Racial and Gender Disparities in Utilization of Outpatient Total Shoulder Arthroplasties.

BACKGROUND: Utilization in outpatient total shoulder arthroplasties (TSAs) has increased significantly in recent years. It remains largely unknown whether utilization of outpatient TSA differs across gender and racial groups. This study aimed to quantify racial and gender disparities both nationally and by geographic regions. METHODS: 168,504 TSAs were identified using Medicare fee-for-service (FFS) inpatient and outpatient claims data and beneficiary enrollment data from 2020 to 2022Q4. The percentage of outpatient cases, defined as cases discharged on the same day of surgery, was evaluated by racial and gender groups and by different census divisions. A multivariate logistics regression model controlling for patient socio-demographic information (white vs. non-white race, age, gender, and dual eligibility for both Medicare and Medicaid), hierarchical condition category (HCC) score, hospital characteristics, year fixed effects, and patient residency state fixed effects was performed. RESULTS: The TSA volume per 1000 beneficiaries was 2.3 for the White population compared to 0.8, 0.6 and 0.3 for the Black, Hispanic, and Asian population, respectively. A higher percentage of outpatient TSAs were in White patients (25.6%) compared to Black patients (20.4%) (p < 0.001). The Black TSA patients were also younger, more likely to be female, more likely to be dually eligible for Medicaid, and had higher HCC risk scores. After controlling for patient socio-demographic characteristics and hospital characteristics, the odds of receiving outpatient TSAs were 30% less for Black than the White group (OR 0.70). Variations were observed across different census divisions with South Atlantic (0.67, p < 0.01), East North Central (0.56, p < 0.001), and Middle Atlantic (0.36, p < 0.01) being the four regions observed with significant racial disparities. Statistically significant gender disparities were also found nationally and across regions, with an overall odds ratio of 0.75 (p < 0.001). DISCUSSION: Statistically significant racial and gender disparities were found nationally in outpatient TSAs, with Black patients having 30% (p < 0.001) fewer odds of receiving outpatient TSAs than white patients, and female patients with 25% (p < 0.001) fewer odds than male patients. Racial and gender disparities continue to be an issue for shoulder arthroplasties after the adoption of outpatient TSAs.

A Preoperative Risk Assessment Tool for Predicting Adverse Outcomes among Total Shoulder Arthroplasty Patients.

BACKGROUND: With the increased utilization of Total Shoulder Arthroplasty (TSA) in the outpatient setting, understanding the risk factors associated with complications and hospital readmissions becomes a more significant consideration. Prior developed assessment metrics in the literature either consisted of hard-to-implement tools or relied on postoperative data to guide decision-making. This study aimed to develop a preoperative risk assessment tool to help predict the risk of hospital readmission and other postoperative adverse outcomes. METHODS: We retrospectively evaluated the 2019-2022(Q2) Medicare fee-for-service inpatient and outpatient claims data to identify primary anatomic or reserve TSAs and to predict postoperative adverse outcomes within 90 days post-discharge, including all-cause hospital readmissions, postoperative complications, emergency room visits, and mortality. We screened 108 candidate predictors, including demographics, social determinants of health, TSA indications, prior 12-month hospital and skilled nursing home admissions, comorbidities measured by hierarchical conditional categories, and prior orthopedic device-related complications. We used two approaches to reduce the number of predictors based on 80% of the data: 1) the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and 2) the machine-learning-based cross-validation approach, with the resulting predictor sets being assessed in the remaining 20% of the data. A scoring system was created based on the final regression models' coefficients, and score cutoff points were determined for low, medium, and high-risk patients. RESULTS: A total of 208,634 TSA cases were included. There was a 6.8% hospital readmission rate with 11.2% of cases having at least one postoperative adverse outcome. Fifteen covariates were identified for predicting hospital readmission with the area under the curve (AUC) of 0.70, and 16 were selected to predict any adverse postoperative outcome (AUC=0.75). The LASSO and machine learning approaches had similar performance. Advanced age and a history of fracture due to orthopedic devices are among the top predictors of hospital readmissions and other adverse outcomes. The score range for hospital readmission and an adverse postoperative outcome was 0 to 48 and 0 to 79, respectively. The cutoff points for the low, medium, and high-risk categories are 0-9, 10-14, ≥15 for hospital readmissions, and 0-11, 12-16, ≥17 for the composite outcome. CONCLUSION: Based on Medicare fee-for-service claims data, this study presents a preoperative risk stratification tool to assess hospital readmission or adverse surgical outcomes following TSA. Further investigation is warranted to validate these tools in a variety of diverse demographic settings and improve their predictive performance.

