HPE Drug stability: What do we need to know? | Page 10

information requirements that hospital pharmacists
need. 14 Finally, unreal stability data are therefore
unacceptable because large financial resources,
mainly paid through social insurance systems, can
be wasted in the case of very costly products.
Thus, for oncology pharmacists, collecting
suitable and objective information on the stability
of an anticancer drug is not easy. Classical books
such as Trissel, or Society recommendations
are invaluable. 15–17 However, other than for well-
evaluated substances, these compilations only
include partial data about vehicles, administering
devices or temperatures, and results are scarce
for new protein-based drugs. Moreover, published
results on drug stability are heterogeneous in terms
of quality and relevance. Stability studies are also
frequently published as posters at conferences,
which are not always readily available, and are
not followed up by publication in peer-reviewed
journals. For older products, the analytical
techniques used are frequently not fully appropriate,
do not conform to the current guidelines and are
unable to detect subtle changes or low levels of
degradation products.
Thus, pharmacists were often unable to
appreciate the quality of the papers because there
were no standardised, best protocols to evaluate the
stability of anticancer drugs in practical situations.
Faced with these problems, a group of European
pharmacists published consensus guidelines
covering the minimal requirements to conduct
good quality, in-use stability studies for anticancer
drugs. 18 Following this, several organisations have
now published more general guidelines on practical
stability studies for hospital preparations. 19–23
Moreover, the Stabilis ® database, freely accessible
on the internet and available in more than 29
languages, provides extensive practical stability data
on 792 drugs (95 anticancer drugs), corresponding to
5313 solutions (including 1128 admixtures and 3082
incompatibilities). 24 Some poster presentations are
also included, which is invaluable because stability
studies are frequently presented at scientific
meetings and thus, rarely accessible. This very
References
1 Bardin C et al. Guidelines
for the practical stability studies
of anticancer drugs:
A European consensus
conference. EJHP: Science and
Practice 2012;19(3):278–85.
2 Astier A. Practical stability
studies: A powerful approach for
reducing the cost of monoclonal
antibodies. Eur J Oncol Pharm
2012;6(2):4–6.
3 Astier A. Issues in stability
of drugs for infusion. Hosp
Pharm Eur 2015;79:27–9.
www.hospitalpharmacyeurope.
com/featured-articles/
issues-stability-drugs-infusion
(accessed August 2019).
4 ICH. Stability testing of new
drug substances and products.
ICH, IFPMA, Geneva;1993.
5 ICH. Stability testing of
biotechnological/biological
products. Q5C, IFPMA,
Geneva;1995.
6 Olver I, Keefe D, Myers M.
Phase II study of prolonged
carboplatin and oral etoposide.
IMJ 2005;35:405–8.
7 Trastuzumab (Herceptin ® )
150mg powder for concentrate
for solution for infusion.
Summary of product
characteristics. Roche Products
Limited, updated August 26,
2018. www.medicines.org.uk
(accessed August 2019).
8 Paul M et al. Long-term
physico-chemical stability of
diluted trastuzumab. Int J Pharm
2013;448(1):101–4.
9 Vieillard V, Astier A, Paul M.
Extended stability of a biosimilar
of trastuzumab (CT-P6) after
reconstitution in vials, dilution
in polyolefin bags and storage
at various temperatures. GaBi
J 2018;7(3):1–9.
10 Rituximab (Mabthera ® ).
Summary of product
characteristics. Roche. Updated
October 5, 2018. www.medicines.
org.uk (accessed August 2019).
11 Paul M et al. Long-term
stability of diluted solutions of the
monoclonal antibody rituximab.
Int J Pharm 2012;436(1–2):282–
90.
12 Vieillard V et al. Extended
stability of the rituximab
biosimilar CT-P10 in its opened
vials and after dilution and
storage in polyolefine bags. Ann
Pharm Fr 2017;75(6) 420–35.
13 Lamanna WC, Heller K,
Schneider D. The in-use stability
of the rituximab biosimilar
Rixathon ® /Riximyo ® upon
preparation for intravenous
infusion. J Oncol Pharm Pract
2017;25:1–10.
14 Vigneron J, D’Huart E,
Demoré B. Stability studies in
oncology. A marketing tool for
pharmaceutical companies,
10 | 2019 | hospitalpharmacyeurope.com
popular database also classifies the publications by
levels of evidence. In some cases, PDFs of the articles
are available, depending on copyright regulations.
This database includes numerous studies that
have been performed by academic or hospital
pharmacy teams on the extended stability of very
costly biologics, such as monoclonal antibodies,
especially those used in oncology. 8–13,25–28 Generally
speaking, the published results demonstrate that
these drugs are largely more stable than indicated
by the manufacturers, especially during temperature
fluctuations.
