Were Needles Everywhere?: Differing Views on Syringe Waste and Disposal Associated With Needs-Based Syringe Services Programs Among Community Partners and Persons Who Inject Drugs.

BACKGROUND: Community concerns surrounding syringe waste are a common barrier to syringe services program (SSP) implementation. In Kanawha County, West Virginia, community opposition to SSPs resulted in the closure of needs-based SSPs prior to and during an HIV outbreak among persons who inject drugs (PWID). This qualitative analysis examines views of PWID and community partners on syringe waste and disposal associated with needs-based SSPs. METHODS: Qualitative interviews with 26 PWID and 45 community partners (medical and social service providers, law enforcement personnel, policymakers, and religious leaders) were conducted. Interviews were recorded, transcribed, and coded. Code summaries described participants' views on syringe waste and disposal and needs-based SSPs. RESULTS: Community partners and PWID who favored needs-based SSPs reported that needs-based SSPs had not affected or reduced syringe waste. Conversely, community partners who favored one-to-one exchange models and/or barcoded syringes described needs-based SSPs increasing syringe waste. Community partners often cited pervasive community beliefs that SSPs increased syringe waste, risk of needlesticks, drug use, and crime. Community partners were unsure how to address syringe waste concerns and emphasized that contradictory views on syringe waste posed barriers to discussing and implementing SSPs. CONCLUSIONS: Participants' views on whether syringe waste was associated with needs-based SSPs often aligned with their support or opposition for needs-based SSPs. These differing views resulted in challenges finding common ground to discuss SSP operations amid an HIV outbreak among PWID. SSPs might consider addressing syringe waste concerns by expanding syringe disposal efforts and implementing community engagement and stigma reduction activities.

A Qualitative Analysis of Barriers to Accessing HIV Prevention Services During an HIV Outbreak among Persons who Inject Drugs in West Virginia.

In response to an increase in HIV diagnoses among persons who inject drugs (PWID) in Kanawha County, West Virginia, West Virginia Bureau for Public Health and CDC conducted a qualitative assessment in Kanawha County to inform HIV outbreak response activities. Interviews with 26 PWID and 45 community partners were completed. Transcribed interviews were analyzed to identify barriers to accessing HIV prevention services among PWID using the risk environment framework. Participants identified numerous political, physical, social, and economic community-level barriers that influenced access to HIV prevention services among PWID. Political factors included low community support for syringe services programs (SSPs); physical factors included low SSP coverage, low coverage of HIV testing outreach events, low HIV preexposure prophylaxis availability, and homelessness; social factors included stigma and discrimination; economic factors included community beliefs that SSPs negatively affect economic investments and limited resources for HIV screening in clinical settings. Individual-level barriers included co-occurring acute medical conditions and mental illness. Community-level interventions, such as low-barrier one-stop shop models, are needed to increase access to sterile syringes through comprehensive harm reduction services.

Structural and Psychosocial Syndemic Conditions and Condomless Anal Intercourse Among Transgender Women - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

Psychosocial and structural syndemic conditions, including polydrug use and experiencing homelessness, frequently co-occur and might jointly increase HIV risk. Limited studies have assessed racial and ethnic differences in exposure to syndemic conditions and behaviors associated with HIV transmission among transgender women. This report examines the relation between syndemic conditions and condomless anal intercourse (CAI) among transgender women in seven urban areas in the United States to develop HIV prevention interventions for transgender women. During 2019-2020, transgender women in seven urban areas were recruited using respondent-driven sampling for a biobehavioral survey. Reported syndemic conditions (psychosocial: polydrug use, sexual violence, and psychological distress; structural: homelessness, incarceration, and exchange sex) were summed to create a syndemic score. Using modified Poisson regression to account for RDS, the study assessed whether the strength of the association between syndemic score and CAI differed by race and ethnicity. To assess additive interaction, the relative excess prevalence owing to interaction (REPI) and 95% CIs for selected pairs of syndemic conditions on CAI prevalence stratified by race and ethnicity were estimated. Of 1,348 transgender women (Black = 546, White = 176, and Hispanic = 626), 55% reported CAI; and 24% reported ≥3 syndemic conditions. Reporting additional syndemic conditions was associated with CAI for White, Hispanic, and Black participants. The association was significantly stronger for White than Black and Hispanic participants. Limited significant superadditive interactions were found, although the majority were between structural syndemic conditions. Racial and ethnic differences in REPI estimates were observed. Reporting more syndemic conditions was associated with increased CAI across racial and ethnic groups, demonstrating that HIV prevention efforts for transgender women should address structural and psychosocial syndemic conditions. Results differed by race and ethnicity, indicating that syndemic-focused interventions for transgender women should be tailored to racial and ethnic groups.