Value-based Reimbursement as a Mechanism to Achieve Social and Financial Impact in the Healthcare System.

Value-based reimbursement strategies have been considered in the continuous search for establishing a sustainable healthcare system. For models that have been already implemented, success is demonstrated according to specific details of the patients' consumption profile based on their clinical condition and the risk balance among all the stakeholders. From fee-for-service to value-based bundled payment strategies, the manner in which accurate patient-level cost and outcome information are used varies, resulting in different risk agreements between stakeholders. A thorough understanding of value-based reimbursement agreements that views such agreements as a mechanism for risk management is critical to the task of ensuring that the healthcare system generates social impacts while ensuring financial sustainability. This perspective article focuses on a critical analysis of the impact of value-based reimbursement strategies on the healthcare system from a social and financial perspective. A critical analysis of the literature about value-based reimbursement was used to identify how these strategies impact healthcare systems. The literature analysis was followed by the conceptual description of value-based reimbursement agreements as mechanisms for achieving social and financial impacts on the healthcare system. There is no single successful path toward payment reform. Payment reform is used as a strategy to re-engineer the way in which the system is organized to provide care to patients, and its successful implementation leads to cultural, social, and financial changes. Stakeholders have reached consensus regarding the claim that the use of value reimbursement strategies and business models could increase efficiency and generate social impact by reducing healthcare inequity and improving population health. However, the successful implementation of such new strategies involves financial and social risks that require better management by all the stakeholders. The use of cutting-edge technologies are essential advances to manage these risks and must be paired with strong leadership focusing on the directive to improve population health and, consequently, value. Payment reform is used as a mechanism to re-engineer how the system is organized to deliver care to patients, and its successful implementation is expected to result in social and financial modifications to the healthcare system.

Changes in Nursing Home Use Following Medicaid-Supported Expanded Access to Home- and Community-Based Services for Older Adults With Dementia.

Importance: New York State's Medicaid managed long-term care (MLTC) program expanded access to home- and community-based services, providing an alternative to nursing home care for people with dementia. Between 2012 and 2015, the state implemented mandatory MLTC for dual Medicare and Medicaid enrollees requiring more than 120 days of community-based long-term care. Objective: To evaluate changes in nursing home use among older adults with dementia following MLTC implementation. Design, Setting, and Participants: This cohort study used longitudinal data from January 1, 2011, to December 31, 2019, from the Minimum Data Set and Medicare administrative data. The study sample included New York State Medicare beneficiaries 65 years and older with dementia. New York City residents were excluded due to insufficient pre-study period data. Data were analyzed from January 1, 2011, to December 31, 2019. Exposure: Mandatory MLTC enrollment. Main Outcomes and Measures: Longitudinal models were used to evaluate changes in annual days of nursing home use following the staggered implementation of MLTC across 13 regions of the state. Two models were estimated: (1) a logistic regression model for any nursing home use in a given year and (2) a linear regression model of total nursing home days, conditional on any nursing home use. Models included annual event-time indicators specified as years until or since MLTC implementation. To capture MLTC effects for dual enrollees relative to non-dual Medicare enrollees, models included interaction terms for dual enrollment and event-time indicators. Results: This sample included 463 947 Medicare beneficiaries with dementia who lived in New York State between 2011 and 2019 (50.2% younger than 85 years; 64.4% women). Implementation of MLTC was associated with lower odds of nursing home use among dual enrollees, ranging from 8% lower odds 2 years post implementation (adjusted odds ratio, 0.92 [95% CI, 0.86-0.98]) to 24% lower odds 6 years post implementation (adjusted odds ratio, 0.76 [95% CI, 0.69-0.84]). Compared with a scenario of no MLTC, MLTC implementation was associated with an 8% reduction in annual days of nursing home use between 2013 and 2019 (mean, -5.6 [95% CI, -6.1 to -5.1] days per year). Conclusions and Relevance: The findings of this cohort study suggest that implementation of mandatory MLTC in New York State was associated with less nursing home use among dual enrollees with dementia and that MLTC may help prevent or delay nursing home placement among older adults with dementia.

