Drugs need to be formulated with scale-up in mind.

Formulation scale-up remains a major hurdle in drug development in part because preliminary formulation research efforts rarely consider the challenges of scaling up production for commercialization. This Perspective outlines considerations around scalability that can be incorporated into formulation design work in order to increase the chances of successful translation. Both technical (unit operations, excipient selection, scaling principles) and non-technical (funding, publications, and personnel) considerations are discussed, with a focus on lab-scale work by academic researchers.

Preparation Times and Estimated Costs for Vancomycin Formulations: Does the Difference Matter?

Objective Infections from methicillin-resistant Staphylococcus aureus are increasingly treated in longterm care facilities, but long-term care pharmacies face high costs in the provision of sterile vancomycin for intravenous administration. This study compares pharmaceutical costs of outsourced, compounded, and room temperature premixed vancomycin formulations in a long-term care pharmacy. Design This retrospective observational study reviewed 124 orders of vancomycin. Means for total pharmacy preparation time, pharmacist labor time, and extrapolated time over complete course of treatment were compared for three vancomycin preparations: outsourced, compounded by pharmacy, and room temperature premixed vancomycin formulations. Cost calculations were generated using ingredient costs as reported by the pharmacy and median pharmacist labor costs as published from national sources. Results Mean total preparation times and pharmacist preparation times were shortest for premixed vancomycin. Over full courses of treatment, mean pharmacy preparation time for compounded was 5 hours 3 minutes (mean of 28 treatments) and 2 hours 8 minutes for premixed (mean of 54 treatments). Data on pharmacist time in outsourced orders were not available. Total pharmacy costs were $993.94 for compounded vancomycin, $2220.34 for outsourced, and $809.36 for room temperature premixed vancomycin. Conclusion There were reduced preparation times for room temperature premixed vancomycin compared with compounded and outsourced formulations for skilled nursing facilities. As multiple drug-resistant organism infections are increasingly treated in long-term care, finding cost-effective approaches to medication provision from pharmacies is critical.

Premix versus On-Demand Workflow Models in a Veterans Affairs Hematology/Oncology Pharmacy: Impact on Estimated Waste Costs and Patient Wait Time.

Background: The balance between reducing patient wait time and mitigating waste of parenteral products has not been well described in literature. Objective: Evaluate the patient wait times and cost-effectiveness of employing a premix versus an on-demand workflow model for compounding parenteral admixtures in a hematology/oncology infusion setting. Methods: This single center, retrospective cost analysis compiled manually documented monthly waste reports and estimated drug pricing for the institution to calculate the cost of waste during both premix and on-demand compounding workflows. Time to administration was audited for one week with both models. Results: Over a period of 28.5 months following the premix model, 564 products were documented as wasted ($1,196,014.01 in estimated drug purchasing cost). Over a period of 3 months following the on-demand model, 12 products were wasted ($34,823.98 in estimated drug purchasing cost). Switching models reduced the monthly average number of wasted products from 20 to 4 per month; the average cost of waste was reduced from $41,965.40 to $11,607.99 per month (P < .0001). Overall patient wait time from clearance until administration, excluding any recommended wait times after premedication administration (if applicable), was similar in both models: an average of 38.26 minutes in the premix model and 40.97 minutes in the on-demand model. Conclusion: Premixing parenteral admixtures was not cost effective at our institution. After resuming an on-demand compounding model, the monthly cost of waste (based on drug pricing alone) was reduced by over 70%. The wait time from clearance to treatment administration was similar in both models.

Prediction Performance and Economic Efficiency of Soft Sensors for in-Line Water Content Monitoring in Fluidized Bed Granulation: PP-Based Model vs. NIRS-Based Model.

