Examination of Particulate Contamination in Parenteral Injections and Infusions Following Fluid Withdrawal Utilizing Conventional Needles and Filter Needles: Assessment of Compliance and Comparative Analysis.

Particulate contamination, the unintentional presence of particles in parenteral fluids, is associated with potential risks such as phlebitis and thrombophlebitis. Recent guidelines recommend the use of filter needles when withdrawing parenteral fluid from vials with a rubber stopper. However, the literature is limited and lacks clarity regarding the advantages of filter needles over conventional needles. The aim of this study was to assess the compliance of parenteral fluids regarding particulate contamination after withdrawing fluid using both conventional needles and filter needles, following the guidelines of European Pharmacopoeia (Ph. Eur.) and United States Pharmacopoeia (USP). Visible particles were counted through visual inspection and sub-visible particles were quantified utilizing the light obscuration particle count test. Particle counts for both types of needles were compared to Ph. Eur. and USP standards and differences in particle contamination were assessed using a Mann-Whitney U test. Both types of needles demonstrated compliance with Ph. Eur. and USP standards regarding particulate contamination of visible and sub-visible particles. However, filter needles exhibited a significantly higher particle count for particles with a size of ≥25 µm compared to conventional needles (p = 0.0029). In conclusion, both types of needles demonstrate suitability for aspirating fluid from vials featuring rubber stoppers regarding particulate contamination. Nevertheless, non-filter needles are preferred for withdrawing fluid from vials with a rubber stopper over filter needles due to their lower cost.

Reducing renal function assessment prior to platinum-based chemotherapy: a real-world evaluation.

BACKGROUND: Platinum-based chemotherapy, a widely used backbone of systemic cytotoxic anticancer treatment, is associated with nephrotoxicity. Currently, renal function is generally assessed prior to each administration of cisplatin or carboplatin, but there is no guideline regarding the frequency of renal function determination. OBJECTIVE: The primary objective was to determine the median time to a clinically relevant dosage adjustment (>10%) due to change in renal function in patients treated with cisplatin and carboplatin. Secondly, variables influencing changes in renal function were assessed. METHODS: We conducted a retrospective analysis of serial renal function assessments in platinum-treated patients with cancer in two academic medical centers, using a query to extract data from the electronic health records between 2017 and 2019. RESULTS: In total, 512 patients receiving cisplatin and 628 patients receiving carboplatin were included. In total, 15% of all cisplatin-treated patients were found to have a renal function less than 60 mL/min at least once during treatment, with a median time to renal function decline of 67 days (range 5-96 days), which did not differ between treatment regimens. For carboplatin 21% of patients were found to have had a dosage variation of more than 10% at least once during treatment, with a median time-to-event period of 64 days (range 5-100 days). INTERPRETATION: Dose adjustments during platinum-based chemotherapy resulting from renal function decline occur after a median time of ≥64 days. Our data provide substantiated guidance to recommend renal function assessment during platinum-based chemotherapy in clinically stable patients to once every 3 weeks.

Investigating the Impact of Drone Transport on the Stability of Monoclonal Antibodies for Inter-Hospital Transportation.

In the field of healthcare logistics, the reliance on conventional transport methods such as cars for the delivery of monoclonal antibodies (mAbs) is susceptible to challenges posed by traffic and infrastructure, leading to increased and unpredictable transport times. Recognizing the potential role of drones in mitigating these challenges, we aimed to investigate the impact of medical drone transport on the stability of mAbs. Compromised stability could lead to aggregation and immunogenicity, thereby jeopardizing the efficacy and safety of mAbs. We studied the transportation of vials as well as ready-to-administer infusion bags with blinatumomab, tocilizumab, and daratumumab. The methodology involved the measurement of both temperature and mechanical shock during drone transport. Moreover, the analytical techniques High Performance Size-Exclusion Chromatography (HP-SEC), Dynamic Light Scattering (DLS), Light Obscuration (LO), Micro-Flow Imaging (MFI), and Nanoparticle Tracking Analysis (NTA) were employed to comprehensively assess the presence of aggregates and particle formation. The key findings revealed no significant differences between car and drone transport, indicating that the stability of mAbs in both vials and infusion bags was adequately maintained during drone transport. This suggests that medical drones are a viable and reliable means for the inter-hospital transport of mAbs, paving the way for more efficient and predictable logistics in healthcare delivery.

