HPE Drug stability: What do we need to know? | Page 12
STUDY DESIGN
Recommendations and design
quality for stability studies
Specific recommendations for stability studies have been written by various expert societies,
and identify methodology requirements for these studies for hospitals and compounding
pharmacy units
Marta Trojniak
PharmD MPH
IRCCS Ospedale Infantile
Burlo Garofolo, Trieste,
Italy
Stability studies refer to two specific
conditions, that is, ‘before’ (shelf-life) and
‘after’ opening of the primary package (in-use
stability). Specific regulations and guidelines for
conducting shelf-life studies are available from
regulatory authorities. The stability of drugs for
hospital needs is a topic of increasing interest for
hospital pharmacy. Manufacturers perform stability
studies in support of a medicinal product’s
marketing authorisation. The stability data in the
Summary of Product Characteristics (SPCs) related to
clinical practice are often insufficient to assign the
appropriate in-use expiry date. Stability data in the
SPCs are frequently limited to 12–24 hours in-use
stability.
Hospital-compounded drugs require well-
documented data on the chemical, physical,
and biological stabilities of the drugs in practical
storage conditions used after reconstitution and
after further dilution with different diluents,
different concentrations, mixtures of drugs,
and compatibilities in different packages. Hence
there is a need to search for alternative scientific
sources that can integrate information into SPCs,
and therefore extend stability beyond 24 hours.
Therefore, reviewing available evidence on practical
stabilities in the clinical environment in the shared
databases, 3 as well as hospital pharmacy teams
conducting good quality stability studies and
research, is necessary. 1,2
Centralised drug preparation units offer
innumerable advantages in terms of organisational
efficiencies and pharmacoeconomics, as well
as important benefits for patients. The drug
production can be realised through traditional
extemporaneous preparation, where the times
between the preparation and the administration are
short and the stability data are usually described in
the SPCs. For both hospital needs and compounding
pharmacy units, the compounding unit might
prepare the standardised, ready-to-use preparations
with or without dose banding, and intermediate
solutions, ready for dilution, which can then be set
up in advance, thereby organising the storage of
medicines for varying times according to clinical
needs and practical storage conditions. In this
scenario, stability of the compounded products in
varying clinical environments, reconstituted or
diluted, and the compatibilities of the products with
medical devices, take on a particular relevance. 3
The concept of stability refers to two specific
conditions: those adopted by the manufacturer to
define the shelf-life; and those adopted by the user
who, after the package has been opened, prepares
the preparations for personalised use starting from
12 | 2019 | hospitalpharmacyeurope.com
the medicinal products (in-use stability). According
to the European Medicines Agency (EMA), specific
storage needs of the user must be taken into account
by the manufacturer in order to conduct appropriate
physico-chemical studies to update the technical
information already available (Pharmacopoeia
monographs, SPCs). 4,5 However, this information is
usually incomplete and therefore does not always
meet the needs of clinical practice and formulation
in hospital pharmacy. Hospital pharmacists mainly
prepare sterile products, including anticancer
drugs, antibiotics, eye drops, medications for use in
intensive care, and parenteral nutrition. Hospital
pharmacists might need to prepare alternative oral
formulations beyond the commercially available
ones, to confer the full benefit of the therapy to the
patient.
Regulatory aspects
Ensuring an acceptable stability during the
development of a pharmaceutical formulation at
industrial level is a challenge. Whereas classically
the stability refers to the loss of chemical or
biological stability due to degradation, in clinical
practice, the term stability refers mostly to the
admissible conservation time before any degradation
product in the formulation reaches a sufficient
quantity to pose a risk to the patient. 6,7
Preparation processes for medicinal products
in pharmacies must meet specified requirements
of safety, efficacy and quality. The pharmacist is
responsible for the quality, safety and efficacy of the
preparation of medicinal products and the required
quality standards are similar in many countries. 3,8–14
The European Pharmacopoeia, 15 the EC GMP 7 and
US Pharmacopeia (USP) 16 require pharmaceutical
processes that affect product quality to be validated,
and that the necessary premises, materials and
equipment are qualified. The validation provides
documented evidence that the processes satisfy
quality assurance systems in practice. In this
context, for evaluation of the stability of a drug, it
is essential to consider critical requirements such as
the chemical, physical and biological stabilities and
sterility of the preparation, which make it possible
to determine its period of validity. There is then
a fundamental requirement for well-documented
data on the stability of drugs after opening of the
primary package; this type of stability is defined
by the EMA as in-use stability. 5 The in-use expiry
date of a medicinal product is the time during
which a product maintains, within defined limits,
the same properties and characteristics that it
possessed at the time of production. As mentioned,
SPCs give insufficient information in relation to