HPE Drug stability: What do we need to know? | Page 15

practice should be specified.
The product under evaluation should be fully
defined in terms of the manufacturer and batch
number, concentration, and final volume, and
storage conditions that reflect real clinical practice.
For sterile drug preparations, microbiological
stability must be guaranteed. Detailed planning,
preparation and monitoring of the entire aseptic
production process have a positive influence on
product quality. The validation should respect
all aspects of the manufacturing process and the
fundamental conditions for aseptic production. The
microbiological safety fundamentally depends on
adherence to good manufacturing practice. Once the
aseptic conditions have been defined, any further
stability assessment will therefore depend on the
chemical and physical stabilities of the preparation.
However, preservation of sterility over time in the
final device depends on the nature of the container
and storage conditions.
So, it is necessary to consider:
1 cleanliness and hygiene of the premises;
2 the workforce;
3 class A clean room;
4 the quality of work tools;
5 the quality of the basic materials;
6 production with aseptic technique.
The European Pharmacopoeia confirms that
sterility must be guaranteed through appropriate
and validated production processes where the goal
of production under aseptic conditions is to preserve
the sterility of a preparation comprising sterile
components.
For cytotoxic drug preparation, biological safety
cabinets or isolators should be utilised for aseptic
production and the process(es) should ensure
consistent quality and sterility for compounded
products.
To achieve this goal at all stages of production, it
is necessary to take suitable precautions to prevent
contamination. The analysis of the relevant hygienic
processes should include personal protective
equipment, cleaning and the aseptic processing
phase itself. Annex 1 of the EU GMP manual 7
defines recommended limits for microbiological
contamination and air particulate matter in clean
rooms.
Acccording to risk levels characterised by the
USP, the following can be said for preparations
undertaken in pharmacies:
• Low risk: manipulations performed in an ISO 5/
References
1 Vigneron J et al. SFPO and
ESOP recommendation for the
practical stability of anticancer
drugs: an update Annales
Pharmaceutiques Francaises
2013;71:376–89.
2 Bardin C et al. Guidelines for
the practical stability studies of
anticancer drugs: A European
Consensus Conference. Annales
Pharmaceutiques Francaises
2011;69:221–31.
3 Good manufacturing practices
in hospitals Bonnes Pratiques
de Préparation – Arrêté du 18
décembre 2007. AFSSAPS.
4 European Agency for the
Evaluation of Medicinal Products.
Note for guidance on maximum
shelf-life for sterile products for
human use after first opening or
following reconstitution; 1998.
5 European Agency for the
Evaluation of Medicinal
Products. Note for guidance in
in-use stability testing of human
medicinal product; 2001.
6 International Council
for Harmonisation of
Technical Requirements for
Pharmaceuticals for Human
Use guidelines. www.ich.org/
products/guideline (accessed
August 2019).
7 EudraLex - Volume 4 - Good
Manufacturing Practice (GMP)
guidelines. https://ec.europa.eu/
health/documents/eudralex/vol-
4_en (accessed August 2019).
8 Quality Standards for the
Oncology Pharmacy Service
(QUAPOS). 6th Edn; 2018: Section
4.5.2 pp 25–7. www.esop.li/
downloads/QuapoS%206.pdf
(accessed August 2019).
9 Trissel LA. Handbook on
Injectable Drugs. 19th edn.
Bethesda, MD: American Society
of Health-System Pharmacists;
2017.
10 Stabilis ® . www.stabilis.org
(accessed August 2019).
11 NHS Pharmaceutical Quality
Specific
recommendations
for good stability
testing practice in
hospital
pharmacies have
been written by
various expert
societies to adapt
the ICH
guidelines, the
European
Pharmacopoeia
and the most
relevant literature
Grade A hood for medicines reconstituted and
diluted extemporaneously for a single patient
• Medium risk: manipulations performed for
multiple patients, with multiple medicinal products
shared to avoid waste and for preparations of
elastomers or the preparation of continuous
infusion devices for several days
• High risk: handling of non-sterile preparations
to be sterilised, but this is uncommon in normal
compounding laboratories.
The quality, efficacy and safety of preparations
is the responsibility of the pharmacists working in
hospitals or similar facilities. Therefore, pharmacists
should be able to have confidence in reliable stability
data, and have basic knowledge of analysis, good
preparation techniques and necessary infrastructures.
Assessment of the stability of the preparations, which
allows their correct preservation over time, confers
important benefits for patients, organisations and
in terms of pharmacoeconomics. When there is a
need for formulations other than those available
commercially, for the drug to be prepared in
advance, or for prolonged and out-of-hospital drug
administration, it is crucial to be able to predict
stabilities. At the organisational level, having ready-to-
use drugs for the weekend, or for a course of therapy,
translates into a reduced number (and duration) of
patient visits to the hospital, decreased waiting times
and greater patient comfort.
Conclusions
The information contained in the SPCs remains the
primary reference in terms of in-use stability. Such
indications often assign reduced in-use stability,
usually close to what is foreseen in regulatory
authorities’ notes, without taking into account
that manipulations occur under aseptic conditions.
When the information in the SPC is not exhaustive
and detailed, it is possible to take into consideration
what is presented in relevant bibliographic
references and available databases, or by performing
practical stability studies. Standards for conducting
stability studies are only fully relevant in industrial
settings. Thus, specific recommendations for good
stability testing practices in hospital pharmacies
have been produced by expert societies to adapt
the ICH guidelines, the European Pharmacopoeia
and the most relevant literature for the clinical
environment, and to identify methodologies
for stability studies in hospital pharmacies and
compounding pharmacy units.
Assurance Committee. A
standard protocol for deriving
and assessment of stability – part
1 – aseptic preparations (small
molecules), 3rd edn. December
2015. www.sps.nhs.uk/articles/
standard-protocol-for-deriving-
and-assessment-of-stability-
part-1-aseptic-preparations-
small-molecules/ (accessed
August 2019).
12 NHS Pharmaceutical Quality
Assurance Committee. A
standard protocol for deriving
and assessment of stability –
part 2 – aseptic preparations
(biopharmaceuticals), 3rd
edn. August 2014. www.sps.
nhs.uk/articles/standard-
protocol-for-deriving-and-
assessment-of-stability-
part-2-aseptic-preparations-
biopharmaceuticals-edition-2-
2015-yellow-cover/ (accessed
August 2019).
13 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. www.sps.nhs.
uk/articles/a-standard-protocol-
for-deriving-and-assessment-
of-stability-part-3-oral-liquid-
medicines-solutions-emulsions-
suspensions-and-syrups-edition-
1-august-2014/ (accessed August
2019).
14 ISOPP Standards of Practice:
Safe handling of cytotoxics.
J Oncol Pharm Practice
2007;13:1–81.
15 European Pharmacopoeia
9th edition. www.edqm.eu/en/
european-pharmacopoeia-ph-
eur-9th-edition (accessed
August 2019).
16 USP General Chapters
for Health Quality & Safety.
Pharmaceutical Compounding:
Sterile Preparation USP, Chapter
797; Hazardous drugs: handling
in healthcare settings. USP,
Chapter 800. www.usp.org/usp-nf
(accessed August 2019).
17 PIC/S Guide to Good
Manufacturing Practice of
preparation of medicinal
products in healthcare
establishment, PIC/S PE 010-4.
www.gmp-compliance.org/
guidemgr/files/PICS/PE-010-4-
GUIDE-TO-GOOD-PRACTICES-1.
PDF (accessed August 2019).
18 Bakshi M, Singh S.
Development of validated
stability-indicating assay
methods – critical review.
J Pharm Biomed Anal
2002;28:1011–40.
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