Soft sensors play a crucial role as process analytical technology (PAT) tools. They are classified into physical models, statistical models, and their hybrid models. In general, statistical models are better estimators than physical models. In this study, two types of standard statistical models using process parameters (PPs) and near-infrared spectroscopy (NIRS) were investigated in terms of prediction accuracy and development cost. Locally weighted partial least squares regression (LW-PLSR), a type of nonlinear regression method, was utilized. Development cost was defined as the cost of goods required to construct an accurate model of commercial-scale equipment. Eleven granulation lots consisting of three laboratory-scale, two pilot-scale, and six commercial-scale lots were prepared. Three commercial-scale granulation lots were selected as a validation dataset, and the remaining eight granulation lots were utilized as calibration datasets. The results demonstrated that the PP-based and NIRS-based LW-PLSR models achieved high prediction accuracy without using the commercial-scale data in the calibration dataset. This practical case study clarified that the construction of accurate LW-PLSR models requires the calibration samples with the following two features: 1) located near the validation samples on the subspace spanned by principal components (PCs), and 2) having a wide range of variations in PC scores. In addition, it was confirmed that the reduction in cost and mass fraction of active pharmaceutical ingredient (API) made the PP-based models more cost-effective than the NIRS-based models. The present work supports to build accurate models efficiently and save the development cost of PAT.

Evaluation of Drug Wastage in the Operating Rooms and Intensive Care Units of a Regional Health Service.

BACKGROUND: Pharmacological treatments for critical processes in patients need to be initiated as rapidly as possible; for this reason, it is a standard of care to prepare the main anesthesia and emergency drugs in advance. As a result, 20%-50% of the prepared drugs remain unused and are then discarded. Decreasing waste by optimizing drug use is an attractive strategy for meeting both cost containment and environmental sustainability. The primary end point of this study was to measure the actual amount of drug wastage in the operating rooms (ORs) and intensive care units (ICUs) of a Regional Health Service (RHS). The secondary end point was to analyze and estimate the economic implications of this waste for the Health Service and to suggest possible measures to reduce it. METHODS: This prospective observational multicenter study was conducted across 12 hospitals, all of which belong to the same RHS in the north-east of Italy. Data collection took place in March 2018 and included patients admitted to ICUs, emergency areas, and ORs of the participating hospitals. Data concerning drug preparation and administration were collected for all consecutive patients, independent of case types and of whether operations were scheduled or unscheduled. Drug wastage was defined as follows: drugs prepared in ready-to-use syringes but not administered at all and discarded untouched. We then estimated the costs of wasted drugs for a 1-year period using the data from this study and the yearly regional pharmacy orders of drugs provided to the ORs and ICUs. We also performed a sensitivity analysis to validate the robustness of our assumptions and qualitative conclusions. RESULTS: We collected data for a total of 13,078 prepared drug syringes. Drug wastage varied from 7.8% (Urapidil, an alpha-1 antagonist antihypertensive) to 85.7% (epinephrine) of prepared syringes, with an overall mean wastage rate of 38%. The estimated yearly waste was 139,531 syringes, for a total estimated financial cost of €78,060 ($92,569), and an additional quantity of medical waste amounting to 4968 kg per year. The total provider time dedicated to the preparation of unused drugs was predicted to be 1512 working hours per year. CONCLUSIONS: The overall extent of drug wastage in ORs and ICUs is concerning. Interventions aimed at minimizing waste-related costs and improving the environmental sustainability of our practice are paramount. Effort should be put into designing a more efficient workflow that reduces this waste while providing for the emergency availability of these medications in the OR and ICU.

Online tools to synthesize real-world evidence of comparative effectiveness research to enhance formulary decision making.