Shock and Temperature Monitoring During Transport of Immunoglobulins from a Hospital to Patients' Homes: A Pilot Study.

Transport of biopharmaceuticals from a hospital to a patient's home is scarcely researched but it is essential to investigate the effects of such transport on the stability of the drug, before home-based care can take place. In this study, transport of biopharmaceuticals in vials that are marketed as ready-to-administer from a hospital pharmacy to patients' homes was investigated. Immunoglobulin packages were tracked with 10 G and 25 G shock indicators and temperature data loggers. In the control group, immunoglobulins were transported from the hospital pharmacy to the outpatient daycare unit. During the transport process to patients' homes (n = 39), almost half of the packages were shocked with 25 G and more than half of all packages exceeded the required temperature range. Fortunately, the results found do not affect the stability of the ready-to-administer vials with immunoglobulins. However, these results indicate that the transport of biopharmaceuticals should be better controlled as not all biopharmaceuticals or formulations are so stable. Therefore, results of this pilot study provide a basis for recommendations for home-based therapy.

Exclusion of Ranitidine From Premedication Regimens During Paclitaxel Treatment.

This cohort study conducted in the Netherlands uses electronic medical records to assess incidence of hypersensitivity reactions with and without H2-receptor antagonist premedication before paclitaxel administration.

Aggregate Formation and Antibody Stability in Infusion Bags: The Impact of Manual and Robotic Compounding of Monoclonal Antibodies.

Monoclonal antibodies (mAbs) can be damaged during the aseptic compounding process, with aggregation being the most prevalent form of degradation. Protein aggregates represent one of several risk factors for undesired immunogenicity of mAbs, which can potentially lead to severe adverse drug reactions and less effective treatments. Since data on aggregate and particle formation by robotic compounding is missing, we aimed to compare the antibody stability between robotic- and manual compounding of mAbs with regard to formation of (sub)visible aggregates. Infliximab and trastuzumab were compounded into infusion bags with the APOTECAchemo robot or manually by nurses or pharmacy technicians. The products were analyzed by quantifying (sub)visible particles with nanoparticle tracking analysis, dynamic light scattering (DLS), light obscuration, micro-flow imaging, high pressure size exclusion chromatography (HP-SEC), and visual inspection. HP-SEC showed high percentages monomers in trastuzumab (99.4 % and 99.4 %) and infliximab (99.5 % and 99.6 %) infusion bags for both manual and robotic compounding, respectively. DLS indicated more consistent and reproducible results with robotic compounding, and confirmed monodisperse samples with a higher polydispersity index for manual compounding (0.16, interquartile range; IQR 0.14-0.18) compared to robotic compounding (0.12, IQR 0.11-0.15). This study shows that the studied compounding methods had a minor impact on the number of aggregates and particles, and that robotic compounding of mAbs provided at least similar quality as manual compounding.

A Tool for Deprescribing Antithrombotic Medication in Palliative Cancer Patients: A Retrospective Evaluation.

Treating palliative cancer patients with antithrombotics is challenging because of the higher risk for both venous thromboembolism and major bleeding. There is a lack of available guidelines on deprescribing potentially inappropriate antithrombotics. We have therefore created an antithrombotics scheme to aid in (de)prescribing antithrombotics. A retrospective single-center clinical cohort observational study was performed to evaluate it. Patients with solid tumors with a life expectancy of less than 3 months seen by the palliative team were included. Comparisons were made between patients who were treated according to the antithrombotics scheme and those who were not. 47.6% of patients used antithrombotics. One hundred and eleven patients were included for analysis. Most patients used antithrombotics according to the scheme (n = 80, 72.1%). Eleven patients experienced a clinical event, seven patients in the scheme adherence group (9.9%) and four in the no scheme adherence group (13.8%), which was not statistically significant (p = 0.726). The higher frequency of clinical events in the group without scheme adherence suggests that (de)prescribing antithrombotics according to the antithrombotics scheme is safe. The results of this study suggest that the antithrombotics scheme could aid healthcare professionals identifying possible inappropriate antithrombotics in palliative cancer patients. Further prospective research is needed to investigate this tool.