The Impact of Nurse Practitioner-Led Primary Care on Quality and Cost for Medicaid-Enrolled Patients in States With Pay Parity.

Studies have established that nurse practitioners (NPs) deliver primary care comparable to physicians in quality and cost, but most focus on Medicare, a program that reimburses NPs less than physicians. In this retrospective cohort study, we evaluated the quality and cost implications of receiving primary care from NPs compared to physicians in 14 states that reimburse NPs at the Medicaid fee-for-service (FFS) physician rate (i.e., pay parity). We linked national provider and practice data with Medicaid data for adults with diabetes and children with asthma (2012-2013). We attributed patients to primary care NPs and physicians based on 2012 evaluation & management claims. Using 2013 data, we constructed claims-based primary care quality measures and condition-specific costs of care for FFS enrollees. We estimated the effect of NP-led care on quality and costs using: (1) weighting to balance observable confounders and (2) an instrumental variable (IV) analysis using differential distance from patients' residences to primary care practices. Adults with diabetes received comparable quality of care from NPs and physicians at similar cost. Weighted results showed no differences between NP- and physician-attributed patients in receipt of recommended care or diabetes-related hospitalizations. For children with asthma, costs of NP-led care were lower but quality findings were mixed: NP-led care was associated with lower use of appropriate medications and higher rates of asthma-related emergency department visits but similar rates of asthma-related hospitalization. IV analyses revealed no evidence of differences in quality between NP- and physician-led care. Our findings suggest that in states with Medicaid pay parity, NP-led care is comparable to physician-led care for adults with diabetes, while associations between NP-led care and quality were mixed for children with asthma. Increased use of NP-led primary care may be cost-neutral or cost-saving, even under pay parity.

Motivations of potential anchor businesses to support community development and community health.

INTRODUCTION: Some for-profit businesses act like non-profit anchor institutions in contributing to community development, particularly health-related initiatives. Their motives are not well understood. We aimed to 1) identify and describe potential anchor businesses, 2) determine their motivations to contribute to community development, and 3) highlight motivations behind health-related initiatives. MATERIALS AND METHODS: We identified a national sample of potential anchor businesses, grouped by those that contributed to 1) both health-related and non-health initiatives, 2) non-health initiatives only, and 3) those without substantial contributions. We conducted an environmental scan, semi-structured qualitative interviews and directed content analysis through rapid review methodology. RESULTS: We identified 4,512 potential anchor businesses nationally. Among the 108 of these included in the environmental scan, 48% substantially contributed to community development (12% in health). Interviewees' company philosophies ranged from the idea that economic well-being of the company and community were intertwined, to the idea that commercial success of the company would benefit the community. Motivations for contributions included improving the hiring pool, improved recruitment and retention, and goodwill. Other common sentiments included strategies to focus on core business strengths to address community needs and a desire that companies should not compete in their giving activities. Further, some participants believed health care companies should be investing in health-related initiatives. CONCLUSIONS: The generosity of potential anchor businesses' local contributions may be determined by company philosophy about its relationship with the community. Stakeholders interested in spurring contributions to local communities might consider messaging to leverage businesses' core strengths and encourage cooperation.

