How are we handling protein drugs in hospitals? A human factors and systems engineering approach to compare two hospitals and suggest a best practice.

Biopharmaceuticals are complex biological molecules that require careful storage and handling to ensure medication integrity. In this study, a work system analysis of real-world protein drug (PD) handling was performed with the following goals: identify main barriers and facilitators for successful adherence to accepted recommendations in PD handling, analyse differences in two organizations, and define a Best Current Practice in the real-life handling of PDs based on the results of the work system analysis. Observational study was held in two university hospitals in Spain and Sweden. Based on the Systems Engineering Initiative for Patient Safety (SEIPS) model, the tools chosen were: the PETT scan, in order to indicate the presence of barriers or facilitators for the PETT components (People, Environment, Tools, Tasks); the Tasks and tools matrices to construct a checklist to record direct observations during the real-life handling of biopharmaceuticals, and the Journey map to depict the work process. Observations were performed between March and November 2022. Each episode of direct observation included a single protein drug in some point of the supply chain and considered all the elements in the work system. Based on the results of the work system analysis and the literature review, the authors propose a list of items which could be assumed as Best Current Practice for PDs handling in hospitals. There were a total of 34 observations involving 19 PDs. Regarding People involved in the work process, there was a diversity of professionals with different previous training and knowledge, leading to an information gap. With respect to Environment, some structural and organizational differences between hospitals lead to risks related to the time exposure of PDs to room temperature and mechanical stress. Some differences also existed in the Tools and Tasks involved in the process, being especially relevant to the lack of compatibility information of PDs with new technologies, such as pneumatic tube system, robotic reconstitution, or closed-system transfer devices. Finally, 15 suggestions for best current practice are proposed. Main barriers found for compliance with accepted recommendations were related to the information gap detected in professionals involved in the handling of protein drugs, unmonitored temperature, and the lack of compatibility information of protein drugs with some new technologies. By applying a Human Factors and Systems Engineering Approach, the comparison of two European hospitals has led to a suggested list of Best Current Practices in the handling of protein drugs in a hospital.

Lipid Peroxidation and Antioxidative Capacity Are Unaltered in Transitional Breast Milk Exposed to Light from Women Giving Birth to Preterm Infants before 32 Weeks of Gestation.

Breast milk (BM) is the primary nutrition for infants and has a high content of lipids. Preterm infants receive expressed BM via tube feeding, and they are frequently treated with phototherapy. When parenteral nutrition (PN) is exposed to light and/or phototherapy, lipid peroxidation (LPO) increases. By light-protecting PN, morbidity and mortality are reduced in preterm infants through the reduction of oxidative stress. We aimed to investigate whether light-protecting breast milk could reduce LPO. Twelve mothers giving birth to a preterm infants of less than 32 weeks of gestational age were included. Transitional BM was collected and divided into three study groups; light-protected, ward light and phototherapy light. Baseline samples were collected after expression and the exposures started within one hour. Feeding syringe samples were exposed to light for 30 up to 360 min. Nasogastric tube samples were run through a tube under the same light conditions. Samples were stored in -80 °C until analyses of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) and total antioxidant capacity (TAC). There were no significant differences in MDA, 4-HNE or TAC levels observed between the different study groups. This study indicates that the light exposure of expressed transitional BM does not affect LPO and the levels of MDA, 4-HNE or TAC.

Examination of the Protein Drug Supply Chain in a Swedish University Hospital: Focus on Handling Risks and Mitigation Measures.

Protein drugs, such as monoclonal antibodies, have proved successful in treating cancer and immune system diseases. The structural complexity of these molecules requires careful handling to ensure integrity and stability of the drug. In this study, a failure mode and effects analysis was performed based on a Gemba Walk method in a Swedish University Hospital. The Gemba Walk is focused on pharmacists observing the actual supply process steps from distributor, pharmacy cleanroom to patient administration. Relevant protein drugs are chosen based on sales statistics within the hospital and the corresponding wards were observed. Further is the Double Diamond design method used to identify major risks and deliver mitigation strategies. The study identified potential stress factors such as temperature, shock by impact, shaking, vibration and light exposure. There were also risks associated with porters' and healthcare professionals' lack of awareness and access to information. These risk factors may cause loss of efficacy and quality of the protein drug, potentially leading to patient safety concerns. In this study, a simulation is also performed to list measures that theoretically should be in place to ensure the quality of the protein drug, for example validated and protocol-based compounding in cleanroom, training and validated transports.