Information transparency with immediate release: Oncology clinician and patient perceptions.

INTRODUCTION: As part of the 21st Century Cures Act (April 2021), electronic health information (EHI) must be immediately released to patients. In this study, we sought to evaluate clinician and patient perceptions regarding this immediate release. METHODS: After surveying 33 clinicians and 30 patients, semi-structured interviews were conducted with a subset of the initial sample, comprising 8 clinicians and 12 patients. Open-ended questions explored clinicians' and patients' perceptions of immediate release of EHI and how they adjusted to this change. RESULTS: Ten themes were identified: Interpreting Results, Strategies for Patient Interaction, Patient Experiences, Communication Strategies, Provider Limitations, Provider Experiences, Health Information Interfaces, Barriers to Patient Understanding, Types of Results, and Changes due to Immediate Release. Interviews demonstrated differences in perceived patient distress and comprehension, emphasizing the impersonal nature of electronic release and necessity for therapeutic clinician-patient communication. CONCLUSIONS: Clinicians and patients have unique insights on the role of immediate release. Understanding these perspectives will help improve communication and develop patient-centered tools (glossaries, summary pages, additional resources) to aid patient understanding of complex medical information.

Meaning Salience and Meaning in Life Prospectively Predict Lower Distress During the COVID-19 Pandemic.

BACKGROUND: The COVID-19 pandemic is a widespread source of stress with adverse mental health impacts. Meaning in life, both as a trait and as momentary awareness of what is personally meaningful (meaning salience), is associated with positive health outcomes and may buffer against the deleterious effects of stress. PURPOSE: This project examines prospective associations between baseline meaning salience (daily, post-laboratory stressor) and meaning in life with perceived stress during COVID-19. METHODS: A community sample of healthy adults (n = 147) completed a laboratory stress protocol in 2018-2019, where perceived stress, meaning in life, and meaning salience (daily, post-stressor) were assessed. During April and July 2020 (n = 95, and 97, respectively), participants were re-contacted and reported perceived stress. General linear mixed-effects models accounting for repeated measures of stress during COVID-19 were conducted. RESULTS: Partial correlations holding constant baseline perceived stress showed that COVID-19 perceived stress was correlated with daily meaning salience (r = -.28), post-stressor meaning salience (r = -.20), and meaning in life (r = -.22). In mixed-effects models, daily and post-stressor meaning salience and higher meaning in life, respectively, predicted lower perceived stress during COVID-19, controlling for age, gender, and baseline perceived stress. CONCLUSIONS: Individuals more capable of accessing meaning when exposed to laboratory stress reported lower perceived stress during a global health crisis. Despite study limitations concerning generalizability, results support meaning in life and meaning salience as important aspects of psychological functioning that may promote well-being by affecting stress appraisals and available resources for coping.

The COVID-19 pandemic is a widespread source of stress. Having a sense of meaning in life, or that you have goals in life and a sense that the things you do are worthwhile and significant, is an important part of psychological well-being and might help reduce stress. We collected data on 147 healthy adults in 2018­2019 regarding their stress levels, sense of meaning in life, and how often they were aware of their life's meaning on daily basis and after a stress task in the laboratory. We re-contacted these adults in both April and July 2020 to ask about their stress, and 95 adults responded. Adults who had higher meaning in life in 2018­2019 experienced less stress during the early months of the COVID-19 pandemic. Adults who were more aware of their life's meaning each day and immediately after a stress task in the laboratory also experienced less stress during the COVID-19 pandemic. Results from this study provide evidence that having a strong sense of meaning in life overall and being aware of your life's meaning each day and during times of stress, may promote psychological well-being and reduce stress during times when stress is widespread and abundant.

