Ready to administer parenteral medication produced by the hospital pharmacy
Larmené-Beld, Karin
DOI:
10.33612/diss.144367021
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2020
Link to publication in University of Groningen/UMCG research database
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
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
INTRODUCTION
AND SCOPE OF THE THESIS
PARENTERAL MEDICATION
Medications intended for parenteral administration are sterile drug products in the form of a solution, suspension, emulsion, or a reconstituted lyophilized powder. Typical routes of administration of a parenteral dosage form include intravenous, subcutaneous and intramuscular injection or infusion. Compared to oral administration, parenteral administration, especially intravenous administration, has a rapid absorption and distribution. Furthermore, parenteral administration circumvents the first pass metabolism in gut and liver and bioavailability is therefore often higher. Often, parenteral medications cannot be administered directly to the patient but require to be reconstituted. The reconstitution can vary from a simple withdrawal from an ampoule to a multi-step process including manipulations such as dissolving of a powder, and dilution of the solution. The term preparation includes the entire process of obtaining the drug product, dilution, reconstitution and labeling of the product. Frequently administered parenteral medications include insulin, antithrombotics, antibiotics, pain medication, anti-emetics, vasopressors and chemotherapeutics. Many parenteral medications have a narrow therapeutic index and a high risk of causing significant harm to patients when used inappropriately.
Although exact figures are not available, a considerably proportion of all parenteral medications is given in hospitals. An estimated 90% of hospital patients receive intravenous medication.1 In the Netherlands over 37.000
hospital beds are available.2 In Isala, a clinical teaching hospital with around
900 beds, more than 850.000 parenteral dosages are administered per year. Extrapolation of this number nationwide, results in more than 36 million parenteral medication administrations per year in the Dutch hospitals.
Medication errors are common in the hospital setting, they may lead to adverse drug events, causing serious harm, such as prolonged hospitalization, permanent disabilities or even death, and involve high costs for the health care system.3-6 The preparation and administration of parenteral
medication are particularly risky processes.7,8 Common preparation errors of
parenteral medications are preparation of the wrong medicine or the wrong dose, calculation errors, choosing the wrong diluent or insufficient hygienic
precautions during preparation. Insufficient hygienic precautions may lead to contamination of the product.9-13
Preparation and administration error rates of parenteral medications varied from 30% up to even 48%.7,14-16 Those high error rates were observed in studies
investigating the traditional systems where preparation and administration of parenteral medication were handled by nursing staff on the wards. Lower preparation error rates were observed in systems where medications were prepared in the pharmacy department.17 Furthermore, the risk for
contamination was also found to differ between the pharmacy environment and the clinical (ward) environment. In a meta- analysis, Austin et al. found a contamination rate of 3.7% for the clinical environment and 0.5% for the pharmacy environment.12 Although, it should be noted that in this study 65%
of the included studies were conducted before 2000 and therefore results may not be representative for current practice.12
Many countries struggle with the problem of optimizing the process of the reconstitution of parenteral medication in hospitals. In Europe, medication preparation in the pharmacy department is performed according to good manufacturing practice (GMP) guidelines or the recently adopted resolution on quality and safety assurance requirements for medicinal products prepared in pharmacies with a special paragraph about reconstitution.18,19 For
preparations in the clinical environment (ward, operating room), a general European guideline has been published recently.20 Furthermore, several
countries have published national guidelines such as the Dutch Hospital Safety Program.21,22 Following all of the different quality standards, hospital
pharmacies play an important role in the safety of parenteral medications. A solution that is frequently mentioned to improve medication safety further, is the use of ready-to-use (RTU) or ready-to-administer (RTA) products. Ready-to-use medications are medications at the required concentration in a container where the required volume is directly transferred to a final administration device (syringe, infusion bag or elastomeric device) for administration to the patient. So only one step is needed to be able to administer the medication. A ready-to-administer product is a product containing the required volume of the drug in the required concentration in
the final administration device (syringe, infusion bag or elastomeric device) which can be directly administered to the patient.20 So no preparation steps
are needed.
RTA- products have been suggested to reduce medication errors in a modelling study by McDowell et al., and in a systematic review on medication errors by Berdot et al.22,23 Also hospital quality standards such
as the Joint Commission International Accreditation Standards for Hospitals advise that hospital dispensed medications should be in the most ready-to-administer form possible to minimize opportunities for error during distribution, preparation and administration.24 In addition, a European
resolution was adopted in June 2016 in which, based on risk management, recommendations are made on how to support the process of preparing parenteral medicines for administration by the pharmacy.