Outdoor environmental effects on cleanrooms - A study from a Swedish hospital pharmacy compounding unit.

In this study we examined how outdoor climate affects indoor conditions of a cleanroom used for the preparation of radiopharmaceuticals in the Uppsala university hospital pharmacy, Sweden. Further objectives were to identify associated risk factors to ensure a consistent extemporaneous manufacturing process. Data for two years from the facility monitoring system (with one minute resolution for temperature, relative humidity (%RH), differential pressure) were compared with meteorological outdoor data from Uppsala (Swedish Meteorological and Hydrological Institute, 60-minute mean data for temperature, relative humidity, wind speed and air pressure). The findings of this study indicate a linear relationship between indoor and outdoor temperature for the autumn, winter and spring seasons. The typical summer outdoor diurnal pattern is also seen for indoor temperature. During the study period, the minimum outdoor temperature was -17.5 °C and the maximum 31.4 °C. This wide temperature range also entails a wide range of air humidity from 10 %RH to 100 %RH indoors. Cleanroom temperature and %RH are factors that may affect the quality of medications, especially the risk of microbiological growth in aseptic processes, stability of medications during storage but also may affect handling of for example uncoated tablets or weighing of powder, especially at high %RH for hygroscopic drugs or at low %RH due to static electricity. Further the risk of damage on electrical equipment from electrostatic discharge at low %RH is discussed with a focus on the need for humidity control of cleanrooms and/or systems for mitigation of electrostatic discharge in climates with outdoor temperature in the wintertime below freezing point.

Manipulations and age-appropriateness of oral medications in pediatric oncology patients in Sweden: Need for personalized dosage forms.

Due to the lack of age-appropriate formulations for children, healthcare professionals and caregivers frequently manipulate dosage forms to facilitate oral administration and obtain the required dose. In this study, we investigated drug manipulation and age-appropriateness of oral medications for pediatric oncology patients with the aim of identifying the therapeutic needs for personalized dosage forms. An observational study at a pediatric oncology ward, combined with analysis of the age-appropriateness of the oral medications, was performed. Nurses frequently manipulated solid dosage forms to administer them via enteral feeding tubes. Of the active pharmaceutical ingredients (APIs) assessed for age-appropriateness, 74% (29 of 39) were identified to need personalization, either because of lack of child-friendly dosage form, suitable dosage strength, or both. Most APIs, due to limited solubility, were sensitive to formulation changes, such as drug manipulation. This study demonstrates problems and therapeutic needs regarding oral dosage forms in treatment of children with cancer. Expertise in formulation design, new manufacturing technologies, and patient-centered information are needed to address age-appropriate formulations for children.

Manipulations of Oral Medications in Paediatric Neurology and Oncology Care at a Swedish University Hospital: Health Professionals' Attitudes and Sources of Information.

Oral administration of medications to children requires age-appropriate dosage forms and strengths. In this study, we: (i) assessed the extent of oral dosage form manipulations, (ii) documented how it is carried out, and (iii) examined the attitudes and sources of information regarding the handling from healthcare professionals. Prospective reviews of electronic records, ward observations, and clinician surveys were performed at a paediatric neurology ward and a paediatric oncology ward in Sweden during April to May of 2018. Approximately 15% of oral medications were manipulated for the studied patient group (median age 12.9 years in oncology, 5.8 years in neurology) with approximately 30% of the patients having an enteral feeding tube. Manipulations were performed both to obtain an appropriate dose from, for example, a fraction of the original tablet or to obtain a powder that could be used to prepare a slurry for administration through enteral feeding tubes. Risks identified were related to patient safety such as cross contamination, suboptimal absorption/pharmacokinetics and inaccurate dose. When examining the working environment of nurses, we observed safe handling of hazardous substances but the nurses occasionally experienced stress and a fear of making mistakes due to absence of information. Paediatricians experienced a lack of time to search for proper information on manipulations. As a step towards improving safety in paediatric medication, we suggest the introduction of clinical pharmacists into the team and further evaluating the possibilities of using more ready-to-administer medications with necessary product information and pharmacovigilance support.

Factors Influencing Breast Milk Fat Loss during Administration in the Neonatal Intensive Care Unit.