Intimate partner violence, HIV-risk behaviors, and HIV screening among heterosexually active persons at increased risk for infection.

ABSTRACTIntimate partner violence (IPV) can increase a person's risk of HIV and other sexually transmitted infections (STIs), and may affect access to sexual health services. We assessed the prevalence of HIV screening and IPV among heterosexually-active persons using data from the 2016 National HIV Behavioral Surveillance. Participants were eligible if they were 18-60 years old, could complete the interview in English or Spanish, and reported having sex with an opposite sex partner in the previous 12 months. People who reported neither injection drug use within the past 12 months nor prior HIV diagnosis, and persons with valid responses to questions regarding HIV screening and physical/sexual IPV within the past 12 months were included (N = 7,777). Overall, 17% reported IPV in the previous 12 months and 19% had never had HIV screening. Abused persons were more likely to have been screened for HIV and to report high risk behaviors than non-abused persons. There was no difference in the proportion being offered HIV screening by their health care provider in the previous year. Findings suggest an integrated approach to violence prevention and sexual health may help increase awareness about clinical best practices and reduce risk for HIV/STIs among at-risk communities.

Notes from the Field: HIV Outbreak During the COVID-19 Pandemic Among Persons Who Inject Drugs - Kanawha County, West Virginia, 2019-2021.

During October 2019, the West Virginia Bureau for Public Health (WVBPH) noted that an increasing number of persons who inject drugs (PWID) in Kanawha County received a diagnosis of HIV. The number of HIV diagnoses among PWID increased from less than five annually during 2016-2018 to 11 during January-October 2019 (Figure). Kanawha County (with an approximate population of 180,000*) has high rates of opioid use disorder and overdose deaths, which have been increasing since 2016,† and the county is located near Cabell County, which experienced an HIV outbreak among PWID during 2018-2019 (1,2). In response to the increase in HIV diagnoses among PWID in 2019, WVBPH released a Health Advisory§; and WVBPH and Kanawha-Charleston Health Department (KCHD) convened an HIV task force, conducted care coordination meetings, received CDC remote assistance to support response activities, and expanded HIV testing and outreach.

Serious Mental Illness Among Young People Who Inject Drugs: An Assessment of Injection Risks and Healthcare Use.

BACKGROUND: Data on behavioral correlates of mental illness among young people who inject drugs (PWID) are limited. We examine injection risks and healthcare use among young PWID with probable serious mental illness (PSMI). METHODS: People who inject drugs were recruited and interviewed in 20 US cities for 2015 National HIV Behavioral Surveillance. Probable serious mental illness was assessed using the Kessler-6 screening scale. Bivariate analyses using log-linked Poisson regression with generalized estimating equations adjusted for design covariates were conducted to examine associations between PSMI and behaviors among PWID ages 18-29 years. RESULTS: Of 1769 young PWID, 45% had PSMI. Compared to those without PSMI, PWID with PSMI were more likely to report injecting more than once a day, receptive syringe sharing, sharing of other injection equipment, and unmet needs for medical care and substance use disorder (SUD) treatment. Those with PSMI were less likely to use syringe services programs than those without PSMI. CONCLUSIONS: Approximately half of young PWID had PSMI. People who inject drugs with PSMI engaged in high-risk injection behaviors and encountered barriers to healthcare. Human immunodeficiency virus prevention programs such as Syringe Services Programs (SSPs) could benefit from screening for mental illness among young PWID and strong linkage to healthcare, including mental health and SUD treatment.

Comprehensive Temperature Excursion Management Program for the Commercial Distribution of Biopharmaceutical Drug Products.

