Volume 5, Issue 1

Objectives Several societies have published guidelines to limit the occupational exposure of workers. Several of these guidelines recommend periodic (once or twice a year) environmental monitoring of specific sites where antineoplastic drugs are prepared and administered. However, most of the guidelines provide no guidance concerning which antineoplastic drugs should be monitored, the preferred sampling sites, appropriate test methods or limits of detection. The aim of this study was to characterize providers that quantify antineoplastic drug measured on surfaces. Methods This was a cross-sectional descriptive study. To identify service providers offering environmental monitoring tests, we searched the PubMed database and used the Google search engine. We contacted each service provider by email between June 3rd and June 15th, 2020. We specified the objective of our study and described the information needed and the variables of interest with standardized questions. Additional questions were sent by emails or via teleconferences. No statistical analyses were performed. Results We identified six providers offering services to Canadian hospitals, either based in Canada or in the United States. Five of these providers were private companies and one was a public organization. Each service provider was able to measure trace contamination of 3–17 antineoplastic drugs. Five of the providers quantified drugs using ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MSMS), which allowed for lower LODs. The sixth provider offered quantification by immunoassay, which has higher LODs, but offers near real-time results; the surface area to be sampled with this method was also smaller than with UPLC-MSMS. The services offered varied among the service providers. The information about LODs supplied by each provider was often insufficient and the units were not standardized. A cost per drug quantified could not be obtained, because of variability in the scenarios involved (e.g. drug selection to be quantified, number of samples, nondisclosure of ancillary costs). Four of the six service providers were unable to report LOQ values. Conclusions Few data are available from Canadian service providers concerning the characteristics of wipe sampling methods for antineoplastics. This study identified six north-American providers. Their characteristics were very heterogeneous. Criteria to consider when choosing a provider include the validation of their analytical method, a low limit of detection, the choice of drugs to be quantified and the sites to be sampled, obtaining details about the method and understanding its limits, and price. This should be part of a structured multidisciplinary approach in each center.

Objectives Concomitant administration of two incompatible drugs in the same infusion line can lead to a precipitation which could have clinical consequences for patients. The objective of this work was to study the physical compatibility of injectable posaconazole with other drugs commonly used in an adult hematology care unit. Methods The most widely used injectable drugs co-administered with posaconazole have been listed with a total of 19 drugs. For some drugs, different conditions have been tested. A total of 24 solutions were produced (not including the posaconazole). In the absence of compatibility data, the physical compatibility was tested for each pair including one of the 24 solutions and posaconazole. For each pair studied, three different ratios were prepared (9:1, 1:1, 1:9). Visual evaluations were performed after the mixture, after one and 4 h. Results Seventy two mixtures have been realised: 55.56% of pairs (n=40/72) resulted in a precipitation, against 44.44% (n=32/72) with no visual modification after a 4-h storage. On the 19 drugs tested, only filgrastim and tacrolimus showed no visual change with posaconazole during a 4-h storage. Conclusions In majority of cases, posaconazole was not compatible with drugs having alkaline pH, commonly used in a hematology unit.

Objectives In patients suffering from chronic liver disease, the hepatic metabolism of drugs is perturbed and the metabolic capacity is difficult to assess. Midazolam could be used as a phenotypical probe to predict the metabolic capacity of CYP3A to adjust dosages of drug substrates of this cytochrome. In this context, a prospective clinical trial is going to be conducted in our institution and a hospital preparation of midazolam capsules suitable for the clinical trial was developed. The objective of the present work was to assess the physicochemical stability of the formulation over 12 months to set shelf life. Methods Three batches of 1 mg capsules were prepared using midazolam hydrochloride and microcrystalline cellulose as a diluent. The capsules were stored at ambient temperature and protected from light. To measure the evolution of the capsules content, a stability-indicating high-performance liquid chromatography (HPLC) method was developed with ultraviolet (UV) detection at 254 nm. Data were confirmed using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method. Results After one year, midazolam hydrochloride content remained higher than 95% of the initial concentration in capsules. Conclusions The results show that 1 mg midazolam capsules are stable for 12 months at room temperature and under dark conditions.

