Large-volume Parenteral Solutions Research Articles

Workforce planning and safe workload in sterile compounding hospital pharmacy services.

DisclaimerIn an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time.PurposeA prospective observational study was conducted to assess sterile compounding time and workforce requirements in a hospital pharmacy, resulting in development of staff benchmarking metrics.MethodsThe study was conducted in the IV room of a quaternary hospital over a total of 7 weeks. Compounding was directly observed and timing data collected for each compounded sterile preparation (CSP). The primary objective was to assess CSP workload, compounding time requirements, and workforce requirements to enable development of a data-driven staffing benchmark.ResultsA total of 320 sterile product preparations were directly observed during the study. Overall, the average time to compound 1 CSP (including small- and large-volume parenteral solutions, chemotherapy CSPs, batched CSPs, and syringes) was 3.25 minutes. Chemotherapy CSPs had the longest average preparation time (17.74 minutes); batched CSPs had the shortest preparation time, at 1.90 minutes per unit. A safe workload analysis indicated that in an 8-hour shift, 1 pharmacy technician can safely prepare 253 batched CSPs; 148 preparations of SVP solutions, LVP solutions, and syringes combined; 31 parenteral nutrition solutions prepared using an automated device; or 29 chemotherapy preparations. Through extrapolation of these results, it was calculated that a hospital with a capacity of 100 beds would require 1.4 pharmacist full-time equivalents (FTEs) and 2.7 technician FTEs to meet its sterile compounding needs, with proportionate increases in those estimates for a 300-bed hospital.ConclusionOrganizations wishing to use external benchmarking information need to understand data characterization, pharmacy services offered, automation, workflows, and workload before utilizing that information for workforce planning.

Excessive Aluminum Accumulation in the Bones of Patients on Long‐Term Parenteral Nutrition

Aluminum (Al) contamination of parenteral nutrition (PN) solutions remains a concern for long-term PN patients. Al accumulates particularly in bone. Excessive exposure to Al may result in increased Al body burden and impaired bone formation and mineralization, leading to bone disease. Although the U.S. Food and Drug Administration (FDA) has limited Al contamination in large-volume parenteral solutions, small-volume parenterals may still contribute considerable amounts of Al to PN solutions. The goal of this study is to determine whether or not long-term adult PN patients remain at risk for increased bone Al accumulation. We measured Al accumulation in autopsy bones from 7 patients who had received PN for 2-21 years and compared bone Al levels with those in living control patients undergoing hip or knee replacement. Electrothermal atomic absorption spectrometry was used for bone Al measurements. When compared with bone Al content in controls, markedly elevated Al levels (P < .0001) were found in the bones of all but 1 patient, who received PN for only 2 years before death. Even greater Al accumulation was found for PN patients who developed late renal impairment (P = .0159). We conclude that long-term adult PN patients continue to be at risk for Al toxicity.

Evaluation of official instrumental methods for the determination of particulate matter contamination in large volume parenteral solutions.

The distribution pattern of particle contamination in nine different types of LV parenteral solutions and the possibility of correlating the counts made with two official instruments (Coulter Counter and HIAC) were studied. Two hundred containers of LV parenteral solutions (corresponding to 40 batches) produced in Italy, were sampled. Each bottle was submitted to HIAC and Coulter Counter countings, for particle sizes ranging between 2 and 25 micron. For about 50% of the products, the two straight lines that represent the distribution of particle contamination obtained with the two methods did not cross-over within the studied size range, the Coulter Counter counts always proving higher than the HIAC ones. In the other cases, the cross-over point of the two lines occurred at varying size levels. Statistical analysis of the results pointed to a relationship between the contamination values obtained with the two counting methods for sizes ranging between 2 and 5 micron, but there was no correlation for sizes equal to, or higher than, 10 micron. From the maximum contamination levels established by the BP and the FU IX for the HIAC method, the corresponding values were calculated for the Coulter Counter method. Similarly the values were calculated the HIAC method based on the maximum values set for the Coulter Counter.

Specification of limits for particulate contamination in pharmaceutical dosage forms.

Limits for the control of particulate contamination in large volume parenteral solutions and metered-dose aerosols are discussed. It is suggested that is would be desirable to use limits based on measurement of both mean and the standard deviation of the particle counts obtained for each of the containers tested. Use of the statistic ST, assuming a target value of zero, is considered to be an appropriate means of measuring the container to container variation in particulate contamination.