RTA PRODUCTS SUPPLIED BY HOSPITAL
PHARMACIES
There is an increasing demand of RTA products as their use is recommended in many quality guidelines as has been highlighted above. Hospital pharmacies are seizing the opportunity to facilitate this process by developing RTA products. In this way RTA products can be supplied to the wards. There are different models on how this can be achieved by the hospital pharmacy. One way to supply RTA products is by having pharmacy assistants prepare the parenteral medications instead of the nurses on the ward. This is done in a dedicated area on the ward. Most of the time the reconstitution process is performed in a laminar airflow cabinet and products are prepared for each individual patient. This approach is chosen in many countries.25
A second approach to supply RTA products is to transfer the preparation process from the ward to the hospital pharmacy. In the Netherlands hospital pharmacies are allowed to produce unlicensed medicinal products under strict condition of the circular letter, authorized by the Dutch Healthcare Inspectorate.26 Currently, in the Netherlands many hospital pharmacies
in the pharmacy. Different semi- automatic systems are used to produce the aseptic syringes with a higher output. These syringes have mostly a shelf life of 31 days in the refrigerator according to the Good Manufacturing Practice- hospital pharmacy guidelines (Dutch).27 Major problems related to
this practice are: the fact that the process is an aseptic process without a final sterilization step, the limited shelf-life, the refrigerator capacity used in the pharmacy and especially on the wards, the fact that the syringes are not qualified as containers and the limited capabilities to upscale the production. A terminally sterilized product is preferred to ensure that sterility quality requirements are met.28 Especially for frequently used products, the regular
production of RTA products in a production setting with a final sterilization step could bring a significant improvement in safety and quality.
To realize the demand for safe RTA products of a high quality in a larger hospital a potential solution can be found in the use of sterilizable syringes. So far, no hospital pharmacy in Europe has implemented the process of production and distribution of RTA Prefilled Sterilized Syringes (PFSSs). As already highlighted, Dutch hospital pharmacies are allowed to produce and distribute unlicensed medicinal products (including PFSSs). However, the Healthcare authorities have set a range of conditions and requirements that must be fulfilled. These include the condition that no licensed alternative medicinal product is available on the Dutch Market, the phamacotherapeutic rationale is demonstrated, product dossiers are available and production complies with Good Manufacturing Practice (GMP).26 One of the indications
for the pharmacotherapeutic rationale is the increase of medication safety by delivering RTA products.
Moving the activities of preparation of medication from the clinical environment to the pharmacy by producing sterilized syringes requires investments in pharmacy equipment and personnel. Such investments may be justified by savings in healthcare costs due to having safer products of a higher quality, e.g. by reducing microbial contamination and preparation errors.18 But this
has not been investigated in a formal cost analysis study, so far.
LABELING OF RTA PRODUCTS
Labeling of medicinal products is an important aspect of medication safety. Good labeling ensures that a medicinal product can be clearly identified to reduce the risk of confusion with other products when selecting a medicine. Also good labeling provides the minimum information on the outer packaging for the safe storage, selection, preparation, dispensing, administration and tracking of medicines in line with the labeling requirements of Directive 2001/83/ EC.29 The American Food and Drug Administration (FDA) estimated
that 20% of medication errors may be attributed to confusing packaging and poor labeling; others suggested even higher rates.30,31 This is illustrated by a
recent case report describing the mix-up of tranexamic acid and bupivacaine HCl ampoules in a hospital due to lookalike labels. The error resulted in lifelong reduction in quality of life for the patients.32
Various strategies are available for label enhancement, like Tall Man lettering (e.g. ceFAZoline, cefTAZidime), colour coding, barcoding or the use of pictograms and symbols.33 But guidelines of the FDA and European Agency
of Medicine (EMA) do not give conclusive advice how to prevent look alike errors.33,34 In the Dutch guideline also no consensus is given about the use
of colour and or Tall Man lettering.35 So far, no systematic review is available
about label enhancement techniques that contribute to a better readability of medication labels leading to a reduction in medication errors. This information is particularly important for hospital pharmacies to choose safe strategies in labeling their RTA products. Further little is known on differences in labeling practices for parenteral medications in hospitals among European countries. Such work will contribute to come to European harmonization on the labeling of parenteral medications.