Extending Practical (In Use) Shelf Life of Oncology Drug Vials Using Spikes.

The global increase of use of oncology drugs combined with the higher costs of these drugs raise the question of how to reduce these costs. One way to reduce the costs is to reduce spillage by extending the beyond-use date by preserving remainders in the vial of (expensive) oncology drugs instead of wasting them. Therefore, we investigated if spikes, instead of the expensive closed-system transfer devices, can be used to extend the beyond-use date of drugs both at room temperature and in the refrigerator during seven days after reconstitution and partial fluid withdrawal of a vial. Six hundred vials containing concentrated tryptic soy broth were reconstituted with 10-mL of sodium chloride 0.9%, after which approximately 3 mL were removed from the vial and discarded using a regular spike for 300 vials and a MicroSpike for the other 300 vials. Subsequently, the vials were stored either at refrigerator temperature or at room temperature for seven days. After seven days, all six hundred vials were transported and incubated at a temperature of 30°C to 35°C for fourteen days. None of the six hundred vials used showed contamination, either punctured with a MicroSpike or with a regular spike, after storage of seven days at room temperature or in the refrigerator and two weeks of incubation. Conclusively, it can be stated that hospital pharmacies play an important role in keeping the high costs of oncology drugs as low as possible. This study shows that using a spike instead of a more expensive closed-system transfer device for preservation of the remainder of oncology drugs will further reduce spillage of expensive drugs resulting in lower healthcare costs.

Container closure integrity testing and process validation of closed system transfer devices for aseptic reconstitution of drug vials connected to fluid bags.

OBJECTIVES: The closure integrity and process validation of closed system transfer devices (CSTDs) should be confirmed before implementation in clinical settings. We aimed to investigate the closure integrity and validate the aseptic procedure of two types of CSTDs by using a combination of the dye ingress test and a media fill test. METHODS: The dye ingress test with methylene blue was used for both CSTDs with 10 samples of drug vials of three brands. A media fill test was performed with both CSTDs (300 samples per CSTD, 150 carried out in a safety cabinet and 150 under non-classified environmental conditions). RESULTS: In all samples of both CSTDs, methylene blue was absent after visual inspection and spectrophotometric analysis. The nutrient media of one sample with CSTD A and none of the CSTD B samples were contaminated when reconstituted in a GMP grade A environment. Under non-classified environmental conditions, one sample of CSTD A and two samples of CSTD B were contaminated. CONCLUSIONS: Both CSTDs connected to the drug vials met the terms of closure integrity by using the dye ingress test. The aseptic procedure of CSTD B was validated with the media fill test when reconstituted in a GMP grade A environment, but failed for CSTD A. Both CSTDs failed the media fill test when reconstituted under non-classified environmental conditions.

Analysis of production time and capacity for manual and robotic compounding scenarios for parenteral hazardous drugs.

BACKGROUND: The increasing amount of hazardous preparations in combination with shortages leads to a call for more efficient compounding methods. This research aims to evaluate the required amount of time, production capacity and direct labour costs of the manual, manual software-supported and robotic compounding of parenteral hazardous drugs. METHODS: This multicentre study was conducted at the clinical pharmacy departments of three Dutch hospitals with different compounding methods: St Antonius hospital (manual software-supported compounding), Amsterdam University Medical Centre (Amsterdam UMC) (both robotic compounding and manual compounding without software support) and OLVG (robotic compounding). Time measurements of individual hazardous drugs were performed in all three hospitals. At Amsterdam UMC and St Antonius hospital, the times per compounding phase, the production capacity and the direct labour costs per preparation were also determined. To reflect real-world situations, the combination of robotic and manual compounding was also studied. RESULTS: The total compounding process, including the actions before compounding and the release-time and cleaning time, lasted 6:44 min with robotic compounding and was faster than manual compounding with and without software support (6:48 and 9:48 min, respectively). The production capacity of one full-time equivalent (FTE) on 1 day (P1FTE1day) was 15 preparations per FTE per day with manual compounding with and without software support, and 57 preparations per FTE per day with only robotic compounding. If manual and robotic compounding were combined, the production capacity was 30 preparations per FTE per day. In this setting, the direct labour costs per preparation were €5.21, while these costs were €13.18 with only manual compounding. CONCLUSION: Compared with manual compounding, robotic compounding was faster over the total compounding process. A combination of manual compounding and robotic compounding could lead to 100% more preparations per FTE and 2.5 times lower direct labour costs compared with manual compounding.

