Application of quality by design concepts and automation to improve manufacturing process consistency of development and clinical-stage cell therapies

Designing manufacturing processes to reproducibly generate process-sensitive human cells of sufficient quantity and quality for clinical application is challenging and complex. Manufacture of cell therapies in manual flask based processes is controlled primarily through adherence to detailed SOPs which may contain subjective user interventions and relatively poorly defined operating controls. This situation can lead to clinical production processes with limited control of critical quality attributes, significant reliance on endpoint quality testing and consequent product wastage. Applying systematic and data driven approaches to process development, many of which form part of the Quality by Design (QbD) toolset, reduces manufacturing process risk. We have applied these approaches with a series of partners and cell types to demonstrate application of QbD tools to cell therapies. This includes statistical capability analysis to define process confidence limits for expansion processes, to identify sources of process variability, and to quantify process performance in relation to the process specification and necessary scale. This further enables risk assessment and gap analysis to identify and prioritise key manufacture process risks with common recurrent elements including input materials, cryo-strategy, and operational parameters pertaining to culture and medium supply strategy. Key variable screening via statistically designed experiments has enabled improvement in process consistency across multiple operations and an improved understanding of process tolerance to parameter levels. It also highlights where automation could be applied to enhance process reproducibility and increase process scale whilst retaining process format with comparability to prior manufacturing development. CompacT SelecT automated manufacturing processes have demonstrated consistently greater cell yields than manual processes with statistical analysis showing significantly improved confidence intervals between multiple production batches and facilitating identification of remaining sources of variation for further targeted process improvement. Example case studies include a partnership with ReNeuron, a UK-based stem cell therapy business currently undergoing a phase II clinical trial with its CTX cell therapy candidate to enhance motor recovery in disabled stroke patients, to develop scalable robust production processes for the CTX cell line

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries