opinion
Stability of drugs:
We need more real data!
Academic studies on the extended stability of drugs remain the most effective way to obtain the accurate
information that pharmacists expect in their daily practice
Alain Astier PharmD PhD
Honorary Professor of clinical pharmacy
and biotechnics; Honorary head,
Department of Pharmacy, Henri Mondor
University Hospitals, Creteil, France
Generally speaking, the stability
of a drug is its ability to retain
its physical, chemical, microbiological
and biological properties within
specified limits. During the marketing
authorisation process, the
manufacturer must submit stability
data of the product in its final
presentation, which will then set the
limit of validity (expiration date). But,
surprisingly, nearly all of these validity
limits are in the range of three to five
years and never higher, even if the
real stability might be much longer
(sometimes up to 15 years). As an
example, based on stability re-testing,
it was shown that the expiration dates
of up to 88% of 122 drugs (about 3000
batches) could be extended for an
average of five years beyond their
original expiration dates. 1
It is thus clear that expiration
dates markedly underestimate the
actual shelf-life of many drugs as
shown by data from the American
Association of Medicine to support
the shelf life extension program
(SLEP) for drugs administered by
the FDA. The consequence of an
unrealistic expiration date is that,
beyond the validity limit, a drug
should not legally be used and must
be destroyed even if it retains nearly
all of its potency. Moreover, in the
context of drug shortages, a situation
that is increasing exponentially, the
unavailability of a drug, regardless of
the initial cause, will be exacerbated
because existing stock that has just
expired or is close to expiration
cannot be used.
Recently, the UK government said
that owing to continued shortages
of epinephrine autoinjectors for
emergency treatment of very serious
allergic reactions, patients can
use batches of EpiPen ® up to four
months after the expiration dates. 2
This decision demonstrates that the
active ingredient remains stable
after its expiration date, suggesting
that shortages could potentially be
minimised if more accurate expiration
dates were used.
Moreover, the concept of practical
stability (or in-use stability) is
becoming more widespread, referring
to the stability of a drug not only
determined under conventional
situations but also taking in account
variations observed in clinical practice
that are defined (for example, long-
term infusion) or unexpected (such
as temperature excursions during
storage). Unreal stability data are
therefore unacceptable because
financial resources can be wasted
in cases of costly products, such as
monoclonal antibodies. 3
A more realistic approach
Stability studies after reconstitution,
or dilution, in the final vehicle that
are performed by the pharmaceutical
industry are only designed to fulfil
licensing requirements. When
reviewing package inserts, the general
assumption is that an injectable drug
will be reconstituted and/or diluted
then administered on a clinical
ward under potentially poor aseptic
techniques. Thus, post-dilution or
post-reconstitution stability data are
frequently limited to only 24 h or 48
h at 4°C in the Summaries of Product
Characteristics for bacteriological
reasons regardless of the true
chemical stability, which could
potentially be much longer. As an
example, the stability of trastuzumab
after reconstitution and dilution is
fixed by the manufacturer at 24 h at
temperatures below 30°C; however,
several papers demonstrated that
the product remains stable up to one
month even when stored at room
temperature. 4
A situation change is required
urgently and for that to occur, a more
realistic approach to drug stabilities
is needed. Indeed, a drug is generally
considered as stable for up to 90% of
drug remaining (or 95% for narrow
therapeutic range drugs), but, in
reality, at the quoted expiration date,
it is very common to find up to 96–97%
remaining, especially for tablets stored
in waterproof blisters. Obviously, just
a few months after the expiration
date, it makes no sense from
a scientific point of view to believe
that the degradation will increase
abruptly. As a result, extrapolations
based on the degradation profile
can reasonably predict when the
remaining amount of drug will have
reached the previously fixed limit.
Two proposals to improve this
unsatisfactory situation can be
suggested. One is for the European
Medicines Agency to require
manufacturers to provide more
realistic stability data, that is, an
actual expiration date for each drug,
corresponding to 90%, 95% (or any
acceptable percentage of the residual
efficacy) of the active ingredient
remaining.
Another potential way would be
to strongly encourage manufacturers
to also provide ‘real life’ stability
data after reconstitution or dilution
(taking into account situations such
as temperature excursions or the
requirements for longer storage of the
bags, reuse of non-administered bags,
dose-banding, etc). For generics or
biosimilars, this could be an excellent
argument for choice when tendering
for particular brands.
However, pending the fulfilment
of these wishes, academic studies on
the extended stability of drugs remain
the most effective way to obtain the
accurate information that pharmacists
expect in their daily practice.
References
1 Lyon RC et al. Stability profiles of drug products
extended beyond labeled expiration dates. J Pharm
Sci 2006;95(7):1549–60.
2 Department of Health and Social Care. Supply
disruption alert. 2018. www.sps.nhs.uk/wp-content/
uploads/2018/09/SDA_2018_001.pdf (accessed
October 2018).
3 Bardin C et al. Guidelines for the practical stability
studies of anticancer drugs: A European consensus
conference. Ann Pharm Fr 2011;69(4):221–31.
4 Paul M et al. Long-term physico-chemical
stability of diluted trastuzumab. Int J Pharm 2013;
448(1):101–4.
hospitalpharmacyeurope.com | 2018 | Issue 90 | 9