Results of randomized controlled trials (RCTs) provide valuable comparisons of 2 or more interventions to inform health care decision making; however, many more comparisons are required than available time and resources to conduct them. Moreover, RCTs have limited generalizability. Comparative effectiveness research (CER) using real-world evidence (RWE) can increase generalizability and is important for decision making, but use of nonrandomized designs makes their evaluation challenging. Several tools are available to assist. In this study, we comparatively characterize 5 tools used to evaluate RWE studies in the context of making health care adoption decision making: (1) Good Research for Comparative Effectiveness (GRACE) Checklist, (2) IMI GetReal RWE Navigator (Navigator), (3) Center for Medical Technology Policy (CMTP) RWE Decoder, (4) CER Collaborative tool, and (5) Real World Evidence Assessments and Needs Guidance (REAdi) tool. We describe each and then compare their features along 8 domains: (1) objective/user/context, (2) development/scope, (3) platform/presentation, (4) user design, (5) study-level internal/external validity of evidence, (6) summarizing body of evidence, (7) assisting in decision making, and (8) sharing results/making improvements. Our summary suggests that the GRACE Checklist aids stakeholders in evaluation of the quality and applicability of individual CER studies. Navigator is a collection of educational resources to guide demonstration of effectiveness, a guidance tool to support development of medicines, and a directory of authoritative resources for RWE. The CMTP RWE Decoder aids in the assessment of relevance and rigor of RWE. The CER Collaborative tool aids in the assessment of credibility and relevance. The REAdi tool aids in refinement of the research question, study retrieval, quality assessment, grading the body of evidence, and prompts with questions to facilitate coverage decisions. All tools specify a framework, were designed with stakeholder input, assess internal validity, are available online, and are easy to use. They vary in their complexity and comprehensiveness. The RWE Decoder, CER Collaborative tool, and REAdi tool synthesize evidence and were specifically designed to aid formulary decision making. This study adds clarity on what the tools provide so that the user can determine which best fits a given purpose. DISCLOSURES: This work was supported by the Health Tech Fund, which was provided to the University of Washington School of Pharmacy by its Corporate Advisory Board. This consortium of pharmaceutical and biotech companies supports the research program of the University of Washington School of Pharmacy across the competitive space. The sponsors seeded the idea for the project and contributed to study design and improvement. The authors had full control of all content development, manuscript drafting, and submission for publication. The REAdi tool was developed by the authors. Chen, Bansal, Barthold, Carlson, Veenstra, Basu, Devine, Yun, Ta, and Beal were supported by a training grant from the University of Washington-Allergan Fellowship, unrelated to this work. Basu reports personal fees from Salutis Consulting, unrelated to this work. Graff is an employee of the National Pharmaceutical Council, which was a partner in the development of the CER Collaborative and funding partner for the CMTP RWE Decoder and the GRACE Checklist. A previous version of this work was presented as an invited workshop at AMCP Nexus 2018; October 22-25, 2018; Orlando, FL.

Review of economic data on closed system transfer drug for preparation and administration of hazardous drugs.

OBJECTIVES: The objectives of this study were to review economic data on the use of closed system drug transfer devices (CSTDs) for preparing and administering hazardous drugs, and to evaluate the quality of data reporting as defined by the Consolidated Health Economic Evaluation Reporting Standards (CHEERS). METHODS: All references from a recent Cochrane review about CSTDs were evaluated for inclusion. A literature review was also conducted. Articles containing economic data about the use of CSTDs were retained for analysis. Two researchers independently graded the articles according to the 24-item CHEERS checklist. RESULTS: Of the 138 articles identified initially, 12 were retained for analysis. Nine of these studies did not report acquisition costs or did not detail acquisition costs. Six studies reported economic benefits associated with the used of CSTDs, all related to extending the beyond-use date. The mean number of CHEERS criteria fulfilled by the included articles was 9.2 (SD 2.4). CONCLUSIONS: CSTDs are costly to acquire. However, few studies have examined the economic impact of these devices, and the existing studies are incomplete. As a result, hospitals planning to implement these devices will be unable to make a sound economic evaluation. Robust economic evaluation of CSTDs is needed.

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.

Quality and Brands of Amoxicillin Formulations in Nairobi, Kenya.

