HPE Drug stability: What do we need to know? | Page 21

life. For less stable molecules, this period can cause
a significant restriction to the overall shelf life.
For biopharmaceuticals there is, at least in
theory, a risk of physical stresses during transport,
particularly over longer distances that outsourcing
options often require. It is important that the impact
of this transport is understood if the product is
handled in this way. In reality, stability studies that
rely on multiple samplings from the same bag over
the study period will be subjected to some handling
trauma including gentle shaking, but the use of
a transport simulation test is a good addition to
stability studies for these products.
Licensed ready-to administer products
There are now several products available in a
licensed ready-to administer presentation including
one cytotoxic preparation, several antibiotics and
epidural infusions as well as multiple pre-filled
syringes. These products normally have an extended
shelf life compared with even the longest assigned
to aseptically compounded products, and represent
a lower risk option when compared with those
prepared aseptically ahead of use. There is potential
in the future, with the increase in dose-banding and
standardisation, that this product group will play
an important role in freeing up capacity in aseptic
units across all sectors. This can sometimes mean
that changes in practice are required, for example
a licensed product is likely to be presented as
multiple volume presentations of a single solution
concentration, compared to each dose being in a
set volume as is the case with traditional aseptically
compounded products. This change in practice can
delay the implementation of these products, but
considering the lower risk associated with them and
the impact on reducing aseptic unit workload, their
use is to be encouraged.
Infusion periods
It is vital that the product stability and shelf life
assessment considers the in-use administration
period, together with any warming period for the
product ahead of the start of infusion. Where the
infusion is via a pump, and the drug reservoir
is remote from the patient, then this should be
considered to by 25 o C unless it is known to be
higher than this. In the case of elastomeric infusors
worn close to the skin, this is more appropriately
studied at 32 o C as a worst-case scenario; this is the
temperature recommended alongside relevant
references in the NHS guidance. 6 The desire for
continuous infusions of antibiotics has led to further
challenges in assuring adequate stability to cover the
infusion period, and this has made the inclusion of
buffering agents in the formulation an important
consideration. The British Society for Antimicrobial
Chemotherapy funded some work in this area and
the first study reporting on buffered flucloxacillin 10
was published in 2018.
References
1 Review of NHS Pharmacy
Aseptic Services www.sps.nhs.
uk/articles/review-of-nhs-
pharmacy-aseptic-services-
summary-of-key-findings/
(accessed July 2019).
2 Council of Europe Resolution
CM/Res (2016)2 on good
reconstitution practices in
health care establishments for
medicinal products for parenteral
use. www.edqm.eu/sites/default/
files/resolution_cm_res_2016_2_
good_reconstitution_practices_
in_health_care_establishments_
for_medicinal_products_for_
parenteral_use_.pdf (accessed
August 2019).
3 Jenkins A et al. Drug stability
working group of the BSAC
UK OPAT initiative. Extended
stability of antimicrobial agents
in administration devices. J
Antimicrobial Chemotherapy
2017;72:1217–20.
4 NHS England. Dose banded
chemotherapy standardised
product specifications. National
standardisation of cytotoxic
chemotherapy. www.england.
nhs.uk/commissioning/spec-
services/npc-crg/group-b/b02/
dose-banded-chemotherapy-
standardised-product-
specifications/ (accessed August
2019).
5 Vial Sharing in Aseptic
Services, Edition 1, August 2014,
NHSPQA committee.
6 Standard Protocol for
Derivation and Assessment
of Stability Part 1 – Aseptic
Preparations Small Molecules
(4th edn, April 2017).
7 Standard Protocol
for Derivation and
Assessment of Stability Part
2 – Aseptic Preparations
-Biopharmaceuticals (3rd edn,
April 2017).
Stability assessments
Many aseptic units do not have access to designated
laboratory facilities and do not have the equipment
or expertise to carry out their own stability studies.
Hence there is a large reliance on assessment of
stability data from published studies and from
unpublished studies based on data supplied by
marketing authorisation holders for the starting
material products or by the suppliers of final
containers (such as elastomeric infusers). It is
important that all of these studies are reviewed
against a suitable specification and standard.
Within the UK, the British Pharmacopoeia (BP)
contains monographs for formulated products and
these include certain unlicensed products, which
are aseptically compounded. BP monographs are
applicable throughout product shelf life and hence
are a useful source of specifications against which
to judge stability studies and assign suitable shelf
lives to aseptically compounded small molecule
products. The standards for stability studies for
licensed products are captured within the various
ICH guidelines but these are not always practical for
stability studies of aseptically compounded products,
the NHS standards documents are a useful reference
here. 6–8
Vial sharing
In the UK, vial sharing is routinely only accepted
on a campaign basis, 5,11 where the same product
is made sequentially and the vials stay within the
grade A zone throughout. In order to maximise the
benefit of this process and hence reduce wastage,
particularly for expensive drugs, then being able to
prepare products in advance of them being required
facilitates campaign vial sharing process. This
requires adequate shelf life on the final presentation
in order that all patients will receive their treatment
before the product expires. One further important
consideration for the efficiency of vial sharing is in
helping to manage the frequent medicines shortages
that seem to now be a fact of life. In some other
European countries, vial sharing beyond the single
campaign is a more accepted practice, and in this
case it is important to understand drug stability
within the pierced vial, or of the reconstituted
solution in order to facilitate this process.
Conclusions
Stability data beyond that stated in products’ SPCs
are of fundamental importance in enabling aseptic
compounding facilities, both commercial and within
the healthcare sector, to better plan and more
efficiently carry out their workload. In these days
of higher workloads and restricted capacity, the
value of these data is clear. A degree of expertise and
understanding is needed in terms of the stability
studies themselves and also in terms of the handling
of products from the first aseptic manipulation until
completion of the infusion.
8 Standard Protocol for
Derivation and Assessment of
Stability Part 4 – Parenteral
Nutrition (1st edn, May 2016)
9 Quality Assurance of Aseptic
Preparation Services 5th Edition
(Royal Pharmaceutical Society
2016).
10 Allwood M et al; BSAC
Drug Stability Working Party.
Assessment of the stability of
citrate-buffered flucloxacillin
for injection when stored in
two commercially available
ambulatory elastomeric
devices: Infusor LV (Baxter)
and Accufuser (Woo Young
Medical): a study compliant
with the NHS Yellow Cover
Document (YCD) requirements.
EJHP 2018. https://ejhp.bmj.
com/content/early/2018/09/18/
ejhpharm-2018-001515.full.
11 Medicines and Healthcare
products Regulatory Agency.
Guidance for Specials Licence
Holders, Edition 2, January 2015.
https://assets.publishing.service.
gov.uk/government/uploads/
system/uploads/attachment_
data/file/400232/Guidance_for__
specials__manufacturers.pdf
(accessed August 2019).
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