HPE Drug stability: What do we need to know? | Page 25

study and the plausibility of the results generated.
Knowledge and understanding of drug stability
requirements and the measures used to ensure
them constitute the basis for assessing these data.
In reality, most products with short shelf-lives and
narrow storage temperature ranges are chemically
unstable. Many monographs by the United States
Pharmacopeia (USP)-National Formulary require
100±10% of the stated efficacy for a product.
Therefore, the t 90 (that is, the time taken for the
concentration of active ingredient to fall below 90%)
of a product will usually reflect its duration unless
other complications are excluded, except for the
loss of the active ingredient. In special situations
(drugs with a low therapeutic index, dose banding,
etc), a t 95 or other limits might be reasonable.
However, all stability limits must be justified and
clinically relevant. Because biological products such
as vaccines, serums and peptide hormones have
special requirements, both for the formulation
and the determination of the content, additional
tolerance limits are set for these. If a product loses
only 5% of its active ingredient content but toxic
decomposition products are formed, its shelf-live
can be limited based on the content of the unwanted
toxic degradation product. Moreover, different
products with the same active ingredient but
different excipients can differ from one another in
regard to the stability of the preparation itself and
the stability of mixtures with other components. 7
A determination of the active ingredient at
time 0 (t 0 ) is thus essential. Without this original
concentration, the initial value is basically
unknown. To simply assume that the original
concentration is the intended target concentration is
not sound practice, because the likelihood for errors
in the preparation of the analysis solutions is high.
In addition to simple human error, producer-related
variations in filling volume and drug concentration,
volume deviations of the infusion solution, and
syringe deviations might contribute to uncertainty
regarding the initial value, and a combination
of all these deviations could easily result in a
starting concentration of 80–120% of the target
concentration.
At the beginning, and for all test intervals,
multiple analyses of several test solutions must
be carried out, thus increasing the accuracy of
the results obtained by minimising the effects of
analyses variabilities and human error. Erroneous
outliers can also be detected more easily. Although
the number of samples tested at each interval
should be tailored to the specific requirements
of each study, duplicate determinations of three
identical test solutions are considered to be the
minimum requirement. 8 The intervals at which
the analyses are carried out should allow adequate
determination of the stability and compatibility
of the active substance in question. If more than
10% decomposition occurs within 24 hours in a test
solution, the importance of intermediate analysis
intervals (for example, four hours) for defining
stability limits is clear. But if more than 10% of an
active substance is degraded in a solution within 24
hours at 25°C, this corresponds to the conventional
definition of an incompatibility. Nevertheless, the
drug could be useful for a shorter period of time,
such as 8 or 12 hours. Applying the concept of
duration of use or time to 10% decomposition (t 90 ) is
more useful in this case than to say a combination is
incompatible. 7
Frequent flaws in stability studies
The validity of the results obtained in the stability
References
1 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.
2 Vigneron J et al. Stability
studies in oncology. A marketing
tool for pharmaceutical
companies, as scientific mission
for hospital pharmacists. Eur J
Oncol Pharm 2019;2(2):pe12.
3 Thoma K, Kerker R.
Photostabilität von Arzneimitteln.
1. Mitteilung über das Verhalten
von nur im UV-Bereich
absorbierenden Substanzen bei
der Tageslichtsimulation. Pharm
Ind 1992;54:169–77.
4 Dasta JF et al. Comparison of
visual and turbidimetric methods
for determining short-term
compatibility of intravenous
critical-care drugs. Am J Hosp
Pharm 1988;45:2361–6.
5 Bannert C, Hehenberger H.
Kompatibilität von Mischungen
und Zumischungen. Taschenbuch
der Krankenhauspharmazie.
Dtsch Apoth-Verlag, Stuttgart;
1987.
6 Illgen B, Köchel D. Zusatz
von Injektionslösungen
zu Infusionsmischungen.
Leitfaden zur Überprüfung
von Kompatibilität und
therapeutischer Zweckmäßigkeit.
Krankenhauspharmazie
1988;9:187–205.
7 Trissel LA. Avoiding common
flaws in stability and compatibility
studies of injectable drugs. Hosp
Pharm 1983;40:1159–60.
8 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).
9 Grimm W, Schepky P.
Stabilitätsprüfung in der
Pharmazie – Theorie und Praxis.
Cantor Aulendorf 1980.
10 United States Pharmacopeia.
Chromatography-system
suitability. United States
Pharmacopeia/The National
Formulary. www.uspnf.com.
11 Trissel LA, Flora, KP. Stability
studies: five years later. Am J
Hosp Pharm 1998;45:1569–71.
tests greatly depends on the examination methods
used. Therefore, several criteria must be met
before studying stability patterns. The goal of
the chemical analysis in the shelf-life test is to
determine if the drug content has changed from
its initial value. Therefore, the method to be
used must differentiate between the intact active
substance and any decomposition product that
might be present; however, most of the methods
listed in Pharmacopoeias do not meet this condition
and are only used for determining identity and
content. The analytical method used must also
be stability-specific (that is, a stability-indicating
assay), so it must be able to determine the intact
active ingredient unambiguously in terms of its
degradation products and other active ingredients
and components. Previously published methods
meeting this requirement can sometimes be used,
but an important change made to a variable of the
method (for example, solvent composition) requires
proof that it is still stability-indicating. In addition,
each method is considered to be specific or selective,
detecting a significant deviation from the starting
point or setpoint. 7 Because it is important to detect
a decrease in content as early as possible, a specific
method is only optimal if it is also sensitive enough
to detect a small deviation from the desired or
initial value. These variations in sensitivity can be
determined with the help of statistical analyses.
If the coefficient of variation has been determined
for a specific method, it is possible to calculate the
change in content that is detectable significantly
in relation to the number of analysis. 9
The USP designates system suitability tests as
an integral part of gas and liquid chromatographic
methods. They are based on the concept that
the equipment, the electronics, the analytical
operations, as well as the samples to be analysed,
form an overall system that can be evaluated as
such. Repeated injections of a standard preparation
used in the assay itself, or other standard solutions,
are compared to ensure that the precision
requirements (ability to repeat an analysis with a
small standard deviation) are met. Unless stated
otherwise, the data from five repeated injections of
analyte are used to calculate the relative standard
deviation if the requirements are ≥2%, whereas data
from six replicate injections are used when the
requirement for the relative standard deviation is
<2%. 10 For determining if the analysis is stability-
specific, one can expose intact drug to a strong
stress, such as extreme pH values, intense heating
or UV light. Alternatively, a solution of the intact
drug can be spiked with known degradation
products. 9
Despite these recurring flaws and limitations in
stability and compatibility studies, improvements
have been observed in reporting the materials,
methods, and test conditions, and in using replicates
of multiple test solution samples, while validation of
the analytical methods remains a challenge in some
instances. 11
Conclusions
Stability tests are conducted to determine the
expiration date of a product or a beyond-use date
of a preparation. Whenever the production
process, the formulation, or the packaging/storage
conditions change, these data become obsolete.
As these changes are very often not communicated
to pharmacists in a timely manner, there is a
significant need for a multi-level improvement
and adaptation of the current procedures for the
preparation of compounded parenteral drugs.
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