Antibiotics are among the most counterfeited anti-infectious medicines in developing countries. Amoxicillin is one of the commonly prescribed, affordable, and easily accessible antibiotic in Kenya. It is a broad-spectrum antibiotic hence commonly used in chemotherapy. This study sought to determine the quality and identify the various brands of amoxicillin and its combination amoxicillin/clavulanic acid marketed in Nairobi County. Nairobi is the capital city of Kenya, gateway for imports and exports, and the headquarters to most of the pharmaceutical distributors. Ten wards in Nairobi County representing different socioeconomic settings were purposively sampled for the study. A detailed questionnaire was used to collect background data on brands of amoxicillin and amoxicillin/clavulanic acid in the market. A total of 106 different brands were found in the market: 85 were imports while 21 were locally manufactured. Fifty-three samples were analyzed with reference to the United States Pharmacopoeia. Amoxicillin and clavulanic acid contents for oral suspensions were determined immediately after reconstitution and 7 days thereafter to determine their stability during the prescription period. On day seven, 23.1% (3 out of 13) of amoxicillin and 66.7% (8 out of 12) amoxicillin/clavulanic acid oral suspensions presented levels below recommended limits. Uniformity of weight for amoxicillin capsules noted 13.6% (3 out of 22) failure rate, while amoxicillin/clavulanic acid tablets complied. Potency determination for all amoxicillin capsules analyzed were within required limits, but amoxicillin/clavulanic acid tablets showed 33.3% (2 out of 6) noncompliance. For amoxicillin capsule and amoxicillin/clavulanic acid tablet dissolution tests, there was 10.5% (2 out of 19) and 50% (2 out of 4) noncompliance, respectively. Overall, 37.7% of the drugs analyzed failed to comply with the Pharmacopoeia. These results highlight the presence of poor-quality amoxicillin formulations in Nairobi County, affirming the need for regular postmarket surveillance to inform on the situation of antibiotic quality in the Kenyan market.

Construction situation, costs and charges associated with pharmacy intravenous admixture services: multi-center cross-sectional survey based on 137 medical institutions in mainland China.

BACKGROUND: To investigate the construction situation, costs and charges associated with pharmacy intravenous admixture services (PIVAS) to provide references for the construction and development of PIVAS in mainland China. METHODS: A multi-center cross-sectional survey was conducted via a WeChat Group targeting PIVAS leaders in hospitals to investigate the basic situation of PIVAS, including opening time, area, number of PIVAS, equipment, management mode, PIVAS costs and charges, as well as numbers of beds, open wards, and staff, and analyze differences in PIVAS construction at different provincial and hospital levels. RESULTS: 137 questionnaires were collected from 29 provinces, representing a response rate of 99.3%. Most participants (88.4%) were from Level III Hospitals. The number of years of operations of PIVAS ranged from 1 to 22 (median: 6). PIVAS site area ranged between 100 and 1973 m2; daily average infusion volume was concentrated in the ranges 0-1000 bags (29.9%, 41/137) and 1001-2000 bags (26.3%, 36/137). In terms of PIVAS management mode, the vast majority used separate pharmacy management (65.0%, 89/137). Only 52.6% (72/137) of PIVAS have standardized charges, and 70.1% (96/137) operate at a loss. The median costs of mixed tumor chemotherapy drugs, total parenteral nutrition, general medicine, antibiotics were 20, 35, 4 and 5 RMB, respectively. With the exception of a few features, PIVAS construction does not obviously differ among different regions and hospital levels. CONCLUSIONS: In recent years, PIVAS in China has developed rapidly and become relatively large. The main problems are that most provinces lack standards for charges and PIVAS construction differs among hospitals. Therefore, standards for PIVAS construction and charges should be developed to provide a reference for the future development of PIVAS.

Transferosomes as nanocarriers for drugs across the skin: Quality by design from lab to industrial scale.

Transferosomes, also known as transfersomes, are ultradeformable vesicles for transdermal applications consisting of a lipid bilayer with phospholipids and an edge activator and an ethanol/aqueous core. Depending on the lipophilicity of the active substance, it can be encapsulated within the core or amongst the lipid bilayer. Compared to liposomes, transferosomes are able to reach intact deeper regions of the skin after topical administration delivering higher concentrations of active substances making them a successful drug delivery carrier for transdermal applications. Most transferosomes contain phosphatidylcholine (C18) as it is the most abundant lipid component of the cell membrane, and hence, it is highly tolerated for the skin, decreasing the risk of undesirable effects, such as hypersensitive reactions. The most common edge activators are surfactants such as sodium deoxycholate, Tween® 80 and Span® 80. Their chain length is optimal for intercalation within the C18 phospholipid bilayer. A wide variety of drugs has been successfully encapsulated within transferosomes such as phytocompounds like sinomenine or apigenin for rheumatoid arthritis and leukaemia respectively, small hydrophobic drugs but also macromolecules like insulin. The main factors to develop optimal transferosomal formulations (with high drug loading and nanometric size) are the optimal ratio between the main components as well as the critical process parameters for their manufacture. Application of quality by design (QbD), specifically design of experiments (DoE), is crucial to understand the interplay among all these factors not only during the preparation at lab scale but also in the scale-up process. Clinical trials of a licensed topical ketoprofen transferosomal gel have shown promising results in the alleviation of symptons in orthreothritis with non-severe skin and subcutaneous tissue disorders. However, the product was withdrawn from the market which probably was related to the higher cost of the medicine linked to the expensive manufacturing process required in the production of transferosomes compared to other conventional gel formulations. This example brings out the need for a careful formulation design to exploit the best properties of this drug delivery system as well as the development of manufacturing processes easily scalable at industrial level.