The objective of this study was to investigate factors influencing fat loss during tube feeding of breast milk to preterm infants. An experimental study with 81 feeding simulations was performed, with nine continuous infusions in each of six modalities: Horizontal Higher, Horizontal Matched, Horizontal Lower, Tilted Higher, Tilted Matched, and Tilted Lower, and for comparison, 27 bolus feedings: nine flushed with air, nine with water, and nine that were not flushed, done at matched height. Each simulation utilized 16 mL of breast milk given over four hours. Continuous infusions were given with a flow rate of 4 mL/h. Bolus was given as 8 mL over the course of 15-20 min every other hour. Analysis for fat, true protein, carbohydrate, total solids, and energy was performed before and after each simulation. The percent of macronutrient loss was compared between all simulations. Continuous infusion resulted in an average fat loss of 40%. Bolus feedings resulted in an average fat loss of 11% (p ≤ 0.001). Considerable fat loss is seen during continuous tube feeding. Neither height in relation to the infant nor tilting of the pump reduce fat loss. To limit fat loss, the bolus feeding method should be utilized.

The Risk of Necrotizing Enterocolitis following the Administration of Hyperosmolar Enteral Medications to Extremely Preterm Infants.

INTRODUCTION: Necrotizing enterocolitis (NEC) is a disease predominantly affecting preterm infants. The administration of hyperosmolar solutions could lead to the development of NEC. The objective of this study was to measure the osmolality of enteral medications used in clinical practice and to assess the risk of NEC following exposure to hyperosmolar medications. METHODS: A retrospective cohort study in extremely preterm infants (gestational age <28 weeks) born between 2010 and 2016 at a tertiary neonatal intensive care unit in Sweden. 465 infants were identified via the Swedish Neonatal Quality register. Data relating to enteral administrations received during a two-week period were collected from the medical records. The osmolalities of medications were measured using an osmometer. Logistic regression was used to calculate the odds ratio of developing NEC. RESULTS: A total of 253 patients met the inclusion criteria. The osmolalities of 5 commonly used medications significantly exceeded the recommended limit of 450 mOsm/kg set by the American Academy of Paediatrics (AAP). Most patients (94%) received at least one hyperosmolar medication. No significant risk of developing NEC could be found. CONCLUSION: The medications used in clinical practice can significantly exceed the limit set by the AAP. This study does not indicate an increased risk of developing NEC in extremely preterm infants following exposure to hyperosmolar medications. Further studies in larger cohorts are needed to determine the specific cut-off level of osmolality in relation to the pathogenesis of NEC.

Parenteral nutrition: a call to action for harmonization of policies to increase patient safety.

Unsafe medication practices and medication errors are leading causes of injury and avoidable harm worldwide and are highest in vulnerable groups. In 2017, the World Health Organization launched the third Medication Without Harm Global Patient Safety Challenge to try to reduce risks related to medical treatment. Parenteral nutrition (PN) is in the unique position that, although licensed products are available from manufacturers, formulas may be prepared ad hoc for first-line use that might not be subject to the same regulatory oversight. Safety issues around PN can arise through lack of harmonization in practices, misinterpretation and product unfamiliarity and can occur at any stage from prescription to preparation to administration. Government legislation and regulation vary considerably, with PN not explicitly handled in many countries. We therefore call on policy leaders in all countries to establish policies that ensure patient safety, and that these include PN along with medicines. The available evidence supports obtaining industry prepared PN as first-line therapy for reasons of safety, primarily, and of cost. If a suitable industry prepared ready-to-use PN is not available, standardized all-in-one PN admixtures should be the next line of care, with individualized PN being reserved for patients whose complex nutritional needs cannot be met using standardized admixtures.

Cost-Consequences Analysis of Increased Utilization of Triple-Chamber-Bag Parenteral Nutrition in Preterm Neonates in Seven European Countries.

The safety of parenteral nutrition (PN) remains a concern in preterm neonates, impacting clinical outcomes and health-care-resource use and costs. This cost-consequence analysis assessed national-level impacts of a 10-percentage point increase in use of industry-prepared three-chamber bags (3CBs) on clinical outcomes, healthcare resources, and hospital budgets across seven European countries. A ten-percentage-point 3CB use-increase model was developed for Belgium, France, Germany, Italy, Portugal, Spain, and the UK. The cost-consequence analysis estimated the impact on compounding error harm and bloodstream infection (BSI) rates, staff time, and annual hospital budget. Of 265,000 (52%) preterm neonates, 133,000 (52%) were estimated to require PN. Baseline compounding methods were estimated as 43% pharmacy manual, 16% pharmacy automated, 22% ward, 9% outsourced, 3% industry provided non-3CBs, and 7% 3CBs. A modeled increased 3CB use would change these values to 39%, 15%, 18%, 9%, 3%, and 17%, respectively. Modeled consequences included -11.6% for harm due to compounding errors and -2.7% for BSIs. Labor time saved would equate to 41 specialized nurses, 29 senior pharmacists, 26 pharmacy assistants, and 22 senior pediatricians working full time. Budget impact would be a €8,960,601 (3.4%) fall from €260,329,814 to €251,369,212. Even a small increase in the use of 3CBs in preterm neonates could substantially improve neonatal clinical outcomes, and provide notable resource and cost savings to hospitals.