Preliminary Study on the Potential Utility of GFP as a Biosensor for Drug Stability in Parenteral Solutions

In the health care setting, drugs added to large volume parenteral solutions (LVPS) are routinely administered to improve therapeutic effects and provide a faster clinical response. The development of analytical techniques that permit the detection of incompatibilities between drugs and parenteral solutions is necessary to guarantee their correct association with minimum adverse effects. Green fluorescent protein (GFP) has been used as a biological indicator of sterilization and disinfection processes because it exhibits a high thermal stability and is easily detected using UV light and spectrofluorometry. The response of GFP structure and/or protonation state to physicochemical changes in the solution favors its potential use as a biosensor for drug stability in parenteral solutions. The stability of the diuretic drugs furosemide and aminophylline, individually or combined, added to parenteral solutions of 20% mannitol and 0.9% NaCl was monitored by absorbance and RP-HPLC immediately and after 20 h of storage at room temperature, with and without 1 h exposure to a strong oxidant, H2O2. Changes in GFP fluorescence intensity were evaluated under the same conditions for purified GFP added to aliquots of the drug/LVPS solutions. Results show that GFP fluorescence intensity was proportional to the loss in drug stability over time and thus may potentially be added to a lot sample of a drug/parenteral solution as an immediate on-site test for defective product.

Study on the thermal stability of green fluorescent protein (GFP) in glucose parenteral formulations

Large volume parenteral solutions (LVPS) that are widely used in the healthcare system must be processed by moist-heat treatment to an assured sterility level in which the efficacy is measured by a bioindicator (BI) that provides fast, accurate and reliable results. This study evaluated the thermal stability of green fluorescent protein (GFP) into glucose-based LVPS (1.5–50%) solutions to determine its utility as a BI for thermal processes. GFP, expressed by Escherichia coli, isolated/purified by TPP/HIC, was diluted in buffered (each 10 mM: Tris–EDTA, pH 8; phosphate, pH 6 and 7; acetate, pH 5) and in water for injection (WFI; pH 6.70 ± 0.40) glucose solutions (1.5–50%) and exposed to constant temperatures from 80 °C to 95 °C. The thermal stability was expressed in decimal reduction time ( D-value, time required to reduce 90% of the GFP fluorescence intensity). At 95 °C, the D-values for GFP in 1.5–50% glucose were: (i) 1.63 ± 0.23 min (pH 5); (ii) 2.64 ± 0.26 min (WFI); (iii) 2.50 ± 0.18 min (pH 6); (iv) 3.24 ± 0.28 min (pH 7); (v) 2.89 ± 0.44 min (pH 8). By the convenient measure of fluorescence intensity and its thermal stability, GFP has the potential as a BI to assay the efficacy of moist-heat processing of LVPS at temperatures ≤100 °C.

Multiparametric Flow System for the Automated Determination of Sodium, Potassium, Calcium, and Magnesium in Large-Volume Parenteral Solutions and Concentrated Hemodialysis Solutions

A multiparametric flow system based on multicommutation and binary sampling has been designed for the automated determination of sodium, potassium, calcium, and magnesium in large-volume parenteral solutions and hemodialysis concentrated solutions. The goal was to obtain a computer-controlled system capable of determining the four metals without extensive modifications. The system involved the use of five solenoid valves under software control, allowing the establishment of the appropriate flow conditions for each analyte, that is, sample size, dilution, reagent addition, and so forth. Detection was carried out by either flame atomic emission spectrometry (sodium, potassium) or flame atomic absorption spectrometry (calcium, magnesium). The influence of several operating parameters was studied. Validation was carried out by analyzing artificial samples. Figures of merit obtained include linearity, accuracy, precision, and sampling frequency. Linearity was satisfactory: sodium, (– g/L), potassium, (50–150 mg/L), calcium, (30–120 mg/L), and magnesium, (20–40 mg/L). Precision (, %, ) was better than %, and accuracy (evaluated through recovery assays) was in the range of %–% (sodium), –% (potassium), %–% (calcium), and %–% (magnesium). Sampling frequencies () were 70 (sodium), 75 (potassium), 70 (calcium), and 58 (magnesium). According to the results obtained, the use of an automated multiparametric system based on multicommutation offers several advantages for the quality control of large-volume parenteral solutions and hemodialysis concentrated solutions.

The effect of composition of parenteral solution on the thermal resistance of Bacillus stearothermophilus and Bacillus subtilis spores.