Objectives The oral route is the most common route of administration of drugs because of the low cost of therapy, ease of administration, patient compliance, and flexibility in formulation. Taking oral medicine is extremely odious to some patients, such as pediatric and geriatric patients. Paracetamol is one of the most used antipyretic and analgesic drugs, used in the management of fever and headache. Difficulty in swallowing (dysphagia) is common among pediatric and geriatric patients. Accordingly, there is a need for a solid form of medicine that is in a form easy to take and swallow, such as lollipops. The main objective of the present research study is to provide a solid form of medicine that is in a form that makes it pleasant to take and swallow by pediatric, geriatric, and bedridden patients, and avoid the dangers of being swallowed as do the other solid forms in those patients. However, lollipop is designed to improve patient compliance, acceptability, transportation, etc. Methods In the present research study, an attempt has been made to prepare sugar-based paracetamol medicated lollipops for pediatrics, geriatrics, and bedridden patients to overcome the administration problem. The paracetamol medicated lollipops were prepared using sucrose and corn syrup. All the formulations prepared were subjected to various physicochemical parameters like hardness, friability, weight variation, drug content, etc. Results The hardness of these lollipops ranges between 8 and 11 kg/cm 3 with good physical characteristics like taste and color, they have good stability and moisture content below 1% and no variation in the IR spectrum. Conclusions Conventional dosage forms have some limitations that make it hard to use in pediatric and geriatric patients such as dysphagia, while medicated lollipops are found to be favorable by them and also effective in delivering the drug with advantages like bypass of the first-pass metabolism and increasing drug contact time in the mouth which increases its bioavailability. Paracetamol medicated lollipops can provide an attractive alternative formulation in the treatment of fever and pain in pediatric and geriatric patients because they are easily swallowed.

Background Stability of low amoxicillin oral dosage form (5 mg) used in reintroduction drug test was not fully documented. Furthermore, the impact of (1) salt moiety of amoxicillin and (2) amoxicillin – excipient interactions upon the antibiotic formulation stability during the storage was not characterized so that the estimation of the pharmaceutical expiration date from shelf-life was uncertain. Thus, the main goal of this study was to estimate the shelf-life of two formulations of amoxicillin, using a semi-predictive methodology. Methods Amoxicillin sodium (AS) and amoxicillin trihydrate (ATH), corresponding to 5-mg amoxicillin, were compounded with microcrystalline cellulose (MCC) in oral hard capsules which were, then, submitted to four environmental conditions (25 °C / 60% or 80% relative humidity (RH); 40 °C / 75% RH; 60 °C / 5% RH) in climatic chambers for 45 and 84 days. Therefore, the characterization of amoxicillin-MCC mixture was assessed by attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR) The profiles of amoxicillin content (determined by stability indicating chromatographic method) as a function of storage time, temperature and RH were fitted to pre-defined kinetic models performed by accelerated predictive stability (APS). Results ATR-FTIR analysis of AS, ATH, MCC and bulk specimens stored in heated and humid atmosphere confirmed water sorption to cellulose described by a broad and unresolved 3600 to 3000 cm −1 band associated with (1) general intramolecular and intermolecular hydrogen bonding between water and hydroxyl groups of the cellulose, and with (2) free hydroxyl in cellulose. Moreover, a dramatic decrease of absorption at 1776 and 1687 cm −1 respectively characteristic of the β-lactam ring ( ν C=O ) and amide group ( ν C=O ), was revealed as a consequence of AS and ATH degradation caused by moisturization of bulk. Amoxicillin degradation was established by chromatographic analysis showing faster AS degradation than ATH throughout time exposure. The combined effects of temperature – RH were successfully modeled by APS, where AS and ATH showed accelerated (auto-catalysis degradation mechanism) and linear degradation, respectively. The faster AS degradation was assumed to be linked to lower hydrogen donor to hydrogen acceptor count ratio and polar surface than ATH, increasing the probability of AS hydrolysis by water adsorption to AS-MCC solid dispersion (e.g., by reduction of protective intramolecular hydrogen bonds between AS molecules). Furthermore, the compounding which involved a drastic homogenization of solids may have affected the crystalline degree of MCC with an increase of amorphous phase more sensitive to water adsorption. Conclusions The improvement of amoxicillin compounding for oral dose forms might be rationalized by taking into account the molecular descriptors of salt moiety and excipients, improved by the choice of an appropriate process of production, characterized from infrared vibrational spectroscopy and chromatographic analysis and finally predicted from accelerated stability assays.