Improved Outcome of Intestinal Failure in Preterm Infants.

OBJECTIVE: The aim of the study was to evaluate the outcome and to identify predictors for survival and enteral autonomy in neonatal intestinal failure (IF). METHODS: A retrospective observational study in a Swedish tertiary centre of children born between 1995 and 2016 with neonatal IF, defined as dependency on parenteral nutrition (PN) ≥60 days, starting with PN before the age of 44 gestational weeks. Data were extracted from medical records and predictors for survival and enteral autonomy were identified by the Cox regression model. Time to death and weaning off PN analysis were performed with Kaplan-Meier curves including log rank test. RESULTS: In total, 105 children were included. Median gestational age was 28 weeks (22-42), 50% were born extremely preterm (<28 gestational weeks). PN started at a median age of 2 days (0-147) with a median duration of 196 days (60-3091). Necrotizing enterocolitis was the dominating cause of IF (61%). Overall survival was 88%, 5 children died of sepsis and 4 of intestinal failure-associated liver disease. Survival increased from 75% during 1995 to 2008 to 96% during 2009 to 2016 (P = 0.0040). Age-adjusted small bowel length of >50% and birth 2009 to 2016 were predictors for survival. Enteral autonomy was achieved in 87%, with positive prediction by small bowel length of >25% of expected for gestational age and remaining ileocecal valve. CONCLUSIONS: Preterm neonates with IF, at high risk of IF-associated morbidity, showed a high overall survival rate. Small-bowel length and being born 2009 to 2016 were predictors for survival and remaining ICV and small-bowel length were predictors for enteral autonomy.

Improved outcome in neonatal short bowel syndrome using parenteral fish oil in combination with ω-6/9 lipid emulsions.

BACKGROUND: Newborn infants with short bowel syndrome (SBS) represent a high-risk group of developing intestinal failure-associated liver disease (IFALD), which may be fatal. However, infants have a great capacity for intestinal growth and adaptation if IFALD can be prevented or reversed. A major contributing factor to IFALD may be the soybean oil-based intravenous lipid emulsions used since the introduction of parenteral nutrition (PN) 40 years ago. METHODS: This retrospective study compares the outcome in 20 neonates with SBS treated with parenteral fish oil (Omegaven) in combination with ω-6/9 lipid emulsions (ClinOleic) with the outcome in a historical cohort of 18 patients with SBS who received a soybean oil-based intravenous lipid emulsion (Intralipid). RESULTS: Median gestational age was 26 weeks in the treatment group and 35.5 weeks in the historical group. All patients were started on PN containing Intralipid that was switched to ClinOleic/Omegaven in the treatment group at a median age of 39 gestational weeks. In the treatment group, direct bilirubin levels were reversed in all 14 survivors with cholestasis (direct bilirubin >50 umol/L). Median time to reversal was 2.9 months. Only 2 patients died of liver failure (10%). In the historical cohort, 6 patients (33%) died of liver failure, and only 2 patients showed normalization of bilirubin levels. CONCLUSIONS: Parenteral fish oil in combination with ω-6/9 lipid emulsions was associated with improved outcome in premature neonates with SBS. When used instead of traditional soybean-based emulsions, this mixed lipid emulsion may facilitate intestinal adaptation by increasing the IFALD-free period.

Prevention and reversal of intestinal failure-associated liver disease in premature infants with short bowel syndrome using intravenous fish oil in combination with omega-6/9 lipid emulsions.

Although premature infants with short bowel syndrome are at the highest risk of developing intestinal failure-associated liver disease (IFALD), they have great capacity for intestinal growth and adaptation if IFALD can be prevented. Conventional soybean oil-based intravenous lipid emulsions have been associated with IFALD. This study presents data on 5 premature neonates with short bowel syndrome treated with a combination of parenteral fish oil- and olive/soybean-based lipid emulsion for periods ranging between 7 and 17 months. Despite an enteral tolerance of less than 50% in 4 of these patients during their first year of life, direct bilirubin levels normalized while on this combination of ClinOleic (Baxter, Maurepas, France)/Omegaven (Fresenius Kabi, Bad Homburg, Germany) at a 1:1 ratio. None of our patients developed irreversible IFALD even though all of them were premature, had undergone multiple major surgical procedures, and had experienced several episodes of sepsis. Thus far, we have not seen any adverse effects of this mixed lipid emulsion in these preterm infants. All 5 patients are growing and developing well and have normal liver function.

