Current Industry Best Practice on in-use Stability and Compatibility Studies for Biological Products.

Evaluating the in-use stability of a biological product including its compatibility with administration components allows to define handling instructions and potential hold times that retain product quality during dose preparation and administration. The intended drug product usage may involve the dilution of drug formulation into admixtures for infusion and exposure to new interfaces of administration components like intravenous (iv) bags, syringes, and tubing. In-use studies assess the potential impact on product quality by simulating drug handling throughout the defined in-use period. Considering the wide range of in-use conditions and administration components available globally, only limited guidance is available from regulators on expected in-use stability data. A working group reviewed and consolidated industry approaches to assess physicochemical stability of traditional protein-based biological products during clinical development and for commercial use. The insights compiled in this review article can be leveraged across the industry and encompass topics such as representative drug product material and administration components, testing conditions, quality attributes evaluated and respective acceptance criteria, applied quality standards, and regulatory requirements. These practices may help companies in the study design, and they may inform discussions with global regulators.

Industry Perspective on the Use and Characterization of Polysorbates for Biopharmaceutical Products Part 2: Survey Report on Control Strategy Preparing for the Future.

Polysorbate (PS) 20 and 80 are the main surfactants used to stabilize biopharmaceutical products. Industry practices on various aspects of PS based on a confidential survey and following discussions by 16 globally acting major biotechnology companies is presented in two publications. Part 1 summarizes the current practice and use of PS during manufacture in addition to aspects like current understanding of the (in)stability of PS, the routine QC testing and control of PS, and selected regulatory aspects of PS.1 The current part 2 of the survey focusses on understanding, monitoring, prediction, and mitigation of PS degradation pathways in order to propose an effective control strategy. The results of the survey and extensive cross-company discussions are put into relation with currently available scientific literature.

Industry Perspective on the use and Characterization of Polysorbates for Biopharmaceutical Products Part 1: Survey Report on Current State and Common Practices for Handling and Control of Polysorbates.

Polysorbates (PS) are widely used as a stabilizer in biopharmaceutical products. Industry practices on various aspects of PS are presented in this part 1 survey report based on a confidential survey and following discussions by 16 globally acting major biotechnology companies. The current practice and use of PS during manufacture across their global manufacturing sites are covered in addition to aspects like current understanding of the (in)stability of PS, the routine QC testing and control of PS, and selected regulatory aspects of PS. The results of the survey and extensive cross-company discussions are put into relation with currently available scientific literature. Part 2 of the survey report (upcoming) will focus on understanding, monitoring, prediction, and mitigation of PS degradation pathways to develop an effective control strategy.

Alcohol and substance use in multiple sclerosis.

BACKGROUND: Few studies have examined the prevalence of alcohol and drug use in individuals with multiple sclerosis (MS). The current study sought to examine the prevalence and associated demographic, disease-related, and psychological correlates of substance use in an East Coast United States outpatient MS sample. METHODS: 157 individuals with MS completed questionnaires prior to, during or after their visit with an MS neurologist. These questionnaires included: the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), CAGE, CAGE-Adapted to Include Drugs (CAGE-AID), Patient Health Questionnaire-9 item (PHQ-9), Beck Depression Inventory-Second Edition (BDI-II) and Hospital Anxiety and Depression Scale-Anxiety (HADS-A). RESULTS: On the AUDIT-C, 40% of individuals with MS met or exceeded the cutoff for excessive alcohol use. They were more highly educated and younger than non-drinkers. Utilizing the CAGE, 6% of the sample met criteria for a lifetime history of excessive alcohol use and men endorsed higher rates of alcohol use than women. Only a small portion of the sample endorsed a history of drug use (CAGE-AID, 4%). Drug use was associated with greater disability and depression symptoms, but lower self-reported anxiety. CONCLUSIONS: Current alcohol use was prevalent in this sample, and excessive use was associated with men, younger age, and more education. Reported drug use was minimal and associated with greater disability, more self-reported depression, but fewer anxiety symptoms.