Independent Evaluation of the New York State 1115 Waiver Amendment: The Children's Design: Interim Findings.

In an effort to streamline care for children and youth under age 21 with needs for home- and community-based services (HCBS), New York State consolidated several prior 1915(c) waivers into a single Children's Waiver and amended their Section 1115 Medicaid Redesign Team waiver. The 1115 waiver amendment allows the state to move services covered by the consolidated Children's Waiver from fee for service to Medicaid managed care (MMC) and to target eligibility to medically needy family-of-one children who meet clinical criteria and are enrolled in the consolidated Children's Waiver but do not qualify for Medicaid due to family income. Together, these waiver amendments are called the "Children's Design," which was implemented in 2019. In this interim evaluation, the authors identify facilitators of, and barriers to, implementation of the Children's Design and describe baseline trends in outcomes of interest to its future evaluation. The authors found that: (1) providers, advocates, MMC plan representatives, and government partners perceived the transition to the Children's Design as challenging and were particularly concerned about the burden of accessing care on children's families and reductions in service availability; (2) prior to the Children's Design implementation, parents of children with chronic conditions had high levels of satisfaction with their primary care providers but were less satisfied with their ability to access special equipment and therapies and with coordination efforts among multiple providers; and (3) at baseline, the levels of quality indicators for children did not change significantly, with the exception of some primary care indicators for young children, which improved.

New York State 1115 Demonstration Independent Evaluation: Interim Report.

The broad goals of New York State's Medicaid Section 1115 Waiver are to enroll a majority of Medicaid beneficiaries into managed care, increase access and service quality, and expand coverage to more low-income New Yorkers. The RAND Corporation was competitively selected as the independent evaluator to assess two components under this 1115 Demonstration Waiver: the Managed Long-Term Care (MLTC) program and the 12-month continuous eligibility policy, which guarantees enrollees Medicaid coverage regardless of changes in income in the 12 months after eligibility determination and enrollment. This final interim evaluation examines whether these two components have helped achieve the program's goals. The RAND team's analyses show that the Demonstration has expanded access to managed care through mandatory MLTC enrollment and 12-month continuous eligibility. The team found no evidence of a significant change in patient safety or quality of care. The authors note that, although this means that there is no evidence the Demonstration achieved the goal of improving quality of care, increasing access without compromising quality of care is a success in its own right.

Cost evaluation of integrating local HIV and housing data to facilitate service coordination in four demonstration sites.

As part of the evaluation of a federal initiative to integrate HIV medical and housing data at four local jurisdictions in the U.S., we estimated the financial costs of implementing data integration occurring from June 2016 to August 2018. We collected data on labor, non-labor, and overhead expenses based on invoices and surveys of staff time, staff compensation, and non-labor expenses. Non-labor expenses were directly charged or allocated to the project using the number of full-time equivalents as the allocation basis. Reported indirect cost rates were used to estimate overhead expenses. Demonstration sites spent an average of $273,656 over the full 27-month period, with an average monthly spending of $10,010 in 2018 U.S. dollars. There was sizable variation in the data integration costs across sites, implementation phases, and data integration models. Findings may help policymakers and potential adopters of similar data integration efforts customize parameters for local conditions and estimate resources required.

Effect of the ExactCare medication care management model on adherence, health care utilization, and costs.