Regulations, liability, safety, and economics related to compounding.

Extemporaneous compounding is a means to tailor a medication to an individual patient's needs and may be required when no commercial product exists to meet that need. Compounded products range from buffered lidocaine to topical creams and ointments. Recent heightened regulations have made compounding more challenging for dermatologists and prompted this review of regulations, liability, and safety related to compounding. With this information, providers may minimize liability and maximize safety while caring for their patients.

Budget impact analysis of introducing a non-reconstituted, hexavalent vaccine for pediatric immunization in the United Kingdom.

Objectives: Non-reconstituted, hexavalent vaccines (HV-NRs) can facilitate clinical practice by shortening vaccine preparation and administration time and by reducing the risk of vaccination errors compared to combination vaccines requiring reconstitution. The aim of this study was to determine the budget impact of introducing an HV-NR into the United Kingdom's (UK) pediatric immunization program, which currently uses a hexavalent vaccine requiring reconstitution (HV-R). Methods: Abudget impact model covering a 10-year time horizon was developed. The target population constituted closed UK birth cohorts from 2020 to 2029. Total direct costs from the payer's perspective consisted of four main categories: vaccine acquisition and management, healthcare provider's service provision, (non-)contaminated needle-stick and sharps injury (NSI), and non-NSI vaccination error costs. The net budget impact was calculated by comparing the costs in two different market share scenarios. Results: The use of HV-NR instead of HV-R was estimated to save £9,079,927 over a 10-year time horizon (i.e. £907,993 per year). Assuming all other vaccine criteria are equivalent the budget impact was most sensitive to changes in time spent by the healthcare provider and management costs. Conclusion: Results suggest, introducing an HV-NR into the UK's pediatric immunization program is potentially cost saving for the healthcare system.

Technology for Triple Fortification of Salt with Folic Acid, Iron, and Iodine.

As many of the maternal and child health complications result from folic acid, iron, and iodine deficiencies; it makes sense to combat these simultaneously. We have developed cost-effective technology to deliver these three micronutrients simultaneously through salt. Our goal was to retain at least 70% of the micronutrients during 6 months of storage. The fortified salt was formulated by spraying a solution that contained 2% iodine and 0.5% or 1% folic acid onto salt and adding encapsulated ferrous fumarate. The formulated triple fortified salt contained 1,000 ppm iron, 50 ppm iodine, and 12.5 or 25 ppm folic acid. The spray solution and the salt were stored for 2 and 6 months respectively at 25, 35, and 45 °C 60 to 70% relative humidity. Even at 45 °C, over 70% of both iodine and folic acid were retained in the salt. The best formulation based on the color of the salt and stability of iodine and folic acid contained 12.5 ppm folic acid, 50 ppm iodine, and 1,000 ppm iron. These results indicate that iron, iodine, and folic acid can be simultaneously delivered to a vulnerable population through salt using the technology described. Also, the quality control of the process can be developed around pteroic acid that was detected as a primary degradation product of folic acid. PRACTICAL APPLICATION: The technology developed is already transferred to India for industrial scale up. When fully operational, the technology will simultaneously solve iron, iodine, and folic acid deficiencies in vulnerable populations at a very low cost.

Cost-reduction strategy for isoproterenol use in radiofrequency catheter ablation procedures.

