HPE Drug stability: What do we need to know? | Page 22

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Manufacturer data: considerations
for provision and interpretation
This article deals with the interpretation and evaluation of manufacturer provided data and discusses
according quality requirements
Robert Terkola
MPharm PhD
Onkoservice, Vienna,
Austria
Hospital pharmacists and pharmacy
technicians regularly prepare parenteral
medications. Most of these products have to be
added to infusion solutions, and it is still common
practice to undertake this without taking into
account the stability of the resulting product, which
might have potential therapeutic implications. The
fact that particularly problematic drugs and
applications are readily recognised, or known as
such before administration, is crucial for patient
safety, but the risks that this prevailing practice
entails can only be counteracted by good
multidisciplinary cooperation among pharmacists
when evaluating the stability of the resulting
products to guarantee optimal outcomes and safety
with parenteral drug therapy.
Because of increased centralisation of services,
these drugs might have to be prepared in advance
of handling by physicians and nurses. Undesirable
events such temperature excursions, interruptions
in the cold chain, poor storage practices in the
wards, inadequate light exposure, prolonged storage
times and delayed administration, as well as dose-
banding, shaking with formation of air bubbles, use
of potentially incompatible devices, long-distance
transportation, and use of pneumatic tubes for the
infusion can have a negative effect on the stability of
the mixture. However, it is only possible to resolve
stability issues by having access to accurate, high-
quality data. 1,2
To be able to use their expertise in
pharmaceutical technology, pharmacists require
access to well-documented stability studies of
the individual drugs in practical situations,
ranging from punctured vials, reconstitution of
a lyophilised product, dilution in various vehicles,
and interactions with medical devices such as
containers, filters and IV lines, but often their needs
are not covered by the information provided in the
Summary of Product Characteristics (SPC) or in the
medical literature. Because it is not always possible
to conduct stability studies in the hospital, this
review addresses the interpretation and evaluation
of manufacturer-provided data and discusses quality
requirements. 2
Stability data provided by manufacturers
Each proprietary drug is the result of a balance
between its galenic formulation and therapeutic
requirements, but these properties might not
be preserved when the individual components
are mixed in an infusion. For example,
photoreactions can result in both visible and latent
incompatibilities between components. In addition
to heat and moisture, light is in fact one of the
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main external factors that induces decomposition
of drugs; numerous excipients can be affected
by light as well. 3 However, insufficiently detailed
information from the manufacturer on the need for
light-shielded storage does not allow any conclusions
to be made on any need for light protection
during the infusion, which might generate
considerable uncertainty in daily practice. This
type of information might not be found in the SPC.
Moreover, the photosensitivity of the drug depends
on the concentration of the active ingredient and
the type of solvent used; therefore, the results of
photostability investigations are of practical use
only if they are carried out under standardised
conditions. The sparse analyses meeting these
requirements that have been carried out so far
indicate, however, that probably no protection
against light is necessary when a large proportion
of preparations are to be stored protected from light
during an average infusion period. The preservation
of the stability of medicinal products can also be
ensured by excluding oxygen during the production
process and the storage period. Hence, it is essential
that pharmaceutical companies disclose if the
immediate packaging filling process is undertaken
without oxygen.
Classical visual inspection is regularly used
to check physical stability. The suitability for
determining short-term compatibility (for
example, in parallel infusions) has been tested
extensively, and questions about the validity of
photometric measurements remain. It has been
shown that visual inspection against a light and
dark background appears to provide more reliable
results than turbidimetry. 4 However, it should be
noted that turbidity and precipitation do not always
occur immediately; on the contrary, due to slow
crystallisation times, precipitations are often only
visible after a number of hours.
Although detailed documentation including data
on photosensitivity and physical stability must be
submitted for regulatory approval of medications,
this information is rarely available post-
commercialisation, despite its obvious usefulness
in the assessment of stability or compatibility
issues. The application for marketing authorisation
must be accompanied by complete shelf-life test
reports, including the context of the proposed
retail packaging, the specific storage conditions
to be used, and any changes in the content and
nature of the active substance. But even though
these data are readily available, they do not reflect
the requirements for compounded products under
practical conditions. In terms of an assessment of a
possible degradation of the compounded product,