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University of Groningen
Ready to administer parenteral medication produced by the hospital pharmacyLarmené-Beld, Karin
DOI:10.33612/diss.144367021
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Citation for published version (APA):Larmené-Beld, K. (2020). Ready to administer parenteral medication produced by the hospital pharmacy:cost, labeling and quality. University of Groningen. https://doi.org/10.33612/diss.144367021
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CHAPTER 7
GENERAL DISCUSSION AND
PERSPECTIVES
Chapter 7
152
SUMMARY OF THE MAIN FINDINGS
The overall aim of this thesis was to explore cost, labeling and quality of
sterilized RTA syringes produced by the hospital pharmacy. Findings of
this thesis support the wider implementation of this process and product in
current hospital pharmacy practices.
With the systematic review and meta- analysis in chapter 2 we show that
the microbial contamination of pharmaceutical products prepared in
the pharmacy environment was much lower (almost zero) compared to
preparation in the clinical environment (7.47%). The data from the systematic
review on contamination rates and data about parenteral administrations
in a top clinical hospital in the Netherlands was used to perform a cost
minimization analysis (chapter 3). This showed that implementing the
production of sterilized RTA syringes by the hospital pharmacy is cost saving.
This analysis showed € 4.9 million of savings (for a 900-beds hospital) when
introducing 50% of the parenteral administrations as RTA syringes and 50%
of the parenteral administrations still to be prepared in a clinical environment.
Most of the costs were related to the costs of possible medication errors and
costs of bacteremia after contamination. In chapter 4a we show the results
of the systematic literature review on strategies to avoid look- alike errors of
labels. There is some evidence that Tall Man lettering contributes to better
readability of labels, based on laboratory-based experiments. Only few
studies evaluated other strategies, like colour coding. The survey performed
in chapter 4b showed that label enhancement techniques for parenteral
medications were not widely implemented and acknowledged in European
hospitals, suggesting an urgent need for improvement.
In chapter 5, we investigated the suitability of syringes made of cyclic olefin
polymer (COP) as primary container for water soluble products with a pH
between 3 and 9. The testing of the syringes with phosphate buffer solutions
with different pH values, NaCl 0.9%, water for injections and isopropyl
alcohol 5% in water, showed only low levels of extractables. These results
demonstrate the suitability of the syringes for use in the hospital pharmacy.
The information is further a good starting point for quality assurance and
stability studies with drug containing solutions.
General discussion and perspectives
153
7
It is known that metabisulfite is incompatible with the COP material of the
syringes. Most catecholamines are stabilized with sodium metabisulfite
to prevent oxidation. Because cathecholamines, like norepinephrine are
widely produced by hospital pharmacies, we developed a new formulation
of 0.1 mg/mL norepinephrine solution for use in prefilled syringes which
is chemically stable and sterile and which is free of sodium metabisulfite
(chapter 6). We show that the norepinephrine (0.1 mg/mL) solution containing
sodium edetate and sodium chloride filled under nitrogen gassing in
syringes followed by heat sterilization is stable for at least 12 months at room
temperature when protected from day light.
DISCUSSION AND PERSPECTIVES
Implications of our findings
Our analysis on delivering sterilized RTA syringes show potential cost savings,
a safer product and a more efficient (less time consuming) production
process compared to other approaches for improving the preparation of
parenteral medications. The sterilized syringes meet high quality standards,
with low extractables and leachables and a potentially long shelf life at room
temperature.
Safety, quality, costs, sustainability, labeling and hospital pharmacy practice
have to be considered when introducing RTA products in the hospital
pharmacy (Figure 1). In the following discussion we will address those aspects
in turn, reflecting on the findings of this thesis. In our experience, in many
Dutch hospitals 25 to 30 active pharmaceutical ingredients make up more
than 30% of the parenteral administrations with a reconstitution step. These
products seem suitable to be further developed as PFSS. On the one hand,
we will reflect on how best PFSS could be implemented. On the other hand,
we also reflect on some of the safety aspects on parenteral medications
for those products where PFSS may not be an option in the near future. In
particular we reflect on the aspects considering the Dutch situation as well as
the situation in other European countries.
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154
Figure 1: Aspects to be considered when introducing sterilized RTA products by the hospital pharmacy.
