Ready to administer parenteral medication produced by the hospital pharmacy
Larmené-Beld, Karin
DOI:
10.33612/diss.144367021
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Publication date: 2020
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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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GENERAL DISCUSSION AND
PERSPECTIVES
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.
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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.
Figure 1: Aspects to be considered when introducing sterilized RTA products by the hospital pharmacy. 10 20 30 40 50 10 Medication safety High quality Cost effectiveness Sustainability
• Less wastage due to longer shelf life product • Automatic production
process
• Less time for preparation
medication 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
product
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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
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
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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
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
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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.
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.
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