HPE Drug stability: What do we need to know? | Page 13
in-use stability, because they are based mainly
on microbiological stability data and not on the
physico-chemical stability of the medicinal product.
Pharmaceutical companies perform stability studies
as an integral part of the information provided to
regulatory authorities in support of the marketing
authorisation of a drug. The manufacturers
adopt the guidelines of the EMA, which generally
recommend, for sterile not preserved products,
a limit of 24 h at 2°–8°C. There is an exception in
cases in which the reconstitution or dilution are
carried out under validated aseptic conditions,
in which it could be assumed that in-use expiry
dates would be extended. These precautionary
provisions refer mainly to the preparation of
sterile medicines in areas having variable storage
conditions, such as hospital wards. By contrast,
pharmacy compounding units can guarantee the
microbiological quality of the compounded product.
Guidance for compounding in pharmacies describes
the characteristics that the premises, equipment
and personnel must have in order to ensure the
appropriate standards for sterile and non-sterile
preparations. 17
The International Council for Harmonisation
of Technical Requirements for Pharmaceuticals
for Human Use (ICH) gives recommendations for
validation of analytical methods and stability
studies: particularly ICH Q1A (evaluation for
stability data), ICH Q1A(R2) (stability testing of
new drug substances and products), ICH Q2A (test
on validation of analytical procedures), ICH Q1B
(stability testing: photostability testing of new
drug substances and products), Q3B (impurities in
new drug products), and Q5C (stability testing of
biotechnological/biological products). 6 However, ICH
guidelines are dedicated to stability but are written
for industry and not for hospitals.
Thus, specific recommendations for stability
studies in hospital pharmacies have been produced
by various expert societies to adapt the ICH
guidelines, European Pharmacopoeia and the most
relevant literature for the clinical environment,
thereby identifying methodologies for stability
studies for hospitals and compounding pharmacy
units. 1,2
In addition, specific guidelines of good
compounding practice are provided by the
PIC/S Guide to Good Manufacturing Practice of
Preparation of Medicinal Products in Healthcare
Establishments (PE 010-4). 17 These standards take
into consideration the hospital situation and
reduced-scale production, which is not comparable
to the industrial situation, where compliance with
GMP standards is mandatory. Another essential
reference for the production of medicines in
hospital pharmacy is Chapter 797 United States
Pharmacopoeia (USP) Establishing a standard practice
for sterile compounding preparation in pharmacy. 16 These
guidelines describe the acceptable microbiological
stability date, given storage conditions and risk of
contamination.
Because the SPCs of medicinal products do
not offer sufficient data to determine the in-use
chemical, physical and biological stabilities, one
can try to evaluate these by referring to the current
legislation, the accredited scientific literature, and
the various European and international guidelines
(EMA, ICH, US Food and Drug Administration).
Because these sources are often not exhaustive,
and sometimes contradictory, the resulting
determination is approximate and therefore
inapplicable from a practical point of view.
In order to validate a production process, specific
experimental studies might be required, conducted
in compliance with guidelines and simulating the
real conditions of use on-site, in order to obtain
reliable data on the in-use stability of a drug and to
identify the best methods for its determination.
Proven stability enables advance preparation,
elimination of the peak moments in workload,
greater efficiency and reduced working costs, the
application ‘dose banding’, reduced drug wastage,
batch preparation, use of returned preparations,
reduced interruptions of therapy and drug
shortages, outsourcing to external compounding
units or commercial partners, and development of
ready-to-administer drugs.
The stability study
should include
testing of all
variables that are
likely to influence
quality, safety and
efficacy, clearly
justified by
relevant
literature, and
include well-
designed stability-
indicating assays
Stability study design
When designing the practical stability study, it
should reflect the clinical needs and real storage
conditions of the studied product brand, evaluating
loss of efficiency and the presence of degradation
products over time. Specific routes of administration
must be also considered. The stability study should
include testing of all variables that are likely to
influence quality, safety and efficacy, clearly justified
by relevant literature, and include well-designed
stability-indicating assays.
According to the EU Pharmacopoeia, stability is
defined as the time during which a drug maintains
its essential chemical and physical properties, or
in which a change occurs within tolerable limits,
with a degradation of the drug not exceeding 10%
of the initial value, without the formation of toxic
degradation products, or a significant decrease in
pharmacological activity. The permissible level of
any degradation product will depend on the dose
and type of toxicity; however, for most drugs, the
permitted levels of a single impurity (without
there being explicit toxicological tests) is generally
less than 1% of the drug (although this can vary
according to the maximum daily dose). The ICH
specifies the amount of impurities that can form
during storage, based on the total daily intake of the
drug.
The parameters that usually need to be studied
in order to determine the in-use stability of
a preparation are:
• Physical: colour, transparency, integrity of the
closure, assessment of particulate matter
• Chemical: content of active ingredient and
any degradation products, levels of degradation
products of antimicrobial and antioxidant
preservatives, pH of the solution
• Microbiological: sterility, possible microbial count
(total viable count), pyrogenicity.
For physical stability, an appropriate sub-visual
evaluation, in addition to a visual inspection,
should be performed over time; this is particularly
important for biological products in order to
evaluate any aggregation. pH should also be
evaluated over time. The packaged drug must be
weighed at all sample times to determine any
water loss to correctly calculate the concentration
of the drug and degradation products. Sequential
temperature designs should be encouraged to
replicate problems seen in daily practice, for
example, rupture of the cold chain, returned
preparation to the pharmacy, etc.
Specific aspects concerning the stability
of biological medicinal products should be
considered because these can undergo more
complex degradation pathways during the various
manipulation steps than chemical drugs. The
main causes of instability include temperature
fluctuations, formulation pH, adsorption,
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