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Acetonitrile Regeneration from Oligonucleotide Production Waste Streams
No full textA distillation concept is described to process organic and aqueous waste streams from an oligonucleotide process to regenerate 85% of the acetonitrile contained in the wastes, for re-introduction back into the oligonucleotide process. Careful selection of the streams to send to regeneration based on their acetonitrile content was shown to simplify the number of processing steps and minimize the size of the equipment required for regeneration. Availability of accurate vapor-liquid equilibrium was shown key to designing the number of processing steps, the operating conditions and to calculate purification performance. A modified classical two-column distillation pressure-swing dewatering system, with an intermediate-pressure column for separation of light boilers was shown to effectively purify and dewater acetonitrile to the required specifications. Use is made of AspenPlus software to generate VLE data and simulate process alternatives
Waiting for surgery after hip fracture-Health and/or economic risk?
No full textObjectives: Waiting for surgery is a disconcerting experience. It can have a negative impact on patients' outcomes and length of stay (LOS) as driver for treatment costs. Process-optimisation may be a strategy to improve quality and cost-efficacy. The study investigates the correlation between waiting for hip fracture surgery and patient characteristics, organisational variables, outcomes, LOS, and the distribution of waiting times and LOS over time, including cost estimates. Thereby the study aims to identify the potential for organisational improvements with respect to managing the waiting time.
Methods: Ten-year routine health data (patient characteristics and follow-up information) and process-indicators that is, waiting time and LOS from a Swiss trauma-centre were analysed retrospectively. Cost-estimates were calculated based on Swiss diagnosis related groups and daily costs to evaluate hospital revenues.
Results: In total, 2572 patients aged ≥60 years with low-energy hip fractures were included. Waiting times >48 h were associated with sub-optimal outcomes. Over the years long waiting times decreased. This reduction was not reflected by a reduction in LOS which remained stable around 10 days, primarily driven by late discharge to in-patient rehabilitation. Reimbursement persisted at an average revenue in the low 4-5-digit range, depending on implant costs.
Conclusions: While there has been a reduction of waiting times, this has not translated into a reduction of LOS or potential savings in health care costs, due to the various dependencies along the patient journey. Managing waiting times may be an area for improvement, increasing cost-efficacy, especially since long waiting times are still associated with inferior outcomes and LOS
A General Three-Component Alkyl Petasis Boron-Mannich Reaction.
No full textAryl amines are one of the most common moieties in biologically active molecules, and approximately 37% of drug candidates contain aromatic amines. Recent advancements in medicinal chemistry, coined "escaping from flatland", have led to a greater focus on accessing highly functionalized C (sp3)-rich amines to improve the physicochemical and pharmacokinetic properties of compounds. This article presents a modular and operationally straightforward three-component alkyl Petasis boron-Mannich (APBM) reaction that utilizes ubiquitous starting materials, including amines, aldehydes, and alkyl boronates. By adaptation of this transformation to high-throughput experimentation (HTE), it offers rapid access to an array of diverse C(sp3)-rich complex amines, amenable for rapid identification of drug candidates
Chimia column: DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
No full textProteolysis Targeting Chimeras (PROTACs) revolutionize drug development by redirecting E3 ligases to ubiquitinate and degrade specific proteins. Curiously, the pivotal ligase CRBN is observed to decline in scenarios of resistance to immunomodulatory inhibitory drugs (IMiDs). This study explores the potential of utilizing the E3 ligase receptor DCAF1, employing a non-covalent DCAF1 binder transformed into a PROTAC E3 ligase anchor. Validation through chemical and genetic experiments confirms specific degradation via the CRL4 E3 ligase. This innovative strategy could provide an alternative to overcome predicted resistance against of CRBN-targeting PROTACS in clinical settings, shedding light on the promising prospect of leveraging DCAF1 for targeted protein degradation in drug development.
The here described DCAF1 ligands expand the spectrum of usable tool compounds to further investigate DCAF1 cellular functions and its potential as a ligase for TPD
Adenosine-mediated immune responses in inflammatory bowel disease.