Catanionic drug-surfactant mixtures: phase behavior and sustained release from gels.

PURPOSE: To study mixtures of SDS and the drugs diphenhydramine, tetracaine, and amitriptyline to compile phase diagrams and to investigate the use of interesting phases for sustained release from gels. METHODS: Phase diagrams were composed by studying large numbers of different compositions of negatively charged SDS and positively charged drug compounds visually, rheologically, and by cryotransmission electron microscopy. Drug release from Carbopol 940 and agar gels containing interesting phases, e.g., vesicle and branched micelle phases, was measured in vitro by the USP paddle method. RESULTS: Vesicles and elongated and branched micelles were formed on the SDS-rich side in all three systems examined. The tetracaine system differed from the other two in that it showed a vesicle area in the drug-rich side. Release of diphenhydramine from Carbopol 940 gels was slowed by at least a factor of 10 when in the form of vesicles or branched micelles. The same delay was found for both drug-rich and SDS-rich tetracaine vesicles. CONCLUSIONS: Mixtures of SDS and positively charged drugs form the same interesting phases as traditional catanionic mixtures. This may prove useful in obtaining functional controlled-release systems when using gels as drug carriers.

Evaluation of drug release from gels on pig nasal mucosa in a horizontal Ussing chamber.

In this study, controlled release gel formulations containing dihydroalprenolol (DHA), hydrocortisone (HC) or testosterone (TS) in Carbopol 934P (C934) were evaluated using pig nasal mucosa in a horizontal Ussing chamber. The controlled release gel formulations were designed by including DHA in vesicle bilayers formed with sodium dodecyl sulphate (SDS) (1.4 and 36 mM) and by partitioning TS to the core of Brij 58 (B58, 1%) micelles. For comparison, unmodified gels and solutions of the drugs and additives were examined in parallel experiments. The viability and toxicity were evaluated with electrophysiological measurements and light microscopy. The results showed that C934 did not affect the viability of the mucosa and that the rate and profile of the appearance on the receiver side was independent of whether the substances were released from an unmodified gel or an unmodified solution. Continuous electrophysiological measurements made during exposure showed that B58 (1%) and SDS (1.4 mM) inactivated the mucosa, whereas SDS (36 mM) activated it. Investigations made after a 90-min exposure to the formulations showed that all the modified gels had inactivated the mucosa and had negative effects on the morphology. For the TS-B58 (1%) and the DHA-SDS (36 mM) gels, the rate-limiting step in transport was the release from the formulation. The results confirmed that gels from C934 are suitable for nasal administration and also clearly indicated the different degrees of toxicity of the controlled release formulations evaluated in this study. The horizontal Ussing chamber method was a suitable tool for the evaluation of gels for nasal administration.

Controlled drug release from gels using lipophilic interactions of charged substances with surfactants and polymers.

The aim of this article was to study interactions between different gel forming polymers and amphiphilic drugs and surfactants with the intention of finding interactions that can be used for designing controlled release formulations. The release from gels was measured by detecting the UV-absorbance of drugs released from 6 mL gel into 250 mL release medium in a dissolution bath. The rheological behavior of gels was characterized using a controlled rate rheometer. The diffusion coefficient of alprenolol was 6.3 x 10(-6) cm(2)/s when formulated in a 1% poly(acrylic acid) gel (PAA) and 2.8 x 10(-6) cm(2)/s in a lipophilically modified gel (LM-PAA). The addition of alprenolol to 1% LM-PAA increased the elasticity, G', from 123 to 182 Pa. Increased gel strength was also observed for a number of other amphiphilic drugs. The addition of 1% Brij 58 to LM-PAA decreased the diffusion coefficient of alprenolol to 2.3 x 10(-6) cm(2)/s. It was possible to sustain the release of charged drugs with high log P by adding surfactant micelles. However, the effect was small and only useful for drugs with adequate lipophilicity. The interaction between LM-PAA and amphiphilic drugs could be seen using rheology and was used for designing controlled release gel formulations. In this way surfactants can be avoided, thus decreasing toxicity problems.