BACKGROUND: Multimorbidity and polypharmacy are common in the United States and are associated with greater risk of disease-related complications and higher health care costs. ExactCare has implemented a high-touch approach that includes home visits, comprehensive ongoing medication reviews, patient education, medication reconciliation, medication compliance packaging, and electronic reminders and trackers. OBJECTIVE: To test whether the ExactCare program improves medication adherence and reduces health care utilization and costs. METHODS: Using a national database from a large U.S. insurer, we identified Medicare Advantage plan members in 8 states from 2007 to 2018 who had both medical and prescription drug coverage. The index year for an ExactCare patient was identified using the date of the first prescription filled by ExactCare, with the previous year being the baseline. All patients without a prescription from an ExactCare pharmacy were considered potential comparison patients. To propensity match ExactCare and comparison patients, the probability of ExactCare participation was modeled using a logistic regression based on demographics, state, year, urban status, Medicaid eligibility, low-income subsidies, comorbidities, and baseline utilization and costs. Multivariate regression analysis was conducted to generate a difference-in-differences estimate of program effect for the matched pairs as well as patient-level fixed effects, while adjusting for additional time-varying characteristics. Adherence outcomes included the proportion of days covered for oral diabetic medications, antihypertensives, and hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins). Utilization outcomes included emergency department (ED) visits, hospitalizations, and skilled nursing facility (SNF) admissions, hospitalization days, and SNF days. Cost outcomes included total cost of care, prescription drug cost, hospital inpatient cost, and SNF cost. RESULTS: ExactCare patients (N = 701) were propensity-matched to comparison patients (N = 1,395) using the nearest 1:2 match approach, with an average follow-up period of 6.6 and 5.4 years for ExactCare and comparison patients, respectively. One year of ExactCare participation was associated with statistically significant increases in adherence to statins (8.4 percentage points; P < 0.001) and antihypertensive drugs (4.9 percentage points; P < 0.001), but the increase in adherence for diabetes drugs was not statistically significant. ExactCare participation was associated with statistically significant decreases in SNF admission rates (-67 SNF stays per 1,000 member-years; P = 0.011), inpatient days (-857 days per 1,000 member-years; P = 0.022), and SNF days (-1,801 days per 1,000 member-years; P = 0.002), but not with the rates of ED visits or hospital admissions. Each year of ExactCare participation was associated with increases in prescription drug costs ($30 per-member per month [PMPM]; P = 0.006) and decreases in total costs (-$196 PMPM; P = 0.023) and medical costs (-$226 PMPM; P = 0.008), largely attributable to decreases in hospital inpatient costs (-$119 PMPM; P = 0.001) and SNF costs (-$30 PMPM; P = 0.007). CONCLUSIONS: ExactCare's medication care management model was associated with improved medication adherence and an approximately $2,400 per member per year reduction in total cost of care, representing a 5% reduction in average costs. DISCLOSURES: This study was funded by ExactCare Pharmacy under a contract with RAND that grants the study authors sole responsibility for data management, study design, data analysis, manuscript drafting, and the decision to publish. The sponsor had no role in the study design and manuscript drafting. All data analysis was conducted by the study authors. A draft manuscript was reviewed by the sponsor, but the study authors made final decisions regarding the content and study conclusions. Shetty, Chen, and Liu are employed by RAND. Rose has nothing to disclose.

Impact of Primary Care Worksite Health and Wellness Clinics on HbA1c Level Among Prediabetic or Diabetic Employees.

PURPOSE: To determine whether the use of worksite health and wellness clinics reduced hemoglobin A1c (HbA1c) for prediabetic and diabetic employees. DESIGN: Hemoglobin A1c values were compared between clinic users and matched non-users. SETTING: The Wonderful Company's (TWC's) agricultural and packaging sites in Central California. SAMPLE: TWC's 2016 to 2017 employees who used clinics (n = 445, defined below) and clinic non-users (n = 217) who had HbA1c screening and worked at TWC for 3 or more months each year. INTERVENTION: A unique worksite health and wellness clinic that offers multidisciplinary primary medical care in synergy with TWC's overall wellness programs. MEASURES: Exposure was clinic use, defined by frequency and patterns of visits. Hemoglobin A1c was the outcome of interest. ANALYSIS: Users and non-users were propensity score matched using the 2016 employee data including HbA1c, and then 2017 HbA1c values were compared between the 2 groups. RESULTS: The 2017 HbA1c of diabetic employees was lower among clinic users compared to non-users (7.42 vs 8.53, P < .001). Differences in HbA1c among prediabetics or diabetics and prediabetics aggregated were not statistically significant, despite TWC's population-level data showing a reduction in prediabetes prevalence. The clinic impact results were robust to multivariate analyses and an alternative definition of utilization. CONCLUSION: The implementation of TWC's Health and Wellness clinics was associated with reductions in HbA1c among diabetics, but further research is needed on prediabetics.