1020
3040
5010
Medication safety
High quality
Cost effectiveness
Sustainability
• Less wastage due to longer shelf life product
• Automatic production process
• Less time for preparationmedication by nurse
Hospital pharmacy
Labeling
• TALL man lettering• Colour coding according
ISO 26825
• Compliant to high risk• Maximum quality and
safety for patient
• Low extractables and leachables profile
• Shelf life >12 months at room temperature
• Production according to GMP• Validated production process
• Reduction healthcare costs by reduction in medication errors
• Less wastage• Time nurse available
for other care tasks
• Niche market• Expertise
productdevelopment
General discussion and perspectives
155
7
Medication safety
Delivering RTA syringes is compliant to high risk medication and improves
medication safety by eliminating the reconstitution step of parenteral
medication and preventing possible dilution or dosing errors.1-3 Further the
risk of contamination is eliminated because no handling is necessary before
administration to patients.
Not all parenteral administrations can be delivered as PFSS. The European
resolution on good reconstitution practices provides a risk assessment which
could help healthcare institutions to decide whether products should be
reconstituted in the pharmacy or in the clinical environment with appropriate
risk- reducing measures, like training and standard operating procedures.4
It also advises to keep track on competence of medical staff performing
preparations in clinical environment. Particularly important are knowledge and
skills in calculation, awareness about hygiene and microbiology, and training
in aseptic handling to prevent errors during preparation of medication.4-6
High quality
With the implementation of sterilized RTA products by the hospital pharmacy
a new type of product with a high quality standard is introduced in the
hospital. The observations in our study confirm the suitability of the COP
syringe as primary packaging material. Cyclic olefin (co)polymer syringes
will be replacing polypropylene, because of the lower extractables and
leachables and the possibility of terminal sterilization, giving a longer shelf
life to the products.
As highlighted above, in our experience, in many Dutch hospitals 25 to 30 drug
products are responsible for more than 30% of the parenteral administrations
with a reconstitution step. These products seem suitable to be further
developed as PFSS. Most of them were already available in a polypropylene
syringe which indicates an easy transition to the sterilized syringes. But for
every product a process qualification and stability study has to be performed
to confirm the suitability of the PFSS packaging material. This study may
go hand in hand with improvements of the formulation as we showed for
norepinephrine, where sodium metabisulfite was no longer necessary in the
Chapter 7
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formulation.7,8 This approach certainly offers potential opportunities for other
catecholamines or drugs where sodium metabisulfite normally is added as
anti-oxidant, like phenylephrine. Simplifying formulations by re-evaluating
the necessity and purpose of each excipient in the new form of administration
could certainly improve the quality and safety of the new products.9
Cost effectiveness
In this thesis, a targeted cost minimization analysis provides insight in the
costs and benefits of the production of PFSS compared to the conventional
preparation method of parenteral medication. In all examined scenarios, PFSS
use resulted in decreased total costs. The cost-savings of PFSS are mainly
driven by the reduction in medication errors and contaminations, which are
substantial parts of the costs of the conventional preparation method.
To further enhance the use of PFSSs, the challenge will be how to offset the
extra costs as the realization of the savings in safety are very difficult to regain
as they are sometimes on the longer term and hidden. The investments for
starting up the production have to be made by the hospital, while the savings
will be in reduction of complications later on and potentially falling within
other budgets than the initial investment. Also, these savings are not part of
the fixed budgets for the hospital. A general shift in thinking is needed to see
innovation in healthcare as an investment with corresponding related benefits
rather cost. Health technology assessment (HTA) is increasingly being used
to evaluate the value of healthcare products and to decide how resources
should be prioritised.10,11 Within a healthcare system with a fixed budget,
value can be defined as health outcomes achieved per unit of money spent.10
However, although effectiveness and safety are key components of value,
the measurement of health outcomes is not straightforward, and commonly
used methods may not capture all relevant aspects of value. For example,
an exploratory survey conducted by different stakeholders (e.g. clinicians,
health economics, academics) indicated that the value of a drug is subjective
and perceived differently by different stakeholders.12 This is illustrative and
probably the same for the implementation of PFSS. Many are convinced of
the better quality of a PFSS produced by the hospital pharmacy compared
to syringes prepared on the ward by a nurse, but the unanswered question
General discussion and perspectives
157
7
is how much this rise in quality may cost? This remains a social discussion in
healthcare.11
Sustainability
Introducing PFSS is a sustainable approach in the medication process which
reduces the number of disposable syringes, needles and gloves needed for
the preparation in the clinical environment. Besides the reduced number of
disposable materials also less wastage is achieved with RTA syringes due to
the longer shelf life.13,14
Introducing PFSS has another advantage, it saves nursing time spent
on reconstituting medications. Nurses spend about 30% of their time on
processes related to the administration of medication to the patients; a major
part of this time is spent on distribution and reconstitution of parenteral
medications.15 With an aging population, the demand for nurses is high and
the availability of well-trained nurses on the labor market is declining.16 This
could be another reason to increase the number of ready to administer
products, leaving more time for the nurse to perform other tasks. We have
not investigated this, but this could be one of the solutions to decrease
the workload for nurses and improve the safety and continuity of care in
hospitals.17
The personnel sustainability also applies to the pharmacy staff itself. The
scarcity of pharmacy assistants on the labor market increases.18 By introducing
an automated process with the syringe filling machine for sterilized RTA
products a higher output will be yielded, with less time and less personnel
compared to a semi-automatic aseptic process with lower output.