Biopharmaceutical drug products may be exposed to temperatures outside of the intended storage temperature range (typically 2-8°C) during commercial distribution due to uncontrolled variables and unexpected events. Pharmaceutical companies are expected to ensure that product quality and stability are not negatively impacted by temperature excursions defined as being acceptable for the product. It is imperative that all firms involved in the distribution understand key elements of the temperature excursion management program in place to overcome the challenges of global distribution and comply with regulatory requirements. Proactive implementation of a comprehensive temperature excursion management program is expected to help achieve successful commercial distribution. In this article, important aspects related to the key elements of a comprehensive temperature excursion management program are summarized, including standard stability testing, regulatory expectations related to the justification of temperature excursions, thermal cycling studies to assess and support potential temperature excursions (including how/when thermal cycling study data is used to support temperature excursions), good distribution practices to minimize temperature excursions and use of theoretical methods/mathematical simulation models to assess temperature excursions. A comprehensive temperature excursion management program is expected to ensure product quality and help minimize, assess, and justify temperature excursions more efficiently, ensure regulatory compliance and avoid business impact caused by the loss of products or inadequate supply.

Distributive Syringe Sharing and Use of Syringe Services Programs (SSPs) Among Persons Who Inject Drugs.

Monitoring distributive syringe sharing (DSS) and syringe services program (SSP) use among persons who inject drugs (PWID) is important for HIV prevention. PWID aged ≥ 18 in 20 US cities were recruited for National HIV Behavioral Surveillance in 2015 using respondent-driven sampling, interviewed and offered HIV testing. Bivariate and multivariable analyses via log-linked Poisson regression with generalized estimating equations were conducted to examine associations between demographic and behavioral variables and DSS. Effect of SSP use on DSS by HIV sero-status was assessed by including an interaction between SSP and sero-status. Analyses were adjusted for sampling design. Among 10,402 PWID, 42% reported DSS. DSS was less likely to be reported among HIV-positive compared to HIV-negative PWID (aPR = 0.51, CI 0.45-0.60), and among those who primarily obtained syringes from SSPs versus those who did not (aPR = 0.82, 95% CI 0.77-0.88). After adjustment, those who primarily used SSPs were less likely to report DSS than those who did not among both HIV-negative PWID (aPR = 0.84, 95% CI 0.78-0.90) and HIV-positive PWID (aPR = 0.54, 95% CI 0.39-0.75). Findings support expansion of SSPs, and referrals to SSPs by providers working with PWID.

Buffer exchange path influences the stability and viscosity upon storage of a high concentration protein.

High concentration protein solutions are generally produced by spin column concentration (SCC) during early development and by tangential flow filtration (TFF) during later stages, when greater quantities of protein become available. This is based on the assumption that the protein generated by the SCC process would be fairly similar to the TFF process material. In this study, we report the case of high concentration solutions of an Fc fusion protein produced by the two processes using the same upstream drug substance (DS) with very different storage stability. The TFF and SCC batches were characterized for aggregation, viscosity, and hydrodynamic radius before and after storage at different temperatures (5°C, 25 °C, and 40 °C). Aggregation and viscosity of the solutions processed by TFF were higher than those processed by SCC upon storage at 25 °C and 40 °C for three months. Differential scanning fluorimetry (DSF) revealed differences in initial protein conformation. Upon exposure to shear stress, protein solutions showed conformational instability and increased aggregation upon storage at 35 °C. In addition, protein solution showed higher aggregation upon shearing under mixed (downstream purification process and final formulation) buffer conditions - which are more likely to be encountered during the TFF, but not SCC, process. These results were further confirmed in an independent experiment by Fourier transform-infrared (FT-IR) spectroscopy and aggregation analysis. Taken together, these data indicate that shearing the protein in intermediate, unstable buffer conditions can lead to conformational perturbation during TFF processing, which led to higher rate of aggregation and viscosity upon storage. This study highlights the importance of testing shear stress sensitivity in the transitional buffer states of the TFF process early in development to de-risk process related product instability.

Changes in Couple Relationship Dynamics among Low-Income Parents in a Relationship Education Program Are Associated with Decreases in Their Children's Mental Health Symptoms.