No full textExtracellular ATP and its derivates mediate a signaling pathway that might be pharmacologically targeted to treat inflammatory conditions. Extracellular adenosine, the product of ATP hydrolysis by ectonucleotidase enzymes, plays a key role in halting inflammation while promoting immune tolerance. The rate-limiting ectoenzyme ENTPD1/CD39 and the ecto-5'-nucleotidase/CD73 are the prototype members of the ectonucleotidase family, being responsible for ATP degradation into immunosuppressive adenosine. The biological effects of adenosine are mediated via adenosine receptors, a family of G protein-coupled receptors largely expressed on immune cells where they modulate innate and adaptive immune responses. Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract, associated with substantial morbidity and often refractory to currently available medications. IBD is linked to altered interactions between the gut microbiota and the immune system in genetically predisposed individuals. A wealth of studies conducted in patients and animal models highlighted the role of various adenosine receptors in the modulation of chronic inflammatory diseases like IBD. In this review, we will discuss the most recent findings on adenosine-mediated immune responses in different cell types, with a focus on IBD and its most common manifestations, Crohn's disease and ulcerative colitis
Preclinical mitigation of 5-HT2B agonism-related cardiac valvulopathy revisited
No full textCardiac valvulopathy (Cardiac Valve Disease; CVD) associated with off-target activation of the 5-hydroxytryptamine (5-HT) 2B receptor has been well recognized, however still today, poorly predicted during drug development. The regulatory guidance proposes the use of 5-HT2B binding data (i.e., Kis values) and of the free maximal therapeutic exposure, Cmax, to calculate safety margins as a threshold of detection (>10) for eliminating the risk of drug-induced cardiac valvulopathy. In this paper, we provide additional recommendations for preclinical prediction of CVD risk based on clinical pharmacodynamic and pharmacokinetic data obtained from drugs with or without 5-HT2B receptor activation. Our investigations showed that 5-HT2B agonist affinity of molecules tested in an in vitro 5-HT2B cell-based functional assay, placed in perspective to their sustained plasma exposure, AUCs (i.e., Area Under the Curve) and not to their peak plasma exposure, Cmax (i.e., maximum therapeutic exposure) provide a solid basement for interpreting 5-HT2B data, for calculating safety margins and then, accurately differentiating drugs associated to a clinical risk of CVD from those which are not (despite for some agonist 5-HT2B activities). In addition, we discuss the risk of multi-organ fibrosis linked to 5-HT2B receptor activation, often underestimated, however well reported in FAERs for 5-HT2B agonists. We believe that our recommendations have the potential to optimize the prevention the clinical development of CVD and fibrosis
Acetonitrile Regeneration from Oligonucleotide Production Waste Streams
No full textA distillation concept is described to process organic and aqueous waste streams from an oligonucleotide process to regenerate 85% of the acetonitrile contained in the wastes, for re-introduction back into the oligonucleotide process. Careful selection of the streams to send to regeneration based on their acetonitrile content was shown to simplify the number of processing steps and minimize the size of the equipment required for regeneration. Availability of accurate vapor-liquid equilibrium was shown key to designing the number of processing steps, the operating conditions and to calculate purification performance. A modified classical two-column distillation pressure-swing dewatering system, with an intermediate-pressure column for separation of light boilers was shown to effectively purify and dewater acetonitrile to the required specifications. Use is made of AspenPlus software to generate VLE data and simulate process alternatives
2023 White Paper on Recent Issues in Bioanalysis: EU IVDR 2017/746 Implementation/Impact, IVD/CDx/CLIA Approved Assays, High Dimensional Cytometry, Multiplexing Technologies, LBA Tissue Analysis, Vaccine Study Endpoints, Cell-Based Assays for Biomarkers, Cell Therapy and Vaccines (PART 2 - Recommendations on Development & Validation of Biomarkers, IVD, CDx, Cell-Based, Flow Cytometry, Ligand-Binding and Enzyme Assays; Advanced Critical Reagents Strategies).
No full textThe 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on 19-23 June 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with these NEW Regulations" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication (Part 2) covers the recommendations on Biomarkers, IVD/CDx, LBA and Cell-Based Assays. Part 1A (Mass Spectrometry Assays and Regulated Bioanalysis/BMV), P1B (Regulatory Inputs) and Part 3 (Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity) are published in volume 16 of Bioanalysis, issues 9 and 7 (2024), respectively
Forced randomization: the what, why, and how.
No full textWhen running a randomized controlled trial (RCT), a clinical site may face a situation when an eligible trial participant is to be randomized to the treatment that is not available at the site. In this case, there are two options: not to enroll the participant, or, without disclosing to the site, allocate the participant to a treatment arm with drug available at the site using a built-in feature of the interactive response technology (IRT). In the latter case, one has employed a "forced randomization" (FR). There seems to be an industry-wide consensus that using FR can be acceptable in confirmatory trials provided there are "not too many" instances of forcing. A better understanding of statistical properties of FR is warranted.We described four different IRT configurations with or without FR and illustrated them using a simple example. We discussed potential merits of FR and outlined some relevant theoretical risks and risk mitigation strategies. We performed a search using Cortellis Regulatory Intelligence database (IDRAC) ( www.cortellis.com ) to understand the prevalence of FR in clinical trial practice. We also proposed a structured template for development and evaluation of randomization designs featuring FR and showcased an application of this template for a hypothetical multi-center 1:1 RCT under three experimental settings ("base case", "slower recruitment", and "faster recruitment") to explore the effect of four different IRT configurations in combination with three different drug supply/re-supply strategies on some important operating characteristics of the trial. We also supplied the Julia code that can be used to reproduce our simulation results and generate additional results under user-specified experimental scenarios.FR can eliminate refusals to randomize patients, which can cause frustration for patients and study site personnel, improve the study logistics, drug supply management, cost-efficiency, and recruitment time. Nevertheless, FR carries some potential risks that should be reviewed at the study planning stage and, ideally, prospectively addressed through risk mitigation planning. The Cortellis search identified only 9 submissions that have reported the use of FR; typically, the FR option was documented in IRT specifications. Our simulation evidence showed that under the considered realistic experimental settings, the percentage of FR is expected to be low. When FR with backfilling was used in combination with high re-supply strategy, the final treatment imbalance was negligibly small, the proportion of patients not randomized due to the lack of drug supply was close to zero, and the time to complete recruitment was shortened compared to the case when FR was not allowed. The drug overage was primarily determined by the intensity of the re-supply strategy and to a smaller extent by the presence or absence of the FR feature in IRT.FR with a carefully chosen drug supply/re-supply strategy can result in quantifiable improvements in the patients' and site personnel experience, trial logistics and efficiency while preventing an undesirable refusal to randomize a patient and a consequential unblinding at the site. FR is a useful design feature of multi-center RCTs provided it is properly planned for and carefully implemented