Large-volume parenteral solutions were submitted to heat treatments after being inoculated with Bacillus stearothermophilus ATCC 7953 (Tr = 121 degrees C) and Bacillus subtilis ATCC 9372 (Tr = 104.5 degrees C) spores. The average decimal reduction time for B. stearothermophilus ranged from a D121 degrees C value of 1.31 to 3.14 min, in glucophysiologic and Ringer's solutions respectively. For B. subtilis, D104.5 degrees C value increased from 0.69 to 1.37 min, in Ringer's (pH=5.91) and 50% glucose (pH 3.05) solutions respectively. The z value ranged from 7.95 degrees C (20% mannitol solution) to 13.14 degrees C (50% glucose solution), corresponding to an activation energy (Ea) of 81.48 and 49.30 kcal/mol, respectively.

Development of a Parenteral Formulation of an Investigational Anticancer Drug, 3-Aminopyridine-2-carboxaldehyde Thiosemicarbazone

ABSTRACTThe objective of this study was to develop an injectable formulation of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) suitable for intravenous infusion. The solubility of 3-AP in different solvents and pH conditions was determined. The developed formulation underwent stability assessment and compatibility testing with large volume parenteral (LVP) solutions. The aqueous solubility of 3-AP was found to be 0.1 mg/ml and could only be increased marginally by altering the pH or adding surfactants. To achieve the desired concentration (>4 mg/ml), 3-AP was formulated at 5–10 mg/ml in a nonaqueous system consisting of 70% polyethylene glycol 300 and 30% ethanol. However, 3-AP readily precipitated from this formulation when diluted with LVP solutions. Dilution-induced drug precipitation was eliminated by acidifying the solution with citric acid. Ascorbic acid, 0.1%, was found to minimize oxidative degradation of 3-AP. Accelerated stability data indicated that the formulation is compatible with the packaging components and is chemically stable at 2–8°C, and retained >90% of 3-AP at 40°C for 3 months. Simulated infusion studies showed that the citric acid formulation was compatible with LVP solutions. However, because of the potential of extraction of plasticizers from polyvinyl chloride (PVC) plastic containers, it is recommended that the formulation be diluted in glass containers prior to administration.

Aluminium, cadmium and lead in large volume parenterals: contamination levels and sources

Aluminium, cadmium and lead levels in large volume parenteral solutions (LVPs) produced in Italy were investigated; 135 samples of parenteral solutions of sterile water, 0.9% NaCl and 5%–10%–33% dextrose in varying volumes, taken from 25 batches and supplied by 3 different manufacturers, were examined. In order to highlight the factors contributing most significantly to the final contamination of LVPs by Al, Cd and Pb, raw material samples and extracts of rubber stoppers were analyzed. The leaching of Al and Cd from glass bottles was also evaluated before and after sterilization. Aluminium levels were in many cases found to be too high, cadmium was detected in appreciable concentrations while lead levels were quite low in all types of solutions examined. Leaching from rubber stoppers was always negligible; the contribution from glass bottles was also very low except for considerable leaching of Al from Type II glass in NaCl solutions. As far as aluminium is concerned, it would be advisable to establish official limits at least for those solutions used in total parenteral nutrition (TPN).

The Interaction of Dobutamine Hydrochloride and Heparin Sodium in Parenteral Fluids

AbstractDobutamine hydrochloride and heparin sodium have been reported to interact in large volume parenteral solutions. The potential for such interactions has been investigated in water, D5W and NS by microcalorimetry. A strong reaction is observed in water and D5W. No reaction is observed in NS and no incompatibility can be expected when the drugs are mixed in NS.

Simultaneous determination of chlorine and sodium in large volume parenteral solutions by instrumental neutron activation analysis

Large volume parenteral solutions are pharmaceutical products containing as active compounds aminoacids, carbohydrates, calcium, chlorine, magnesium, potassium and sodium. A very simple fast and accurate method has been developed for the simultaneous determination of chlorine and sodium in large volume parenteral solutions by instrumental neutron activation analysis. Two reference materials were used for the precision and accuracy tests. The applicability of the method was checked by the assay of chlorine and sodium in large volume parenteral solutions from the Greek market. The results from all the analyzed samples showed that the proposed method with the advantages of simplicity (no chemical procedure is needed), rapidity (two-element analysis in one sample with one set of runs in 20 minutes) high precision and high accuracy is suitable for routine determinations of chlorine and sodium in large volume parenteral solutions.