This finding is crucial in optimising patient
care and hospital organisation, and in saving
considerable resources. 28–32
Conclusions
It would be useful if the European Medicines Agency
could encourage manufacturers to provide stability
data after reconstitution or dilution that take into
account real-life situations such as temperature
deviations or requirements for longer storage of
the bags (reuse of non-administered bags; dose-
banding). Since this recommendation would need
to be changed in the marketing authorisation
requirements and might not be welcomed by some
manufacturers, a number of strategies to promote
more in-use stability studies can be proposed. First,
developing and undertaking stability studies at the
level of hospital pharmacy and in research should
be encouraged. 33 However, the problem of obtaining
financial support from public funds remains.
Second, encouraging medical societies, payers’ and
key stakeholders (such as hospital directors) to
support in-use stability studies as an additional value
to improve the patient care and to save financial
resources. Third, and possibly the most important,
pharmacists should systematically include in-use
stability data in their hospital tender processes. 15,33
Indeed, considering some recent experiences in the
introduction of biosimilars in France, this additional
value could be an excellent additional argument
of choice for the tenders and price negotiations
between brands, including the originators. 34
a scientific mission for hospital
pharmacists. EJOP 2019;
2:2(e12).
15 Trissel LA, Trissel’s Stability of
Compounded Formulations, 3rd
Edn, APhA 2005:512 pp.
16 Astier A, Pinguet F,
Vigneron J. The practical
stability of anticancer drugs:
the recommendation of SFPO
and ESOP. Eur J Oncol Pharm
2010;4(3):4–10.
17 Vigneron J et al. SFPO and
ESOP recommendations for the
practical stability or anticancer
drugs: An update. Ann Pharm Fr
2013;71(6):379–86.
18 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.
19 Methodological guidelines
for stability studies of hospital
pharmaceutical preparations.
Under the aegis of SFPC (French
Society of Clinical Pharmacy)
and GERPAC (Evaluation and
Research Group on Protection in
Controlled Atmosphere), 1st edn.
2013:74 pp.
20 NHS Pharmaceutical Quality
Assurance Committee. A
standard protocol for deriving
and assessment of stability – part
1 – aseptic preparations (small
molecules), 3rd edn. December
2015: 16pp.
21 NHS Pharmaceutical Quality
Assurance Committee. A
standard protocol for deriving
and assessment of stability –
part 2 – aseptic preparations
(biopharmaceuticals), 3rd edn.
August 2014: 16pp.
22 NHS Pharmaceutical
Quality Assurance Committee.
A standard protocol for
deriving and assessment of
stability – part 3 – oral liquid
medicines (solutions, emulsions,
suspensions and syrups), 1st
edn. August 2014;16pp.
23 Quality Standards for the
Oncology Pharmacy Service
(QUAPOS). ESOP. www.esop.li/
downloads/QuapoS%206.pdf
(accessed July 2019).
24 Vigneron J. Stabilis 4.0. www.
stabilis.org. (accessed July 2019).
25 Vieillard V et al. One-month
stability study of a biosimilar
of infliximab (Remsima ® ) after
dilution and storage at 4°C and
25°C. Ann Pharm Fr 2017;75:
17–29.
26 Paul M et al. Long-term
stability of bevacizumab
repackaged in 1mL polypropylene
syringes for intravitreal
administration. Ann Pharm Fr
2012;70(3):139–54.
27 Lahlou A et al. Mechanically-
induced aggregation of the
monoclonal antibody cetuximab.
Ann Pharm Fr 2009;67(5):340–52.
28 Bardo Brouard P et al.
Stability of ipilimumab in its
original vial after opening allows
its use for at least 4 weeks and
facilitates pooling of residues,
Eur J Cancer 2016;58:8–16.
29 Walker SE, Charbonneau LF,
Law S. Stability of bortezomib
2.5mg/ml in vials and syringes
stored at 4(C and room
temperature (23°C). Can J Hosp
Pharm 2014;67:102–7.
30 Duriez A et al. Stability of
azacitidine suspensions. Ann
Pharmacother 2011;45:546.
31 Balouzet Cet al. Stability
of 25mg/ml 5-azacitidine
suspension kept in fridge after
freezing. Pharm Technol Hosp
Pharm 2017;2:11–16.
32 Vieillard V et al. Stabilité
physico-chimique de solutions de
Nivolumab à 1 mois. Poster SFPO
Congress 2017, Nantes, France.
33 Vigneron J. Stability studies:
a scientific mission of
the hospital pharmacist.
Pharm Technol Hosp Pharm
2017;2:143–4.
34 Descoutures JM. Personal
communication.