Limited Health Risks in Performing Drug Reconstitution and Handling Tasks in Pharmacies-Results of an Occupational Risk Assessment Study.

OBJECTIVE: Some drugs need processing before they can be administered or dispensed. We measured airborne exposure of pharmacy staff to small particles when performing these tasks. METHODS: Reconstitution of powdered drugs in vials; crushing, splitting, and counting of tablets; and opening of capsules, using different ventilation strategies, were investigated in five pharmacies after in a worst-case approach. Airborne particulate matter was determined for a range of particles sizes. RESULTS: Mean particle concentrations ranged from not detectable to 1.03 µg/m 3 (<1 µm) and 589.7 µg/m 3 (<10 µm). Dust exhaust made tasks safer. Most hazardous was pouring out tablets from a bulk supply, and least hazardous was reconstitution of a powder for injection. CONCLUSIONS: Occupational exposure during routine handling of drugs can occur, but the risks vary greatly with the nature and duration of the tasks.

The handling of biopharmaceuticals used in home-based therapy for cancer patients.

BACKGROUND: Due to their low bioavailability, biopharmaceuticals are typically administered via injection or infusion in a hospital setting. Home-based therapy could be a valuable alternative for cancer patients. However, when exposed to stressors, such as high or low temperatures, particles can form in the biopharmaceutical solution, compromising the safety and efficacy of the biopharmaceutical. AIM: This research investigated current practises with ready-to-administer biopharmaceuticals to determine if it is possible to offer cancer patients home-based therapy with monoclonal antibodies. METHODS: First, a questionnaire was conducted with the survey tool Survalyzer among Amsterdam UMC patients receiving immunoglobulins at home. Secondly, a web-based questionnaire (Survalyzer) was sent to pharmacists throughout Europe with a home-based therapy programme in place. RESULTS: The patient questionnaire (n = 52) showed that the biopharmaceutical is stored outside the recommended temperature range by 38% of the patients. Additionally, 17% of the patients do not recall getting any information on how to store their biopharmaceuticals, and 23% would like more information on the subject. Furthermore, the questionnaire amongst pharmacists (n = 21) showed that there is a lack of resources and logistical challenges when home-based therapy is applied to biopharmaceuticals used in cancer therapy. CONCLUSION: Home-based therapy with monoclonal antibodies for cancer patients is challenging to implement.

Pilot study of a European oncology regimen reference library and matching algorithm.

OBJECTIVES: As yet, there is no European data standard for naming and describing oncology regimens. To enable real-world cancer treatment data comparisons, the Oncology Data Network created a unified reference database for systemic anti-cancer regimens used in practice across Europe. Data are extracted from clinical systems and mapped to a single standard called the "Core Regimen Reference Library (CRRL)". An automated matching algorithm has been designed based on: drug combinations; administration schedule; and dosing and route of administration. Incomplete matches are flagged for expert review. The aim of this pilot study is to have an expert pharmacist panel test the algorithm's feasibility by comparing computerised and manual matching of regimens that are currently in use in different European countries. METHODS: The combined team pooled a diverse sample of 47 reference regimens used in Europe for solid and haematological cancers. These were then codified to the developed common data standard and the algorithm was used to match them to the CRRL. The expert pharmacist panel from the European Society of Oncology Pharmacy (ESOP) selected 12 regimens from the sample set, ranging from simple to complex, and performed a single-blind test of the algorithm, by systematically matching each original regimen to the CRRL. RESULTS: ESOP validated the algorithm's feasibility based on full concurrence between manual and computer matches thereby validating the algorithm rules and logic with regard to what defines the core characteristics of a regimen and how to compare similarities and differences. CONCLUSIONS: ESOP's validation of the matching algorithm and approach to curating a master library provides confidence in their utility for reliable comparison of real-world regimen usage across Europe.

European Groundshot-addressing Europe's cancer research challenges: a Lancet Oncology Commission.

Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative technological outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.

Safe handling of cytostatic drugs: recommendations from independent science.