Labeling
RTA products need to be easily identified and readability of the label on
the product is of paramount importance to prevent medication errors. In
our systematic literature review different methods of label enhancement
techniques are used and more research is needed to strengthen the evidence
based on safe labeling methods in order to guide practice.19 Such research
needs to be approached from a practical perspective, as labeling is only
Chapter 7
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one aspect of a multidimensional process aimed to improve safe medication
use in hospitals, including procedures such as double checking and the safe
preparation of parenteral medications as already mentioned.3,20-23 In addition,
the use of a barcode on the label in combination with computerized decision
support may further decrease the risk of medication errors.24 This is urgently
needed when the number of RTA products produced by the same pharmacy
increases.
Despite the fact that all label enhancements methods are applied, especially
colour, the risk of look-alike products remains due to medications belong to
the same substances class and maybe also have the same syringe volume.
This may urge standardisation across Europe to improve safety, as using
different colour coding systems, could create confusion and compromise
patient safety. Collaborations across European countries could be very useful
to drive this agenda forward.
Hospital pharmacy
Currently, most hospital pharmacies in the Netherlands facilitate the use of
RTA syringes by aseptic filling of polypropylene single use syringes. This is
an aseptic process and at a given moment the output will reach a maximum,
due to stock capacity (refrigerator in the pharmacy and ward) and also
because of a limited speed of the used machines. In this thesis we show that
the production of PFSSs produced by the hospital pharmacy using a (semi)-
automatic filling and closing machine results in a high quality product that is
able to meet the higher demand for ready to administer products.
Not all drugs are suitable for delivering as PFSS, well known examples are
antibiotics and insulin. Antibiotic solutions cannot undergo a sterilization
process. For this type of products, when sterilization is not an option, the
aseptic process is a good alternative. The hospital pharmacy has different
opportunities for delivering RTA products to the clinical wards, varying from
sterile syringes, aseptic filled syringes to also sterile infusion bags. Depending
on how the drug is administered (as injection or as infusion with or without
an infusion pump) the choice of an appropriate RTA product may increase
quality and compliance.4,25
General discussion and perspectives
159
7
The completion of this thesis is timely, as the current COVID-19 pandemic
shows the central role that hospital pharmacies have in ensuring supply of
essential medications such as propofol and norepinephrine.26,27 Throughout
Europe shortages of several medications including midazolam products
arose. Many hospital pharmacies started/ increased the production of
midazolam products and because of the already high stress levels on the
intensive care units, maximum support is given by producing RTA products.
In this thesis, the focus was on investigating the production of sterilized
RTA syringes by the hospital pharmacy. Another approach could be the
production of RTA syringes by the pharmaceutical industry. Currently, not
many of these products in the generic category are available, probably due
to high investment costs of new production lines and low margins. However,
it should be realized that more and more hospitals will adopt this new
type of product in the future, which requires a higher production capacity
as currently available. When 50% of all injections will be delivered as RTA
product in the Netherlands, 18 million products have to be produced. This
market potential could make it interesting for the pharmaceutical industry to
start with production, with the consequences that a registered alternative is
available and the hospital pharmacy is not allowed to produce it anymore,
only for their own patients. But this makes the work of a hospital pharmacist
interesting and challenging, still working in a niche market with searching for
a new product with added value for the patient.
In this thesis, the different aspects of introducing PFSS produced by the
hospital pharmacy were investigated. Ranging from reviews on contamination
rate and labeling practices and a cost minimization analysis to showing
the suitability of the packaging material and product development of
norepinephrine. All those aspects are within the expertise of the hospital
pharmacist and taken together they contribute to improving the safety and
quality of medication use in practice.
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CONCLUSION
In conclusion, the PFSS investigated in this thesis have the potential
to become a high quality and safe product. The product may lead to
significant cost savings in the hospital budget, due to the reduction in the
number of medication errors and contaminations of parenteral medications.
Further standardization in conjunction with research for evidence based
enhancement techniques for the label is needed to guide improvement in
labeling practices.
Finally, the containers show low leachables and extractables. For further
implementation the field will have to come up with a strategy how the range
of interesting products is going to be qualified in the future.
General discussion and perspectives
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7
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