HPE Drug stability: What do we need to know? | Page 29

Clear limits or
acceptance
criteria for each
parameter
measured should
have been clearly
defined before the
study commenced
returned back to storage conditions for a period
followed by re-testing. This approach has the
advantage that the effect of storing an infusion and
then taking it to the clinic for use can be exactly
replicated and, unlike with parallel temperature
studies, the stability of the infusion that is actually
administered is accurately established. This also
allows a clear judgment to be taken on whether
infusions returned from the clinic unused may
be returned to storage for later use or must be
discarded since temperature-cycling effects on the
infusion are accounted for. The disadvantage of
the sequential design is the additional complexity,
workload and cost.
Ideally, the stability assessment should be
conducted with three different batches of the drug
from the manufacturer and at each time-point
samples should be taken from triplicate containers. 4
This also enables the reporting of the mean drug
concentration and mean % of drug remaining
(100% at time zero) at each time point, and enables
the calculation of the dispersion of results at
each sample time. These are reported as standard
deviation and coefficient of variation.
The injections or infusions on study should be
subjected to identical conditions to those intended
to be used in practice, particularly in terms of light
protection and overwraps. The duration of the
study should encompass the stability period
required (or hoped for) in practice, and there should
be at least four different time points at which the
infusions under study are tested. 4 This gives more
confidence to the results than say only two time-
points, and also enables any trends to be observed
(for example, drug degradation over time).
The schedule of testing at each time-point should
be comprehensive. For chemical stability, HPLC is
frequently used, but this must be fully validated
(see methods, below) to isolate and quantify the
main analyte (usually the active drug) under study.
Physical stability at each time-point would be
assessed by measuring pH, infusion appearance
and absence of visible particles, sub-visual particle
counts and the monitoring of weight changes in
the infusion to identify any loss of water through
the walls of the infusion container under storage.
This last point is important because any loss of
water could effectively concentrate the infusion
and mask any drug degradation by maintaining
the drug concentration over time. Sub-visual
particulate counts cannot normally be interpreted
to the limits set in the Pharmacopoeia for
terminally sterilised injectables but are useful
to monitor trends of particulate aggregation
that indicate impending physical instability and
precipitation.
Some experts advocate the ‘tracking’ of
degradation products during stability studies. This
is very difficult because in many cases the identity
of degradation products is not fully understood,
which makes quantification difficult. Furthermore,
degradation products are often present at very
low concentrations in dilute infusions, adding to
analytical difficulties. Degradation products are also
conflated with impurities or ‘related substances’
arising from the manufacturing process of the active
drug. In fact, these are normally quite different and
the related substances will be quantified for each
batch by the manufacturer to ensure they are within
the product specification.
Methodologies
Infusions or injections for sterility testing must
be prepared from drugs and consumables that are
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