Stability and Visual Compatibility of Bretylium Tosylate with Selected Large-Volume Parenterals and Additives

The stability of bretylium tosylate when mixed with large-volume parenteral (LVP) solutions was assessed over a four-week period, and the compatibility of bretylium tosylate when mixed with eight frequently used drugs was evaluated. Bretylium tosylate admixtures of approximately 1 mg/ml were prepared in both polyvinyl chloride (PVC) bags and glass bottles of 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection. The admixtures were examined visually and stored for four weeks at 25 +/- 0.5 degree C under fluorescent light. The concentrations of bretylium tosylate were determined spectrophotometrically at times 0.25, 0.5, 1, 3, 8, 24, and 48 hours and twice weekly thereafter for four weeks. Spectrophotometric assays were confirmed with high-pressure liquid chromatography. Admixtures of bretylium tosylate were prepared with aminophylline, calcium gluconate, digoxin, regular insulin, lidocaine hydrochloride, phenytoin sodium, procainamide hydrochloride, and quinidine gluconate in 5% dextrose injection and 0.9% sodium chloride injection. The admixtures were examined visually for 48 hours. The concentration of bretylium tosylate did not change appreciably during the four-week study period. There were no signs of haze, precipitation, color change, or evolution of gas. There were no apparent differences in stability when comparing the glass with the PVC containers. Bretylium tosylate was also found to be compatible with all the additives tested except phenytoin sodium; a precipitate formed immediately when the latter drug was added to the bretylium tosylate solution. Bretylium tosylate was stable for four weeks in the LVP solutions studied in both glass and PVC containers. The admixtures of bretylium sodium with the other drugs were all visually compatible except those containing phenytoin sodium.

Piperacillin sodium: antibacterial spectrum, pharmacokinetics, clinical efficacy, and adverse reactions.

Piperacillin sodium is a beta lactam antibiotic with a broad range of antibacterial activity that includes gram-negative bacilli, gram-positive cocci (except penicillinase-producing S. aureus) and anaerobic pathogens such as Clostridium difficile, and Bacteroides fragilis. Piperacillin inhibits many of the members of the Enterobacteriaceae, including Klebsiella sp and Pseudomonas, at lower concentrations than required for carbenicillin and ticarcillin. Piperacillin sodium is administered by intramuscular and intravenous injection and is widely distributed throughout body fluids and tissues. Like other newer penicillins, piperacillin is excreted by both renal and biliary mechanisms. The primary route of elimination is by glomerular filtration, which results in high urinary concentrations of the unchanged compound. Piperacillin has been approved for patients with serious infection caused by susceptible strains of specific organisms in intra-abdominal, urinary tract, gynecologic, lower respiratory tract, skin and skin structure, bone and joint, and gonococcal infections and septicemia. As with other penicillins, piperacillin has a low frequency of toxicity. The usual dose of piperacillin in adults with serious infections with normal renal function is 3-4 g every 4-6 hr as a 20-30 min infusion, with a maximum dose of 24 g per day. It is stable in most large volume parenteral solutions. Less serious infectins (requiring smaller dosages) may be treated by intramuscular injection; however, no more than 2 g should be given at any one injection site. Overall, piperacillin has a greater degree of activity than other penicillins. Evidence from prospective studies indicates that piperacillin is a highly effective agent for the treatment of patients with infections caused by susceptible organisms.

Stability of dobutamine hydrochloride in selected large-volume parenterals

Stability of dobutamine hydrochloride when mixed with large-volume parenteral solutions was assessed. Dobutamine hydrochloride was added to large-volume solutions of 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringer's injection, and 5% dextrose and 0.45% sodium chloride injection, in both glass and polyvinyl chloride containers; the initial concentration was 1 mg/ml. After 0.25, 1, 3, 8, 24, and 48 hours, the concentration of dobutamine hydrochloride was determined by high-pressure liquid chromatography assay, and each solution was visually examined for evidence of haze, precipitation, color change, or evolution of gas. Concentration of dobutamine hydrochloride in the samples did not exhibit any appreciable change over the 48-hour period, and no HPLC peaks indicating degradation products were noted. Color changes were observed in some of the solutions, but no other visual changes occurred. There were no apparent differences in stability between the admixtures packaged in glass and those in polyvinyl chloride bags. At the concentration studied, dobutamine hydrochloride is stable in the admixtures tested for a minimum of 48 hours.