CONTAINERS USED FOR RTA PRODUCTS
Historically glass (ampoules) and polypropylene (syringes, infusion bags) are the main primary packaging materials used for production of parenterals in hospital pharmacy. There is considerable knowledge about products and their interaction with these packaging materials. With the introduction of the PFSSs a new primary packaging material has been introduced,
since polypropylene is not suitable for final heat sterilization. The material that the PFSSs are made of, is a cyclic olefin polymer (COP), which differs in characteristics from polypropylene and glass. The advantages of using COP syringes were transparency, low weight, high breaking resistance, low chemical reactivity providing a high compatibility, low levels of extractables and leachables and suitability for gamma- sterilization and autoclaving after filling. Extractables are compounds which may migrate from the packaging material into the solution under laboratory test conditions (stress conditions may include high temperature, extreme pH values, or different organic solvents). Leachables are compounds which may migrate from the packaging material into the drug containing solution under normal conditions of storage and use. Leachables are typically a subset of extractables or are derived from extractables.36
The introduction of a new type of primary packaging material into a production process requires the qualification of the container for its intended use. It is the responsibility of the drug product manufacturer to ensure that the new packaging material (being a combination of compliant materials) does not adversely affect product quality and the related patient safety.37 The suitability
of the container should be proven for each product it will be used for.
MEDICATIONS SUITABLE FOR STERILIZED RTA
Medications that are suitable to deliver as a RTA-PreFilled Sterilized Syringe (PFSS) should fulfill the following criteria:
■ the medicine is usually administered in a fixed-dose concentration, ■ the medicine is suitable for injection or infusion with a pump, and ■ the volume of administration does not exceed 50 mL.
In Isala, about 1,8 million parenteral medications per 1000 hospital beds are administered each year. Excluding cytostatic drugs, ready-to-administer parenteral products (infusions, syringes) supplied by industry, high risk drug products (e.g. concentrated electrolytes, methotrexate), and total parenteral nutrition, more than 1 million parenterally administered medications per
1000 hospital beds with a reconstitution step remain. About 23% of the administrations are probably not suitable to deliver as PFSS due to chemical or physical properties of the medication (e.g. instability of antibiotics). Twenty-five active pharmaceutical ingredients (APIs), probably suitable for PFSS production, accounted for more than 345,000 administrations per 1000 beds per year. Examples of these twenty- five APIs are midazolam, morphine, and norepinephrine. Analysing drug supply data from similar hospitals to the Isala, should result in comparable estimations.
In summary, RTA sterilizable syringes appear to be a good alternative to existing processes to facilitate the supply of safe parenteral medications by the hospital pharmacy. However, it is unknown whether this is a cost-effective approach and whether the container is suitable as primary packaging material for these products. Another important aspect while introducing this new type of product is the labeling of the product, knowing that look alike products may cause medication errors.
SCOPE OF THE THESIS
The aim of this thesis is to explore the cost, labeling and quality of sterilized RTA syringes produced by the hospital pharmacy.
In chapter 2 a systematic literature review is performed to establish and compare the contamination rate of parenteral medications prepared in the clinical environment and the pharmacy environment. Chapter 3 describes a cost minimization analysis of the conventional preparation method (CPM) by the nurses in the clinical environment and the use of PFSSs in total and a 50-50% distribution. The cost analysis is focused on the premises and equipment needed to produce PFSS in a hospital pharmacy, but also on the savings in treatment costs of patients due to reductions in medication errors and contamination rates with corresponding decreases in infection rates and lengths of stay and increased quality of care.
In chapter 4a we performed a systematic literature review to evaluate the current evidence on strategies to minimize medication errors due to look-alike labels. Based on these results and the fact that there is no consensus
about labeling practices across Europe we conducted a survey among hospital pharmacies to obtain an overview of the labeling practices for parenteral medications, in relation to national guidelines, in The Netherlands, Germany and the United Kingdom. These results are described in chapter 4b.
Before a new product can be introduced in the hospital it has to be qualified. This is also applicable to new (primary) packing materials. Based on a risk analysis an extensive qualification program was designed and performed for the new PFSS. The description of the methods and results is provided in chapter 5.