Learning and cognitive fatigue trajectories in multiple sclerosis defined using a burst measurement design.

BACKGROUND: Compromised learning and cognitive fatigue are critical clinical features in multiple sclerosis. OBJECTIVES: This study was designed to determine the effect of repeated exposures within and across study visits on performance measures of learning and cognitive fatigue in relapsing-remitting multiple sclerosis (RRMS). METHODS: Thirty patients with RRMS and 30 controls were recruited. Using a burst measurement design (i.e. repeated assessments within and across study visits) the oral version of the Symbol Digit Modalities Test (SDMT) was administered three times during the baseline and two consecutive monthly follow-up visits for a total of nine test administrations. Learning was assessed within and across study visits whereas cognitive fatigue was assessed during the course of each test administration that was divided into three 30-second intervals. RESULTS: Linear mixed-effect models revealed compromised learning within (95% CI: 2.6355 to 3.9867) and across (95% CI: 1.3250 to 3.1861) visits and worse cognitive fatigue (95% CI: -2.1761 to -0.1720) in patients with RRMS compared with controls. Among patients with RRMS, worse self-rated cognitive dysfunction predicted poor learning within (95% CI: -0.1112 to -0.0020) and across (95% CI: -0.0724 to -0.0106) visits. CONCLUSIONS: Burst design is optimal to study learning and cognitive fatigue. This methodology, using the SDMT or other time-efficient tests as outcome measures, can be successfully implemented in longitudinal studies and clinical trials.

Cognitive fatigue defined in the context of attention networks.

We examined the effect of cognitive fatigue on the Attention Networks Test (ANT). Participants were 228 non-demented older adults. Cognitive fatigue was operationally defined as decline in alerting, orienting, and executive attention performance over the course of the ANT. Anchored in a theoretical model implicating the frontal basal ganglia circuitry as the core substrate of fatigue, we hypothesized that cognitive fatigue would be observed only in executive attention. Consistent with our prediction, significant cognitive fatigue effect was observed in executive attention but not in alerting or orienting. In contrast, orienting improved over the course of the ANT and alerting showed a trend, though insignificant, that was consistent with learning. Cognitive fatigue is conceptualized as an executive failure to maintain and optimize performance over acute but sustained cognitive effort resulting in performance that is lower and more variable than the individual's optimal ability.

Final adult height of children with inflammatory bowel disease is predicted by parental height and patient minimum height Z-score.

BACKGROUND: This study was designed to elucidate the contribution of parental height to the stature of children with inflammatory bowel disease (IBD), who often exhibit growth impairment. Accordingly, we compared patients' final adult heights and target heights based on measured parental heights and examined predictors of final adult height in pediatric IBD patients. METHODS: We prospectively analyzed the growth of 295 patients diagnosed between ages 1 and 18 (211 Crohn's disease [CD], 84 ulcerative colitis [UC]) and their family members (283 mothers, 231 fathers, 55 siblings). RESULTS: Twenty-two percent had growth impairment (height for age Z-score <-1.64, equivalent to <5th percentile on growth curve) in more than 1 measurement since diagnosis; most growth-impaired patients had CD (88% CD versus 12% UC). Parents of the growth-impaired group had lower mean height Z-scores compared to parents of nongrowth-impaired patients (-0.67 versus 0.02 for mothers [P < 0.001]; -0.31 versus 0.22 for fathers [P = 0.002]). For 108 patients who reached adult heights and had available parental heights, the growth-impaired group continued to demonstrate lower adult height Z-scores (-1.38 versus 0.07; P < 0.001). Adult heights were within 1 SD of target heights even for the growth-impaired group. Only 11.3% remained persistently growth-impaired in adulthood. Multivariate regression analysis demonstrated lower parental height and minimum patient height Z-score as significant predictors of lower final adult height in IBD. CONCLUSIONS: Parental height is a powerful determinant of linear growth even in the presence of chronic inflammation, and should be an integral part of the evaluation of growth in IBD children.