase when added to unbuffered
solutions. However, because the optimal pH for
stability is chosen in the preparation of a solution
for injection, deviations from this value could
possibly result in changes in the active substance. 6
It must be noted that manufactured products
are often in a labile state of equilibrium because
balanced formulations are generated for stabilisation
purposes. This state can be disturbed easily by
changes in environmental conditions; therefore,
stabilisation involves physical, chemical and/or
antimicrobial measures. In addition to the drug
itself, excipients and solvents that might be required
must not be disregarded. Furthermore, interactions
with the materials in containers, closure systems,
and application systems and devices might affect
stability.
Evaluation and transposition of ‘outsourced’
stability data
As the quality of stability data provided by third
parties might vary markedly, it is essential to check
the validity of the methods used in the stability