Having a new container available for producing ready-to-administer products raises questions whether the material is suitable for the process of sterilization and whether the container material is compatible with the drug product. In chapter 6 we describe a reformulation of a norepinephrine solution which normally contains sodium metabisulfite as anti-oxidant. But this antioxidant cannot be used in this case due to incompatibility with the barrel of the syringe.
In chapter 7 we discuss the findings of the thesis in a broader perspective.
REFERENCES
1. Giuliano KK. Intravenous smart pumps: Usability issues, intravenous medication
administration error, and patient safety. Crit Care Nurs Clin North Am. 2018;30(2):215-224. doi: S0899-5885(18)30006-6 [pii].
2. Dutch hospital data/ E. The state of health and care, key figures
. https://www.staatvenz.nl/kerncijfers/ziekenhuisbedden. Updated 2019. Accessed 25 November, 2019.
3. Hoogervorst-Schilp J, Langelaan M, Spreeuwenberg P, de Bruijne MC, Wagner C. Excess length of stay and economic consequences of adverse events in dutch hospital patients.
BMC Health Serv Res. 2015;15:531-5.
4. Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. adverse drug events prevention study group. JAMA. 1997;277(4):307-311.
5. van den Bemt, P. M., Fijn R, van der Voort, P. H., Gossen AA, Egberts TC, Brouwers JR. Frequency and determinants of drug administration errors in the intensive care unit. Crit
Care Med. 2002;30(4):846-850.
6. Sutherland A, Canobbio M, Clarke J, Randall M, Skelland T, Weston E. Incidence and prevalence of intravenous medication errors in the UK: A systematic review. Eur J Hosp
Pharm. 2020;27(1):3-8. doi: 10.1136/ejhpharm-2018-001624 [doi].
7. Keers RN, Williams SD, Cooke J, Ashcroft DM. Prevalence and nature of medication administration errors in health care settings: A systematic review of direct observational evidence. Ann Pharmacother. 2013;47(2):237-256.
8. Berdot S, Gillaizeau F, Caruba T, Prognon P, Durieux P, Sabatier B. Drug administration errors in hospital inpatients: A systematic review. PLoS One. 2013;8(6):e68856.
9. Macias AE, de LS, Huertas M, et al. Endemic infusate contamination and related bacteremia.
Am J Infect Control. 2008;36(1):48-53.
10. Macias AE, Huertas M, Ponce de LS, et al. Contamination of intravenous fluids: A continuing cause of hospital bacteremia. Am J Infect Control. 2010;38(3):217-221.
11. Van GJ, Foudraine NA, Nooteboom F, Crombach WHJ, Oldenhof NJJ, Van DH. Unexpected high risk of contamination with staphylococci species attributable to standard preparation of syringes for continuous intravenous drug administration in a simulation model in intensive care units. Crit Care Med. 2002;30(4):833-836.
12. Austin PD, Hand KS, Elia M. Systematic review and meta-analysis of the risk of microbial contamination of parenteral doses prepared under aseptic techniques in clinical and pharmaceutical environments: An update. J Hosp Infect. 2015;91(4):306-318.
13. Kuitunen S, Niittynen I, Airaksinen M, Holmström AR. Systemic causes of in-hospital intravenous medication errors: A systematic review. J Patient Saf. 2020. doi: 10.1097/ PTS.0000000000000632 [doi].
14. Taxis K, Barber N. Incidence and severity of intravenous drug errors in a german hospital.
Eur J Clin Pharmacol. 2004;59(11):815-817.
15. Taxis K, Barber N. Ethnographic study of incidence and severity of intravenous drug errors.
BMJ. 2003;326(7391):684.
16. Parshuram CS, To T, Seto W, Trope A, Koren G, Laupacis A. Systematic evaluation of errors occurring during the preparation of intravenous medication. CMAJ. 2008;178(1):42-48.
17. Adapa RM, Mani V, Murray LJ, et al. Errors during the preparation of drug infusions: A randomized controlled trial. Br J Anaesth. 2012;109(5):729-734. http://dx.doi.org/10.1093/ bja/aes257. doi: 10.1093/bja/aes257.
18. Committee of Ministers, Council of Europe. Resolution CM/ResAP(2011)1 on quality and safety assurance requirements for medicinal products prepared in pharmacies for the special needs of patients. https://www.edqm.eu/sites/default/files/resolution_cm_ res_2016_1_quality_and_safety_assurance_requirements_for_medicinal_products_ prepared_in_pharmacies.pdf. Accessed June, 5, 2020.