OBJECTIVES: Due to their mechanism of action, most classical cytostatic drugs have carcinogenic, mutagenic and/or reprotoxic properties. Therefore, occupational exposure of healthcare staff to these drugs should be prevented. Our objective was to lay out European legislation on this topic and reflect on the process of revising the European CM-directive. We summarise independent European and Dutch studies, and give a concise set of basic recommendations for safe working with cytotoxic drugs in healthcare facilities. METHODS: We were directly involved in the process of revising the CM-directive: first, through an EU commissioned workshop in the Netherlands, and after that by contributing to the pan-European stakeholder symposium. For this aim, we had to gather the relevant study data from the Netherlands and from Europe. We analysed all relevant industry-independent studies and collated a set of basic recommendations. RESULTS: Independent studies show that the development of measures in recent years can lead to a safe work environment. Standardising the cleaning process leads to a significant improvement in environmental contamination in the majority of hospitals. In the Netherlands, exposure of workers was shown to be well beneath the limit value of 0.74 µg cyclophosphamide per week, therefore showing that the measures taken in recent years are adequate. CONCLUSIONS: The safety of healthcare workers is of the utmost importance. Current practice in the Netherlands show that measures taken in recent years are adequate. European legislation should be based on independent scientific research and practice. The first goal should be to bring countries with less safe working levels to a higher level instead of introducing measures that only increase healthcare budgets but not healthcare safety.

Frequency of measuring body weight in (sub)populations of patients with cancer treated with chemotherapy.

OBJECTIVES: Most cytostatics used in cancer treatment are dosed on body surface area (BSA). To administer an appropriate dose it is therefore necessary to know the patient's correct body weight. However, evidence is lacking on how often, after initiation of treatment, body weight should be measured to recalculate BSA. We aimed to assess the relevance of weight measurements during chemotherapy treatment. METHODS: Over a 2 year period we analysed BSA changes in adult patients undergoing chemotherapy treatment. The frequency of and median time to ≥10% BSA change was determined. We assumed a 10% BSA change required dose adjustment and was therefore clinically relevant. RESULTS: Using a database query, data from 2276 patients were used for descriptive statistics, life table analyses and generalised estimating equations. The frequency of ≥10% BSA change occurred in a maximum of 7.6% of the patients, depending on the tumour type. Descriptive statistics in the indications with more than 100 patients showed that BSA changes of ≥10% occurred after 84 days. The groups with the earliest BSA changes were patients with acute leukaemia, lymphoma and pancreatic cancer. CONCLUSIONS: Our observations from real-world data indicate it is safe to omit the current requirement for monthly weight measurements. We advise that during chemotherapy, measuring the body weight in patients who have acute leukaemia, lymphoma or pancreatic cancer or who are under 20 years of age, should be performed at least every 3 months. For other patients, extending this period to a 6-monthly weight measurement should be considered.

An economic evaluation of vial sharing of expensive drugs in automated compounding.

Background Manual compounding of expensive cytotoxic drugs often leads to drug wastage, due to residual product in vials not being used. Aim To determine the cost savings that can be achieved by implementing an automated compounding process with a vial sharing strategy, instead of manually compounding drugs. Method The drug wastage during automated compounding was compared with that of three simulation scenarios using manual compounding, in a general teaching hospital. All automatically compounded preparations of rituximab, pemetrexed, bevacizumab, and trastuzumab from September 2019 and up until February 2020 were included. A vial sharing strategy was implemented during the automated compounding process (scenario 1). In this scenario, all residual drugs could be reused for up to seven days. Two of the simulation scenarios for manual compounding were executed using a batch compounding strategy, for an entire working day (scenario 2), and twice a day (scenario 3). The third manual compounding simulation was executed without making use of a batch compounding strategy (scenario 4). Results There was no drug wastage during automated compounding with vial sharing (scenario 1). The cost of drug wastage for 1001 preparations, over a period of six months for rituximab, pemetrexed, bevacizumab, and trastuzumab combined, were € 34,133 for scenario 2, € 46,688 for scenario 3, and € 88,255 for scenario 4. The estimated total cost savings between 2017, when the compounding robot was commissioned, and 2021, was more than € 280,000. Conclusion Vial sharing of expensive drugs during automated compounding can prevent drug wastage, resulting in an economic and environmental advantage as opposed to manual compounding.