Evaluation of the Connections to Care (C2C) Initiative: Interim Report.

At least one in five adult New Yorkers is likely to meet the criteria for a mental health diagnosis, yet most do not receive mental health services to treat these problems. Mental health problems, such as depression and anxiety, disproportionately affect historically underserved segments of the population, such as racial/ethnic minority and low-income individuals, and these groups are least likely to receive mental health services. The Connections to Care (C2C) Collaborative developed the C2C program, which integrates mental health support into the work of nonclinical community-based organizations (CBOs) through task shifting; task shifting is an approach extending evidence-informed health care skills to community-based partners under the oversight of trained professionals to expand the health care workforce. This study uses data from interviews, surveys, and CBO-provided progress indicators to describe how C2C has been implemented within and across the 15 CBOs. This study also describes study methods and a description of the baseline sample for the impact evaluation at the time of writing.

Participation in an innovative patient support program reduces prescription abandonment for adalimumab-treated patients in a commercial population.

PURPOSE: Nonadherence to indicated therapy reduces treatment effectiveness and may increase cost of care. HUMIRA Complete, a Patient Support Program (PSP), aims to reduce nonadherence in patients prescribed adalimumab (ADA). The objective of this study was to assess the relationship between participation in the PSP and prescription abandonment rates among ADA-treated patients. PATIENTS AND METHODS: This longitudinal study using patient-level data from AbbVie's PSP linked with medical and pharmacy claims data included patients ≥18 years with an ADA-approved indication, ≥1 pharmacy claim for ADA, and available data ≥3 months before and ≥6 months after the index date (defined as the initial ADA claim [01/2015 to 02/2017]). Abandonment was defined as reversal of initial ADA prescription with no paid claim during 3-month follow-up. Abandonment rates were compared between PSP and non-PSP cohorts using multivariable logistic regression controlling for potentially confounding baseline characteristics. RESULTS: In 17,371 patients (9,851 PSP; 7,520 non-PSP), the overall abandonment rate was 10.8-16.8% across indications. The odds of ADA abandonment were 70% less for PSP vs non-PSP patients (5.6% vs 20.4%, odds ratio [OR]=0.30, [95% confidence interval (CI)=0.27-0.33] P<0.001), 38% less for patients using specialty vs retail pharmacy (OR=0.62, 95% CI=0.56-0.69, P<0.001), 20% less for those with income of $50-99K vs $0-49K (OR=0.80, 95% CI=0.69-0.92, P<0.01), and 78% greater for those with copayment of $26-100 vs $0-25 (OR=1.78, 95% CI=1.55-2.05, P<0.001). CONCLUSION: Participation in the PSP, higher income, and using a specialty pharmacy were associated with lower odds of abandoning ADA therapy, whereas increased copayments were associated with greater abandonment. PSPs should be considered to improve initiation of ADA therapy.

Economic benefits of microprocessor controlled prosthetic knees: a modeling study.