Witnessing intimate partner violence (IPV) among parents negatively impacts millions of children in the United States each year. Low-income families are disproportionately affected by IPV compared to middle- and high-income individuals, and are beginning to be the focus of IPV secondary prevention interventions, including relationship education programs. Despite these developments, few studies have examined changes in psychosocial functioning among children of parents participating in relationship education programs. The current study examined the extent to which changes in specific couple dynamics among individuals from low-income backgrounds participating in a couple relationship education program, Within My Reach, were associated with changes in child mental health symptoms. A second purpose of this paper is to examine whether changes in parent⁻child relationship quality mediates the association between changes in couple dynamics and changes in child mental health difficulties. Participants (n = 347) were parents who participated in Within My Reach as part of programming offered at a large community agency. Decreases in negative couple conflict behaviors, including conflict engagement, withdrawal and compliance, over the course of the program were linked to decreases in child mental health difficulties. In addition, increases in parent⁻child relationship quality partially mediated the associations between decreases in compliance, as well as increase in overall couple relationship quality, and decreases in child symptoms. Community-based couple relationship education programs for low-income families can potentially have multiple positive impacts throughout the family system, including for children.

An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices.

A High-Throughput Bioluminescent Assay to Monitor the Deamidation of Asparagine and Isomerization of Aspartate Residues in Therapeutic Proteins and Antibodies.

Since the introduction of Herceptin and Rituximab in 1986, therapeutic antibodies have gained tremendous momentum in the treatment of broad range of several diseases such as cancer and inflammation. Selection of the clinical candidate mAb usually starts with large-scale in vitro screening and profiling of multiple mAbs to identify candidates that show high in vitro or in vivo activity, and thus it is necessarily to identify and eliminate potentially unstable mAbs during the lead selection process. Antibodies undergo a variety of degradation reactions that may result in compromised bioactivity and safety profile. The nonenzymatic post-translational modification of both deamidation of asparagine and isomerization of aspartate residues is one of the major chemical reactions occurring in proteins during production and storage resulting in formation of protein variants that may affect the quality, safety, and functionality of the therapeutic proteins. Current methods (HPLC and liquid chromatography and mass spectrometry) for monitoring isoaspartate (isoAsp) formation are time consuming, require specialized equipment and trained personnel, and are not amenable to high-throughput scaling. We have developed a robust, homogenous, high-throughput formatted, and sensitive assay to accurately monitor the formation of isoAsp under several conditions, such as new formulations, storage periods, and temperature.

Investigating the Degradation Behaviors of a Therapeutic Monoclonal Antibody Associated with pH and Buffer Species.

This study aimed in understanding the degradation behaviors of an IgG 1 subtype therapeutic monoclonal antibody A (mAb-A) associated with pH and buffer species. The information obtained in this study can augment conventional, stability-based screening paradigms by providing the direction necessary for efficient experimental design. Differential scanning calorimetry (DSC) was used for studying conformational stability. Dynamic light scattering (DLS) was utilized to generate B 22*, a modified second virial coefficient for the character of protein-protein interaction. Size-exclusion chromatography (SEC) and hydrophobic interaction chromatography (HIC) were employed to separate degradation products. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used for determining the molecular size and liquid chromatography mass spectrometry (LC-MS) were used for identifying the sequence of the separated fragments. The results showed that both pH and buffer species played the roles in controlling the degradation behaviors of mAb-A, but the pH was more significant. In particular, pH 4.5 induced additional thermal transition peaks occurring at a low temperature compared with pH 6.5. A continual temperature-stress study illustrated that the additional thermal transition peaks related to the least stable structure and a greater fragmentation. Although mAb-A showed the comparable conformational structures and an identical amount of aggregates at time zero between the different types of buffer species at pH 6.5, the aggregation formation rate showed a buffer species-dependent discrepancy over a temperature-stress period. It was found that the levels of aggregations associated with the magnitudes of protein-protein interaction forces.

A Fluorescence-Based High-Throughput Coupled Enzymatic Assay for Quantitation of Isoaspartate in Proteins and Peptides.

Formation of isoaspartate (IsoAsp) from spontaneous asparagine (Asn) deamidation or aspartate (Asp) isomerization is one of the most common non-enzymatic pathways of chemical degradation of protein and peptide pharmaceuticals. Rapid quantitation of IsoAsp formation can enable rank-ordering of potential drug candidates, mutants, and formulations as well as support shelf life prediction and stability requirements. A coupled enzymatic fluorescence-based IsoAsp assay (CEFIA) was developed as a high-throughput method for quantitation of IsoAsp in peptides and proteins. In this note, application of this method to two therapeutic candidate proteins with distinct structural scaffolds is described. In addition, the results obtained with this method are compared to those from conventional assays.