PURPOSE: A cost-reduction strategy for isoproterenol use in radiofrequency catheter ablation procedures was evaluated. SUMMARY: A medication-use evaluation at a 454-bed tertiary medical center revealed that the cardiac catheterization laboratory was the highest user of isoproterenol. Isoproterenol was removed from all AcuDose-Rx machines Omnicell, Mountain View, CA, and compounding was performed by pharmacy personnel. It was initially provided to the cardiac catheterization laboratory as an 8-µg/mL concentration in 20-mL 0.9% sodium chloride injection syringes with a 24-hour beyond-use date. This resulted in an initial cost savings but with an unacceptably high rate of wastage. Isoproterenol was then compounded as a 4-µg/mL concentration in 30 mL 5% dextrose in water syringes with a 9-day beyond-use date after a thorough literature search supported longer stability with this admixture. After 12 months of our current process, isoproterenol use during radio frequency catheter ablations (RFCAs) in the cardiac catheterization laboratory was reduced by 85%, decreasing the number of ampules used from 11.15 to 1.66 per week. CONCLUSION: A pharmacy-initiated process to mitigate an extraordinary increase in isoproterenol acquisition cost resulted in a reduction in usage in a tertiary care community hospital. Isoproterenol usage was reduced 85% after two different interventions were implemented, which is estimated to save $1,839 per procedure.

Multicenter study to evaluate the benefits of technology-assisted workflow on i.v. room efficiency, costs, and safety.

PURPOSE: The benefits of technology-assisted workflow (TAWF) compared with manual workflow (non-TAWF) on i.v. room efficiency, costs, and safety at hospitals with more than 200 beds are evaluated. METHODS: Eight hospitals across the United States (4 with TAWF, 4 without) were evaluated, and the characteristics of medication errors and frequency of each error type were measured across the different institutions. The average turnaround time per workflow step and the cost to prepare each compounded sterile preparation (CSP) were also calculated, using descriptive statistics. RESULTS: The TAWF hospital sites detected errors at a significantly higher rate (3.13%) than the non-TAWF hospital sites (0.22%) (p < 0.05). The top error reporting category for the TAWF sites was incorrect medication (63.30%), while the top error reporting category for the non-TAWF sites was incorrect medication volume (18.34%). Use of TAWF was associated with a preparation time decrease of 2.82 min/CSP, a compounding time decrease of 2.94 min/CSP, and a decrease in overall cost to prepare of $1.60/CSP. CONCLUSION: The use of TAWF in the i.v. room was associated with the detection of 14 times more errors than the use of non-TAWF, demonstrating different frequency of error in the results. TAWF also led to a faster preparation time that had a lower cost for preparation.

Utilization, Cost, and Pricing Scheme of Compounded Medications for Public Health System Patients: The California Workers' Compensation System, 2011-2013.

