HPE Drug stability: What do we need to know? | Page 30

biological peptide/protein drugs are beyond
the scope of this article, but suffice to say, that
establishing the conservation of the active site and
the secondary and tertiary structure of biologicals
requires an array of sophisticated and specialised
techniques including LC-MS, circular dichroism,
electrophoresis and ELISA immunoassays.
Results
The results for chemical and physical testing at
each time-point must be clearly reported and any
gaps in the data or outlier points identified and
justified. It is also helpful if stability reports include
methodology validation data and details of any
statistical methods used.
within the manufacturer’s expiry date and must be
produced according to the principles of EU GMP. The
initial drug concentration must be within 10% of
the target value and the batch numbers and expiry
dates of all drugs, containers and diluents must be
recorded.
Storage incubators and refrigerators used for the
study must be subject to continual temperature
monitoring and any variances must be recorded.
Similarly, any deviation in sample times from the
study protocol should have been recorded and
justified.
All analytical methods must have been
fully validated. For HPLC, the validation will
include linearity of analytical response over the
concentration range expected for diluted samples,
inter- and intra-day precision, and the assay must be
shown to be ‘stability-indicating’. This means that
the assay will be sensitive to any drug degradation
and can separate degradation product peaks from
the main drug analyte peak that is to be quantified.
This aspect is often validated using forced
degradation conditions to break down the drug
deliberately (acid, alkali, oxidising agents, light) and
ensure that degradation products are well resolved
chromatographically from the drug analyte. Modern
HPLC systems record the peak-purity of the analyte
peak to ensure this condition is met.
pH meters and sub-visual particulate measuring
systems should have been calibrated according
to Pharmacopoeia recommendations, and visual
inspections should follow Pharmacopoeial principles
using light and dark backgrounds.
The methodologies for stability studies on
30 | 2019 | hospitalpharmacyeurope.com
References
1 Manufacturers Summary of
Product Characteristics. www.
emc.org.uk (accessed August
2019)
2 Stabilis stability data base.
www.stabilis.org (accessed
August 2019).
3 Bardin C et al. Guidelines for
practical stability studies of
anticancer drugs: A European
Consensus Conference. Ann
Pharm Fr 2011;69(4):221–31.
4 NHS Pharmaceutical Quality
Control Committee. A Standard
Protocol for Deriving and
Assessment of Stability Part
1: Aseptic Preparations (Small
Molecules), Edition 4, April 2017
(yellow cover).
5 NHS Pharmaceutical Quality
Control Committee.
A Standard Protocol for Deriving
and Assessment of Stability
Part 2: Aseptic Preparations
(Biopharmaceuticals), Edition 3,
April 2017 (yellow cover).
6 Kaestner S, Sewell G.
A sequential temperature cycling
study for the investigation of
carboplatin infusion stability to
facilitate dose-banding. J Oncol
Pharm Pract 2007;13(2):119–26.
Interpretation
Clear limits or acceptance criteria for each
parameter measured (for example, drug assay,
infusion pH) should have been clearly defined
before the study commenced. Any trends need to
be accounted for and the point at which infusion
stability falls outside the pre-determined acceptance
criteria must be clearly identified. If a single
container falls outside the acceptance criteria for a
particular test, this cannot be ignored and should
have been investigated.
When applying stability data to assign a shelf-
life, it is crucial that the conditions used in the
study match those to be used in practice (see
appropriateness, above). It might be acceptable
to interpolate stability study data, for example
applying the study finding to a different
concentration range that fits within the range
used in the study. However, extrapolation of
stability data to, for example, higher drug
concentrations, different container materials
or different storage temperatures must never
be attempted without consultation with
a recognised expert and a document rationale
for the variance.
The acceptance criteria used in stability studies
is a source of constant debate. For example, should
the active drug concentration remain within ±5% of
the original concentration, or is ±10% acceptable? In
practice this depends on the reproducibility of the
drug assay, the toxicity of the degradation products
and the therapeutic index of the drug. For cytotoxic
drugs, where the identity and pharmacology of most
degradation products is unknown, 5% limits are
normally appropriate.
Conclusions
Aseptic infusions and injections are usually
required for very sick patients, and any significant
instability of the infusion or active components
may compromise treatment efficacy and could even
cause patient harm if decomposition products are
toxic. Stability studies reported in the literature
continue to become more complex and there is a
critical requirement to ensure that infusions stored
or used over extended periods remain effective
and safe. This brief article summarises the clinical
and pharmaceutical need for shelf-life extension,
pharmacist responsibilities and practical guidance
on how to assess and interpret stability literature
when assigning product shelf-lives. It is important to
recognise, in addition to any chemical and physical
stability issues, that infusions and injections must
remain sterile over the assigned shelf-life. Evidence
that microorganisms are excluded and integrity
of containers and closures is maintained over the
duration of the shelf-life must be included in the
assignment of product shelf-lives.