Objectives Drugs are developed for adults, making it difficult to find suitable treatments for children. Hospital pharmacy has developed alternatives to respond to this medical need. The objective of this study is to present a new liquid formulation of ursodeoxycholic acid (UDCA) at a concentration suitable for treatment of neonatal jaundice, and to introduce a novel high pressure liquid chromatography (HPLC) assay method. Methods Four formulations have been developed using suspension vehicles due to the low solubility of the active ingredient, and different concentrations of excipient, xanthan gum, needed to facilitate resuspension. An HPLC method coupled to a diode array detector (DAD) has been developed. This method was used to analyze chemical and microbiologic stabilities, as well as physicochemical properties and palatability. Results After formulation was chosen, our new HPLC method assay was developed and validated for the quantification of chemical and microbiological stabilities of our product. Both parameters were stable over three months. Palatability has been improved thanks to the addition of universal suspension adjuvants. Odor, appearance and taste were judged pleasant despite a bitter aftertaste, with a persistence of the UDCA resuspension after one month. Conclusions Three months after informing neonatal department about the availability of the drug, patients and caregivers are satisfied, and production campaigns are routinely planned.

Introduction To reduce costs of gallium-68 activity in nuclear medicine, a subcontracting activity has been settled for [ 68 Ga]Ga-edotreotide preparations. Cold kits are radiolabeled in our radiopharmacy and shipped out to nearby hospitals. According to the Summary of Product Characteristics (SmPC), preparations must be stored below 25 °C until expiration (4 h). Objective The aim of this study was to define the impact of high temperature on preparation quality during shipping. Materials & methods After radiolabeling, vials were placed in “type A” package until their expiry date. Four kits were stored in “Type A” container exposed to an outside temperature of 50 °C to represent extreme temperature conditions and one kit was kept at room temperature and used as a control. For each preparation, pH, organoleptic properties and radiochemical purity (RCP) were evaluated. RCP was measured using two radio thin layer chromatography, to evaluate the rates of gallium-68 colloids and free gallium-68. Samples were withdrawn at the end of preparation (t 0 ), at t 0  + 1 h or at t 0  + 2 h and at t 0  + 4 h. Results RCPs and pH of the radiopharmaceutical were all conform from t0 to t 0  + 4 h. Four hours storage in “type A” package at 50 °C does not show any impact on physical and chemical quality of the preparation. Thanks to it expanded polyethylene foam which absorbs impacts; “Type A” package might acts as thermal barrier and enables the temperature regulation of shipped vials. Conclusion A monitored expedition in temperature-controlled vehicle does not seem necessary in those conditions.

In the context of batch production of cytotoxic drugs in hospital pharmacies with the need of sterility testing, the objective was to validate the use of Rapid Microbiological Method (RMM), and to develop adequate neutralization method in case of inhibition of bacterial growth. The potential microbiological growth inhibitory effect of three anticancer drugs (5 fluorouracil, irinotecan and oxaliplatin) selected for batch production was assessed on BacT/ALERT® system. Among cytotoxic drugs, only 5FU exhibited inhibitory effect on microbiological growth using rapid microbiological method. To counteract this effect our purpose was to use neutralizing agents complexing the drug i. e. activated carbon or ion exchange resins. The microbiological bactericidal concentration of 5FU was very low (1.10–4 mg/mL) indicating the absolute need to neutralize the whole drug before sterility test. The complexation was validated by High Performance Liquid Chromatography control of the residual 5FU concentration in solution after the use of neutralizing agents. Only activated carbon was able to fully capture 5FU when previously diluted at 5 mg/mL. Conversely, the resins, in the condition of the study, were not able to fully capture 5FU whatever the dilution. The microbiological growth on BacT/ALERT® system after active carbon treatment was successfully confirmed with Staphylococcus aureus . Based on this validation results a method was then developed to routinely be able to perform sterility test of the batches produced and was confirmed on five microbiological species (i. e. S. aureus, Pseudomonas aeruginosa, Bacillus subtilis, Candida albicans, Aspergillus brasiliensis ). Our work gives a new insight for considering sterility testing by rapid microbiological method even for drugs exhibiting inhibitory effect on microbiological growth.

