HPE Drug stability: What do we need to know? | Page 27

about their pharmacology or toxicology. Infusions
that contain degradation products could cause harm
if administered to the patient, particularly at high
concentrations.
Many pharmacy Bachelor or Masters’ first
degree curricula contain the basic educational
components needed to evaluate stability studies
and apply shelf-lives to aseptic preparations.
These include pharmaceutics, pharmaceutical and
analytical chemistry, pharmaceutical microbiology,
pharmacology and clinical pharmacy. A higher
research degree or degree with a research
component will provide additional skills in
literature critique, and a postgraduate research
or taught qualification in a specialised area
such as formulation, pharmaceutical analysis or
microbiology would be particularly helpful. In terms
of experience, a combination of pharmacy technical
services, quality assurance and clinical pharmacy
roles would be ideal. This helps the pharmacist to
see the whole picture, including the disease state,
treatment goals and patient management issues
when evaluating stability data and approving shelf-
lives.
National and international special interest groups
run study days or conference streams on stability of
aseptic products which are valuable in developing
knowledge and skills, and stability features as a
part of some specialised courses designed around
the needs of hospital pharmacy technical services
and aseptic compounding. Online tutorial material
remains scarce and of variable quality; pharmacists
new to this speciality are best advised to seek
mentorship from colleagues with a track-record
in evaluating stability data while they build their
own experience. The development of partnerships
between hospital pharmacies and academic
pharmaceutical sciences departments is also likely
to build and develop the required expertise.
Physical
Physical stability refers to visual and sub-visual
particulate levels in the infusion, which might
increase as a result of precipitation of poorly-soluble
components in the infusion or particle growth
arising from the dilution of solubilising agents
present in the original drug vial or an unfavourable
infusion pH. In complex admixtures, precipitation
can occur because two or more components form
insoluble complexes.
Physical instability can result in the loss of
active drug onto in-line administration set filters,
which can reduce efficacy, block the giving set or,
where there is no in-line filter, present the risk of a
pulmonary embolism and severe patient harm.
Adsorption of drug or other components onto
surfaces of containers is considered a physical
stability issue that has the potential to reduce
the therapeutic effect, especially at low drug
concentrations where the proportion of drug lost is
higher. A detailed discussion on the compatibility
of containers and other devices in contact with
infusions is beyond the scope of this article but it
is important to ensure that container and device
components such as plasticisers and heavy metals
(Fe, Cr) are not leached into the infusion during
storage and use.
Microbiological
It is known that aseptic processes present a
greater risk of microbiological contamination than
terminal sterilisation and so the assignment of an
extended shelf-life must take this into account.
Aseptic processes must be controlled through the
rigorous application of EU Good Manufacturing
Practice (GMP) and quality assurance programmes.
In some cases, extended stability does permit
the use of prospective sterility testing as part of
a quality control process, but sample sizes are
usually limited in small batch production. In
practice, microbiological assessments are usually
made locally on a case-by case basis by experienced
quality control teams with access to environmental
monitoring and in-process control data.
Pharmacist responsibilities, education
and experience
A nominated pharmacist must be responsible and
accountable for the shelf-life assigned to aseptically
prepared medicines. For infusions prepared ‘in-
house’, this may be either the aseptic services
manager or the quality assurance pharmacist. In
the case of infusions bought in from other hospitals
or commercial compounding units, the purchasing
pharmacist might also share some responsibility.
The responsible pharmacists must satisfy themselves
independently that expiration dates are based on
rigorous stability studies and robust data. They
must ensure that any interpretation of data is
scientifically, pharmaceutically and clinically
justified, and that the conditions reported in
studies cited as evidence correspond to the practice
situation where they are applied. These can include,
for example, storage and in-use temperatures, drug
concentration, choice of diluent, container and the
manufacturer/formulation of the medicinal
product. The process of shelf-life assignment should
be seen as part of the total quality management
programme.
In terms of
experience,
a combination
of pharmacy
technical
services, quality
assurance and
clinical pharmacy
would be ideal
Resources for stability studies of aseptic
pharmaceuticals
Pharmaceutical manufactures include stability
data and information on infusions prepared
from their products in the Summary of Product
Characteristics (SPC). 1 This information will form
part of the product licence and will usually be of
excellent quality. However, manufacturers have no
control over the quality of facilities in which aseptic
manipulation of their product occurs so they will
normally limit their extended shelf-lives to 24 hours
maximum on microbiological grounds. The value of
this source is mainly limited to short expiry dates,
although some manufacturers may share, or have
even published, longer-term stability studies on
their products.
Original studies on infusion/injection stability
are published in a range of peer-reviewed journals
coving pharmaceutical science and pharmacy
practice. Examples include the European Journal of
Pharmaceutics and Biopharmaceutics and the Journal
of Oncology Pharmacy Practice (contains studies on
anticancer agent infusions).
There are some excellent databases of stability
studies and one of the most comprehensive is the
Stabilis database. 2 This web-based resource has links
to the original publications and the experienced
data-base management team have also included an
assessment of quality for each study reported. This
is intended to guide the investigator and does not
absolve the pharmacist assigning the shelf-live from
professional responsibility.
In recent years some excellent guidelines on the
conduct, and interpretation, of high-quality stability
studies for aseptic medicines have been published.
A European example is the Guidelines for practical
stability studies of anticancer drugs: A European Consensus
Conference. 3 As the title suggests, this report was
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