Compatibility of propranolol hydrochloride injection with intravenous infusion fluids in plastic containers

The visual and chemical compatibility of propranolol hydrochloride injection admixtures in large-volume parenteral solutions (LVPs) packaged in plastic containers was studied. Propranolol hydrochloride injection was mixed with five different LVPs manufactured by three suppliers and packaged in plastic containers. Two concentrations (0.5 and 20 micrograms/ml) were tested. Samples were obtained via administration sets with 0.2-micron final filters. Visual appearance, pH, and propranolol hydrochloride concentration (HPLC method) of the admixtures were evaluated at 0, 4, 8, and 24 hours after preparation at room temperature and with ambient lighting. No change in visual appearance was observed. The pH of the admixtures ranged from 3.9 to 6.4, depending on the composition of the intravenous infusion fluid and propranolol hydrochloride concentration. There was no significant loss in potency during the test period. Additionally, there was no adsorption of propranolol hydrochloride onto the surface of polyvinyl chloride bags or polyolefin containers, or onto the filters. Propranolol hydrochloride can be mixed with common intravenous infusion fluids for 24 hours without compatibility problems when administered under normal conditions.

Stability of an extemporaneous formulation of injectable cholecalciferol

THe stability of an extemporaneous formulation of injectable cholecalciferol 40,000 IU/ml was assessed. A preparation of cholecalciferol 40,000 IU/ml in a solution of propylene glycol with ethanol 10% was prepared. The solution was stored at 4 degrees C in 2-ml sterile glass vials protected from light. Cholecalciferol content was measured initially and periodically for 199 days using a high-pressure liquid chromatography technique. A 7.3% loss of cholecalciferol potency from baseline was observed over the 199-day period. In contrast to currently available preparations, this extemporaneous formulation of injectable cholecalciferol potentially offers a versatile dosage form for therapeutic or prophylactic therapy of vitamin D deficiency. It was easily prepared and retained more than 90% potency of cholecalciferol for at least six months. The addition of this formulation to large-volume parenteral or parenteral nutrition solutions is not recommended, however, because compatibility data are not available. In addition, the biological activity of the preparation has not been assessed.

Cimetidine hydrochloride compatibility. II: room temperature stability in intravenous infusion fluids

The visual compatibility and chemical stability of cimetidine hydrochloride diluted in 19 intravenous infusion fluids were investigated. Cimetidine hydrochloride injection was added aseptically to large-volume parenteral solutions at concentrations of 120 and 500 mg/100 ml. Cimetidine concentration was analyzed by high-pressure liquid chromatography initially and after storage periods of 24, 48, 72, and 168 hours at room temperature. Cimetidine hydrochloride in each of the dilutions remained visually compatible for one week, exhibiting no changes in color, clarity, or odor; pH values remained constant. The addition of cimetidine to Normosol-R pH 7.4 resulted in solutions having pH values of 6.3 and 6.0 at 120 and 500 mg/100 ml, respectively. Cimetidine remained chemically stable in each of the intravenous fluids studied. Cimetidine hydrochloride is visually and chemically stable for at least one week when added to the intravenous fluids studied at concentrations of 120 and 500 mg/100 ml and stored at ambient room temperature.

Solubility characteristics of diazepam in aqueous admixture solutions: Theory and practice

The solubility of diazepam was investigated to determine compatibility limits for diluting diazepam injection in four large-volume parenteral (LVP) solutions. A solution of diazepam powder (15 mg/ml) in absolute alcohol and of the commercially available diazepam injection (5 mg/ml) were used in the study. Either 1.0 ml of the alcoholic solution or 3.0 ml of the commercial injection were added to 50 ml of the LVPs studied-sterile water for injection (WFI), 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection. Diazepam was assayed sprectrophotometrically at 367 nm. The solubility of diazepam in WFI was 0.041 mg/ml after equilibration for 24 hours at 25 degrees C. The solubility of diazepam in the LVPs ranged from 0.04 to 0.05 mg/ml at 25 degrees C. The effects of solution dielectric constants on nonelectrolyte solubility and the minimal fraction of protonated (ionized) diazepam present in typical admixtures are deduced to be negligible determinants of diazepam solubility in i.v. solutions at pH greater than or equal to 5.4 prepared from greater than or equal to 1:10 volume dilutions of diazepam injection. The aqueous solubility data for diazepam corroborate other reported values and are tantamount to recommending against less than a 1:100 volume dilution of diazepam injection when compounding i.v. admixtures.

Size Distribution Characteristics of Particulates from Glass and Plastic Lvp's

AbstractAn automated microscopic system was used to detect particulates from four different large-volume parenteral solutions in glass and plastic containers. Solutions from glass containers were found to contain a significantly greater number of particles; however, the mean diameter of particles from plastic containers was greater. Characteristics of the size distribution of particles from glass and plastic containers were also different. An overall (particle size 5-50μ) cleanliness factor was calculated. Cleanliness factors for glass containers were larger by 55.5% to 264.1% than those for plastic.