Objectives The objectives were to assess the microbiological stability and the physical enclosure integrity of the overwrapping for batch production of standard cytotoxic injectable solutions. Methods Broth culture media were used in place of cytotoxic drugs to assess the worst case in term of microbiological contamination risk. Iterative sterility tests on batches were performed for 60 days using rapid microbiological method. Validation of microbiological growth of culture media was assessed by direct inoculation of <100 CFU/mL of six microbiological strains recommended by European Pharmacopeia. Validation of the ability of growth of microorganisms in 11 cytotoxic solutions and one monoclonal antibody was assessed using eight strains. In addition, the physical integrity of the seal of the overwrapping containing cytotoxic preparations was assessed by dynamometric method and dye penetration test. Results No microbiological contamination was observed on all units of batches for 60 days of investigation. The ability to detect microbiological growth in cytotoxic solutions was validated for the eight challenge microorganisms after 1/10 dilution for cytotoxic investigated, except for 5 Fluorouracil, gemcitabine and cisplatin. In addition, physical integrity testing of the seal of overwrapping pointed out the need of specific validation of heatsealer and operator education. Conclusions Besides physico-chemical testing, microbiological stability testing combined to physical integrity testing is the additional part of the development method for batch production of sterile drugs in hospital.

Objectives Preparation of 5-FU elastomeric pumps is a time-consuming activity inducing musculoskeletal disorders (MSDs). Our unit has developed an automated filling system consisting of two peristaltic pumps (one for the diluent, one for the cytotoxic drug). The objective was to validate the accuracy of the assembly and evaluate the impact of automation on the compounding time, occurrence of MSDs and cost of preparation. Methods Accuracy was determined by calculating the total error on the volumes injected by the pumps. Measurements were made for 2 brands (AMF, Baxter), 3 different volumes; repeated 3 times at 3 times of the day. The time-saving study compared 24 measurements in manual filling and 24 in automated mode. Impact of automation on the occurrence of MSDs was evaluated by a self-assessment questionnaire. Finally, a comparison between the price of a manually prepared elastomeric pump and an automated prepared elastomeric pump was performed. Results Volumes administered by the pumps were accurate (total error < 2.5%). Preparation time was divided by 2. Occurrence of MSD decreased (8.7 manual filling vs. 23.5/28 automated filling). Overcost was moderate (14.7% for AMF; 10.3% for Baxter). Conclusions Using peristaltic pumps, 5FU preparation was optimized for moderate additional cost.

Background Hazardous drugs pose risks to health care workers. To reduce the risk of occupational exposure for all workers, several protective and monitoring measures have been recommended and implemented over the past two decades. This study was undertaken to describe traces contamination with ten antineoplastic drugs in the oncology care unit of two university hospitals. Methods In this descriptive interrupted time series study, data was collected in two hospitals (a pediatric hospital and an adult hospital) in two consecutive years (12 December 2017 and 27 March 2018, defined as Period 1; 17 April 2019 and 12 June 2019, defined as Period 2). In both Period 1 and Period 2, 36 sites were sampled in each inpatient care unit to explore the contamination of surfaces with hazardous drugs. Results A total of 144 samples from the oncology care unit of the two hospitals were obtained for measurement. Overall, 40 % (58/144) of the sampling sites were positive for at least one hazardous drug. In the pediatric centre, 50 % (18/36) and 36 % (13/36) of the sites sampled in Period 1 and Period 2, respectively, were positive for at least one hazardous drug, whereas in the adult hospital, the percentage of sites that were positive for at least one hazardous drug was 19 % (7/36) in Period 1 and 56 % (20/36) in Period 2. Conclusion The surfaces of inpatient care units sampled in this study were contaminated with antineoplastic drugs, and contamination was present throughout the care units (including structures, furniture, medical equipment, and office equipment). Hospitals’ environmental surveillance programs should encompass inpatient care units.