BACKGROUND: Advanced prosthetic knees allow for more dynamic movements and improved quality of life, but payers have recently started questioning their value. To answer this question, the differential clinical outcomes and cost of microprocessor-controlled knees (MPK) compared to non-microprocessor controlled knees (NMPK) were assessed. METHODS: We conducted a literature review of the clinical and economic impacts of prosthetic knees, convened technical expert panel meetings, and implemented a simulation model over a 10-year time period for unilateral transfemoral Medicare amputees with a Medicare Functional Classification Level of 3 and 4 using estimates from the published literature and expert input. The results are summarized as an incremental cost effectiveness ratio (ICER) from a societal perspective, i.e., the incremental cost of MPK compared to NMPK for each quality-adjusted life-year gained. All costs were adjusted to 2016 U.S. dollars and discounted using a 3% rate to the present time. RESULTS: The results demonstrated that compared to NMPK over a 10-year time period: for every 100 persons, MPK results in 82 fewer major injurious falls, 62 fewer minor injurious falls, 16 fewer incidences of osteoarthritis, and 11 lives saved; on a per person per year basis, MPK reduces direct healthcare cost by $3676 and indirect cost by $909, but increases device acquisition and repair cost by $6287 and total cost by $1702; on a per person basis, MPK is associated with an incremental total cost of $10,604 and increases the number of life years by 0.11 and quality adjusted life years by 0.91. MPK has an ICER ratio of $11,606 per quality adjusted life year, and the economic benefits of MPK are robust in various sensitivity analyses. CONCLUSIONS: Advanced prosthetics for transfemoral amputees, specifically MPKs, are associated with improved clinical benefits compared to non-MPKs. The economic benefits of MPKs are similar to or even greater than those of other medical technologies currently reimbursed by U.S. payers.

The Impact of Worksite Clinics on Teacher Health Care Utilization and Cost, Self-Reported Health Status, and Student Academic Achievement Growth in a Public School District.

OBJECTIVE: The aim of this study was to examine the impact of worksite clinics on health care utilization and cost, self-reported health status, and student achievement growth in a public school district. METHODS: We used insurance claims, health risk assessment, and student achievement growth data for active teachers during 2007 to 2015. A difference-in-differences approach was applied to measure the impact of worksite clinics. RESULTS: Compared with using a community-based clinic as the usual source of primary care, using a worksite clinic was associated with significantly lower inpatient admissions (53 vs 31 per 1000 teacher years), annual health care cost ($5043 vs $4298 in 2016 US dollars, a difference of $62 per teacher per month), and annual absent work hours (63 vs 61). No significant differences were detected in self-reported health status or student achievement growth. CONCLUSION: Worksite clinics reduce teacher health care cost and absenteeism.

Identification of tobramycin impurities for quality control process monitoring using high-performance anion-exchange chromatography with integrated pulsed amperometric detection.

Commercial-scale fermentation for tobramycin manufacture is carried out with Streptomyces tenebrarius. Impurity profiling during various phases of pharmaceutical production is important for evaluating the effectiveness of a processing step and meeting regulatory requirements. High-performance anion-exchange (HPAE) chromatography with integrated pulsed amperometric detection (HPAE-IPAD) is a highly sensitive method used to assay tobramycin and to assess purity, but no prior publications demonstrated the capability of this technique to monitor purity at various stages of production at either the typical concentrations or in the typical matrices of a manufacturing process. In addition, the identities of the impurity peaks observed in commercial sources of tobramycin when assayed by using HPAE-IPAD are mainly unknown. Regulatory agencies generally require these impurities to be characterized when found above certain limits, and when present at higher levels require toxicological studies. In this paper, we analyze tobramycin samples using HPAE-IPAD at different stages of production and show the impurity profile and concentration changes through the manufacturing process. We successfully identified nearly all the impurity peaks found in commercially available tobramycin, based on known degradation pathways deduced from extreme pH forced degradation studies, which we experimentally reproduced, and based on previously known related substances found in S. tenebrarius fermentation broth. In crude and final tobramycin products, we identified the peaks for neamine, kanamycin B, nebramine, kanosamine, 2-deoxystreptamine. We tentatively identified deoxystreptamine-kanosaminide in crude and final products, and kanamycin A, carbamoyl-kanamycin B and carbamoyl-tobramycin in down stream process intermediates of a S. tenebrarius fermentation culture. Results presented in this paper support the effective use of the HPAE-IPAD method for in-process impurity profiling of tobramycin, and as a stability-indicating technique after product purification.