Particle Characterization for a Protein Drug Product Stored in Pre-Filled Syringes Using Micro-Flow Imaging, Archimedes, and Quartz Crystal Microbalance with Dissipation.

Micro-flow imaging (MFI) has been used for formulation development for analyzing sub-visible particles. Archimedes, a novel technique for analyzing sub-micron particles, has been considered as an orthogonal method to currently existing techniques. This study utilized these two techniques to investigate the effectiveness of polysorbate (PS-80) in mitigating the particle formation of a therapeutic protein formulation stored in silicone oil-coated pre-filled syringes. The results indicated that PS-80 prevented the formation of both protein and silicone oil particles. In the case of protein particles, PS-80 might involve in the interactions with the hydrophobic patches of protein, air bubbles, and the stressed surfaces of silicone oil-coated pre-filled syringes. Such interactions played a role in mitigating the formation of protein particles. Subsequently, quartz crystal microbalance with dissipation (QCM-D) was utilized to characterize the interactions associated with silicone oil, protein, and PS-80 in the solutions. Based on QCM-D results, we proposed that PS-80 likely formed a layer on the interior surfaces of syringes. As a result, the adsorbed PS-80 might block the leakage of silicone oil from the surfaces to solution so that the silicone oil particles were mitigated at the presence of PS-80. Overall, this study demonstrated the necessary of utilizing these three techniques cooperatively in order to better understand the interfacial role of PS-80 in mitigating the formation of protein and silicone oil particles.

Travel-Associated Zika Virus Disease Cases Among U.S. Residents--United States, January 2015-February 2016.

Zika virus is an emerging mosquito-borne flavivirus. Recent outbreaks of Zika virus disease in the Pacific Islands and the Region of the Americas have identified new modes of transmission and clinical manifestations, including adverse pregnancy outcomes. However, data on the epidemiology and clinical findings of laboratory-confirmed Zika virus disease remain limited. During January 1, 2015-February 26, 2016, a total of 116 residents of 33 U.S. states and the District of Columbia had laboratory evidence of recent Zika virus infection based on testing performed at CDC. Cases include one congenital infection and 115 persons who reported recent travel to areas with active Zika virus transmission (n = 110) or sexual contact with such a traveler (n = 5). All 115 patients had clinical illness, with the most common signs and symptoms being rash (98%; n = 113), fever (82%; 94), and arthralgia (66%; 76). Health care providers should educate patients, particularly pregnant women, about the risks for, and measures to prevent, infection with Zika virus and other mosquito-borne viruses. Zika virus disease should be considered in patients with acute onset of fever, rash, arthralgia, or conjunctivitis, who traveled to areas with ongoing Zika virus transmission (http://www.cdc.gov/zika/geo/index.html) or who had unprotected sex with a person who traveled to one of those areas and developed compatible symptoms within 2 weeks of returning.

Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.

BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.

An Approach to Mitigate Particle Formation on the Dilution of a Monoclonal Antibody Drug Product in an IV Administration Fluid.

To support dose reduction, low dose of a monoclonal antibody (mAb) was required to be administered via IV infusion at a concentration of 0.1 mg/mL. To achieve the target protein concentration, the infusion solution was prepared by diluting the drug product containing 10-mg/mL mAb with normal saline, a 0.9% sodium chloride injection solution. However, particles were observed in the diluted solution. Particle formation must be avoided to administer the low dose using the existing drug product. To mitigate the particle formation, an unconventional compounding approach was used. With this approach, a stabilizing vehicle containing polysorbate-80 was added to saline before drug-product dilution to maintain suitable surfactant level to prevent precipitation of the mAb. In this way, use of the stabilizing vehicle to support low doses ensured suitable quality across a wider range of mAb concentrations, thereby allowing additional flexibility to the clinical trial. Such an approach may be useful for broader application in early-stage clinical trials where there is an uncertainty regarding doses or the need to revise to lower doses based on clinical observations or other drivers.