In the context of securing medication management systems (MMS) in healthcare habilities, implementation of an electronic MMS is a priority area of work. The quality requirements for the production of radiopharmaceuticals have increased significantly in the field of radiopharmacy. The deployment of Information Technology (IT) tools is essential to secure the radiopharmaceutical medication use process. The aim of this work is to propose the first consensual tool to validate radiopharmacy software approved by a panel of experts. A literature review was conduced related to the validation of hospital pharmacy software. The Delphi method was chosen for achieving a consensus in this study. Surveys were sent by mail to selected experts involved in the MMS. Twenty-seven replies were recorded (77%) to the first round, and 17 responses were recorded to the second survey. The final tool is a grid with 44 items. We proposed the first consensual tool to validate radiopharmacy software. This tool could be implemented in all French radiopharmacy to improve quality.

Objectives Infliximab diluted solutions have been shown to be physicochemically stable for long periods, however the adsorption of infliximab during infusions has not been readily investigated. This study aimed to evaluate potential adsorption phenomena of infliximab during administration through Polyvinylchloride (PVC) and Polyurethane (PU) infusion sets. Methods Infliximab (INFLECTRA®) solutions at 0.4 mg/mL and 2 mg/mL were submitted to static (at T0, 24 and 96 h) and dynamic contact (flow rate of 2 mL/min during 2 h with analysis times at T0, 5 min, 30 min, 60 min and 120 min) with three different infusion sets. Two contained PVC plasticized with tris(2-ethylhexyl) trimellitate (TOTM) tubings and one set was in PU tubing. Infliximab was quantified at each analytical time by protein total quantification using UV-spectroscopy according to European Pharmacopeia Monography (2.5.33) and size exclusion chromatography (SEC) which allowed a specific quantification of the monomeric form and was able to highlight potential modification such as aggregation or oligomer formation. Results For all analysis times and conditions, infliximab concentrations remained unchanged with a maximum variation of 2.81 and 4.63% from the initial concentrations assessed by SEC and UV spectroscopy and the percentage of monomeric form remained unaltered. Conclusions Our study showed that there was no significant loss of infliximab. According to these results each of the three infusion sets could be used for the administration of infliximab solutions without causing any loss of active substance.

Alsace, in particular Haut-Rhin, is one of the main clusters of COVID-19 in France. There has been a shortage of essential supplies in the area, especially alcohol-based hand sanitizer. In this context, and in accordance with the decree dated March 6, 2020, our hospital management team asked us to start local production of alcohol-based handrub. This was a real challenge: In one week, we had to implement the production of handrub to meet the needs of a 1,400-bed hospital. The production had to comply with the French preparation guidelines and take place on specific premises, with qualified and calibrated equipment, by qualified staff, under the supervision of a pharmacist. The other big challenge we faced was the supply of pharmaceutical raw and packaging materials. During this particular critical period, all suppliers were out of stock. Here, we describe the organizational set-up and the decisions made, e. g., to use technical-grade ethanol before the publication of the decrees dated March 13 and March 23, 2020.

All dosage forms prepared in hospital pharmacies should be labelled with an appropriate shelf-life. This shelf-life should be validated taking chemical, physical and microbiological data into consideration. This guidance focuses on parenteral aseptically prepared products, as they are high-risk preparations. The risk is exacerbated by a requirement for longer shelf lives for reasons of economy and efficiency. The scope of this guidance includes individual patient preparations, preparations prepared in series (same type of preparation being repeatedly prepared) and batch preparations prepared from the same initial bulk admixture.