19. European Commission. EudraLex - volume 4 - good manufacturing practice (GMP) guidelines. http://ec.europa.eu/health/documents/eudralex/vol-4_en. Accessed 5 June, 2020.
20. Committee of Ministers, Council of Europe. Resolution CM/res(2016)2 on good reconstitution practices in health care establishments for medicinal products for parenteral use. https://www.edqm.eu/sites/default/files/resolution_cm_res_2016_2_ good_reconstitution_practices_in_health_care_establishments_for_medicinal_products_ for_parenteral_use_.pdf. Accessed 5 June, 2020.
21. VMS, ed. High risk medication: Preparation and administration of parenteralia. Utrecht, The Netherlands: VMS; 2009.
22. McDowell SE, Mt-Isa S, Ashby D, Ferner RE. Where errors occur in the preparation and administration of intravenous medicines: A systematic review and bayesian analysis. Qual
Saf Health Care. 2010;19(4):341-345.
23. Berdot S, Roudot M, Schramm C, Katsahian S, Durieux P, Sabatier B. Interventions to reduce nurses' medication administration errors in inpatient settings: A systematic review and meta-analysis. Int J Nurs Stud. 2016;53:342-350.
24. Joint Commission International. Joint commission international Accreditation Standards for
hospitals. U.S.A.: Joint Commission International; 2013:305.
25. Scheepers H, Beaney AM, Le Brun PPH, Veerup Handlos V, Schutjens M, Walser S, Neef C. Aseptic preparation of parenteral medicinal products in healthcare establisments in europe. European Journal of Hospital Pharmacy: Science and Practice. 2016(23):50-53. 26. Dutch inspectorate. Circulaire 'handhavend optreden bij collegiaal doorleveren van eigen
bereidingen door apothekers'. https://www.igj.nl/zorgsectoren/geneesmiddelen/ documenten/circulairen/2016/08/22/circulaire-handhavend-optreden-bij-collegiaal-doorleveren-van-eigen-bereidingen-door-apothekers. Updated 2019.
27. Dutch association of hospital pharmacists, (NVZA). Z3 aseptische handelingen . . 2013.
28. Agalloco JP. Increasing patient safety by closing the sterile production Gap—Part 1. introduction. PDA journal of pharmaceutical science and technology. 2017;71(4):261-268. 29. Goedecke T, Ord K, Newbould V, Brosch S, Arlett P. Medication errors: New EU good
practice guide on risk minimisation and error prevention. Drug safety. 2016;39(6):491-500. 30. Berman A. Reducing medication errors through naming, labeling, and packaging. J Med
Syst. 2004;28(2):9-29.
31. Thomas MR, Holquist C, Phillips J. Medication error reports to FDA show a mixed bag. FDA
Saf Page. 2001;October(145 (19)):23-24.
32. van Lanschot Hubrecht, W Justine, Be WKM, Fredriks IM, Dalman JE. Mix-up of medication in spinal anaesthetics. Nederlands tijdschrift voor geneeskunde. 2018;163. https://www.ncbi. nlm.nih.gov/pubmed/30570934.
33. European Commission. Guideline on the readability of the labelling and package leaflet of medicinal products for human use. . 2009;Revision 1. doi: //ec.europa.eu/health/files/ eudralex/vol-2/c/2009_01_12_readability_guideline_final_en.pdf.
34. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry; safety considerations for container labels and carton labeling design to minimize medication errors. . 2013. 35. Werkgroep etikettering Dutch Association of Hospital pharmacists. Richtlijn etikettering van
apotheekbereidingen. . 2011:1-56.
36. Jenke D, Odufu A, Couch T, Chacko M, Strathmann S, Edgcomb E. Evaluation of the general solution compatibility of polymer materials used in medical devices such as syringes. PDA journal of pharmaceutical science and technology. 2012;66(4):286-306. https://www.ncbi.nlm.nih.gov/pubmed/22767879. doi: 10.5731/pdajpst.2012.00869. 37. Committee for medicinal products for human use, (CHMP), Committee for medicinal products for veterinary use, (CVMP). Guideline on immediate packaging materials . European medicines agency. 2005.