BACKGROUND: Although medically necessary in some cases, there is growing concern that compounded medications are being overprescribed, leading to questions about safety and necessity for high use and cost. Safety concerns regarding compounded medications were highlighted by the 2013 contamination of steroid injections by the New England Compounding Center, which caused serious infections and other injuries to at least 751 patients and resulted in at least 64 patient deaths. A study contributed to our understanding of compounded medication use and cost, finding in a sample of commercially insured population that the average ingredient cost for compounded medication prescriptions was $710.36, which is 130% higher than for noncompounded medication prescriptions. The literature on use and cost of compounded medications in noncommercially insured populations and related regulations, however, is sparse. The California Workers' Compensation System (CAWCS)-the largest U.S. workers' compensation system and a public health system experiencing high compounded medication costs-provided an opportunity for additional analysis of these issues. Furthermore, CAWCS data on compounded medication use and cost allow for the exploration of alternative pricing mechanisms that may control costs. OBJECTIVES: To (a) examine use, cost, and billing and reimbursement practices for compounded medications in a public health system-CAWCS- and (b) evaluate regulations and recommend an alternative pricing mechanism that could control costs in California. METHODS: Descriptive statistics for use, cost, and reimbursement patterns of all compounded medication prescriptions included in CAWCS's Workers Compensation Information System claims datasets from 2011 to 2013 were determined. This study coded a unique dataset that (a) identified compounded medications at the ingredient level; (b) grouped compounded medications from ingredient level to compounded medications as a whole; and (c) categorized compounded medications into applicable Colorado pricing categories. T-tests assessed if regulation AB 378, which targets compounded medications, was associated with a difference in mean cost. The Colorado pricing scheme was applied to estimate cost and provide recommendations. RESULTS: Despite the AB 378 requirement for compounded medications to be billed at the ingredient level for reimbursement, 15% of pharmacy-dispensed and 6% of physician-dispensed medications were not billed at the ingredient level. For pharmacy-dispensed compounded medications billed at the ingredient level, mean amount paid (SD) per ingredient was $45.40 (195.97), and for those medications billed at the single compounded medication level, mean amount paid (SD) per medication was $95.20 (326.33) over all years. For physician-dispensed medications billed at the ingredient level, mean amount paid (SD) per ingredient was $75.47 (205.51), and when billed at the single medication level was $204.83 (221.01). T-tests showed a mean increase in compounded medication mean amount paid between pre- and post-AB 378 groups of $12.27 (P < 0.001) for pharmacy-dispensed medications and $11.34 (P < 0.001) for physician-dispensed medications, suggesting that AB 378 did not curb compounded medication mean amount paid. CONCLUSIONS: The average cost of CAWCS pharmacy- and physician-dispensed compounded medications consistently increased. Various factors may have influenced this increase, but AB 378 did not achieve its full regulatory intent to standardize billing and reimbursement and control cost. Grouping of ingredients into compounded medications allowed for application of the Colorado pricing scheme to CAWCS claims data. Adoption of Colorado pricing would save 46% of current compounded medication cost for less complicated medications, while increasing cost for more complicated medications. The analyses recommended a revised Colorado pricing scheme, which would provide improved incentives for accurate billing and lead to savings for CAWCS. DISCLOSURES: Funding for this study was provided by the California Workers' Compensation System. The authors had final control regarding study design, study conduct, and writing of the manuscript. The authors report no conflicts of interest.

Using online content uniformity measurements for rapid automated process development exemplified via an X-ray system.

This paper addresses the relevance of automated content testing for the rapid automated process development (RAPD). Our previous work demonstrated that RAPD allowed a fast and efficient development of a continuous capsule-filling process. Target was the mean weight and the relative standard deviation of the weight. Likewise important are the content and the content uniformity. However, an implementation demands a certain level of automation. In general, technology is available that can detect active pharmaceutical ingredient (API) inside the capsules but the final application is linked to additional development and investment in machinery. To eliminate doubts regarding the benefits of an automated content check within the RAPD we present an application example. First, an X-ray system was used to detect barium sulfate accurately inside capsules. Second, a process was developed where barium sulfate was filled. The concentration of excipients was modified in the experiments, as well as the setting of the process parameter. The obtained model provided an explicit understanding of the process. Subsequently, the content uniformity model was compared to a model of the capsule weight relative standard deviation, confirming the benefits of an automated content check in the RAPD. Moreover, we presented another example illustrating the advantages of a connected continuous filling process, which permits evaluation of all process steps and their interactions (i.e. evaluation of the entire process).

Pursuing use of optimal formulations for paediatric HIV epidemic control - a look at the use of LPV/r oral pellets and oral granules.

INTRODUCTION: Despite a significant reduction in mother-to-child transmission of HIV, an estimated 180,000 children were infected with HIV in 2017, and only 52% of children under 15 years of age living with HIV (CLHIV) are on life-saving antiretroviral therapy (ART). Without effective treatment, half of CLHIV die before the age of two years and only one in five survives to five years of age. DISCUSSION: Over the past four years, the United States Food and Drug Administration tentatively approved new formulations of lopinavir/ritonavir (LPV/r) in the form of oral pellets and oral granules. However, the slow uptake of the aforementioned formulations in the low- and middle-income countries with the highest paediatric HIV burden is largely due to three challenges: limited manufacturing capacity; current unit cost of the pellets and granules; and slow uptake of these new formulations by policy makers and health care workers. CONCLUSIONS: Solutions to overcome these barriers include ensuring availability of an adequate supply of LPV/r oral pellets and oral granules, considering all programmatic and clinical factors when selecting paediatric ART formulations, and leveraging current resources to decrease paediatric HIV morbidity and mortality.