Multi-objective biopharma capacity planning under uncertainty using a flexible genetic algorithm approach

This paper presents a flexible genetic algorithm optimisation approach for multi-objective biopharmaceutical planning problems under uncertainty. The optimisation approach combines a continuous-time heuristic model of a biopharmaceutical manufacturing process, a variable-length multi-objective genetic algorithm, and Graphics Processing Unit (GPU)-accelerated Monte Carlo simulation. The proposed approach accounts for constraints and features such as rolling product sequence-dependent changeovers, multiple intermediate demand due dates, product QC/QA release times, and pressure to meet uncertain product demand on time. An industrially-relevant case study is used to illustrate the functionality of the approach. The case study focused on optimisation of conflicting objectives, production throughput, and product inventory levels, for a multi-product biopharmaceutical facility over a 3-year period with uncertain product demand. The advantages of the multi-objective GA with the embedded Monte Carlo simulation were demonstrated by comparison with a deterministic GA tested with Monte Carlo simulation post-optimisation

Fast genetic algorithm approaches to solving discrete-time mixed integer linear programming problems of capacity planning and scheduling of biopharmaceutical manufacture

The previous research work in the literature for capacity planning and scheduling of biopharmaceutical manufacture focused mostly on the use of mixed integer linear programming (MILP). This paper presents fast genetic algorithm (GA) approaches for solving discrete-time MILP problems of capacity planning and scheduling in the biopharmaceutical industry. The proposed approach is validated on two case studies from the literature and compared with MILP models. In case study 1, a medium-term capacity planning problem of a single-site, multi-suite, multi-product biopharmaceutical manufacture is presented. The GA is shown to achieve the global optimum on average 3.6 times faster than a MILP model. In case study 2, a larger long-term planning problem of multi-site, multi-product bio-manufacture is solved. Using the rolling horizon strategy, the GA is demonstrated to achieve near-optimal solutions (1% away from the global optimum) as fast as a MILP model

Modern day monitoring and control challenges outlined on an industrial-scale benchmark fermentation process

This paper outlines real-world control challenges faced by modern-day biopharmaceutical facilities through the extension of a previously developed industrial-scale penicillin fermentation simulation (IndPenSim). The extensions include the addition of a simulated Raman spectroscopy device for the purpose of developing, evaluating and implementation of advanced and innovative control solutions applicable to biotechnology facilities. IndPenSim can be operated in fixed or operator controlled mode and generates all the available on-line, off-line and Raman spectra for each batch. The capabilities of IndPenSim were initially demonstrated through the implementation of a QbD methodology utilising the three stages of the PAT framework. Furthermore, IndPenSim evaluated a fault detection algorithm to detect process faults occurring on different batches recorded throughout a yearly campaign. The simulator and all data presented here are available to download at www.industrialpenicillinsimulation.com and acts as a benchmark for researchers to analyse, improve and optimise the current control strategy implemented on this facility. Additionally, a highly valuable data resource containing 100 batches with all available process and Raman spectroscopy measurements is freely available to download. This data is highly suitable for the development of big data analytics, machine learning (ML) or artificial intelligence (AI) algorithms applicable to the biopharmaceutical industry

Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients

Background: The gut-brain axis and the intestinal microbiota are emerging as key players in health and disease. Shifts in intestinal microbiota composition affect a variety of systems; however, evidence of their direct impact on cognitive functions is still lacking. We tested whether faecal microbiota transplant (FMT) from aged donor mice into young adult recipients altered the hippocampus, an area of the central nervous system (CNS) known to be affected by the ageing process and related functions. Results: Young adult mice were transplanted with the microbiota from either aged or age-matched donor mice. Following transplantation, characterization of the microbiotas and metabolomics profiles along with a battery of cognitive and behavioural tests were performed. Label-free quantitative proteomics was employed to monitor protein expression in the hippocampus of the recipients. We report that FMT from aged donors led to impaired spatial learning and memory in young adult recipients, whereas anxiety, explorative behaviour and locomotor activity remained unaffected. This was paralleled by altered expression of proteins involved in synaptic plasticity and neurotransmission in the hippocampus. Also, a strong reduction of bacteria associated with short-chain fatty acids (SCFAs) production (Lachnospiraceae, Faecalibaculum, and Ruminococcaceae) and disorders of the CNS (Prevotellaceae and Ruminococcaceae) was observed. Finally, the detrimental effect of FMT from aged donors on the CNS was confirmed by the observation that microglia cells of the hippocampus fimbria, acquired an ageing-like phenotype; on the contrary, gut permeability and levels of systemic and local (hippocampus) cytokines were not affected. Conclusion: These results demonstrate that age-associated shifts of the microbiota have an impact on protein expression and key functions of the CNS. Furthermore, these results highlight the paramount importance of the gut-brain axis in ageing and provide a strong rationale to devise therapies aiming to restore a young-like microbiota to improve cognitive functions and the declining quality of life in the elderly

Clinical perspectives on secular trends of intervertebral foramen diameters in an industrialized European society

Low back pain origins have been a matter of great controversy. While spinal stenosis is now radiologically traceable, the alteration of intervertebral foramen is less clear. The aim of this study was to assess "secular trends"-alterations occurring from one generation to the next-in osseous intervertebral foramina of the major vertebral segments in an industrialized society, and to discuss their possible clinical implication. The macerated "maximum intervertebral foramen width" and "intervertebral foramen height" of all major vertebral levels in 71 non-pathologic Swiss adult skeletons from the nineteenth and early twentieth century, with known individual age and sex and similar geographic and socio-economic background, were measured by sliding caliper at validated landmarks. A secular trend of the increase in "maximum intervertebral foramen width" is found for most levels, with females showing a more prominent alteration. Additionally, the non-pathologic "maximum intervertebral foramen width" does not change with respect to individual age, nor is a significant side difference detectable. "Intervertebral foramen height," hereby defined as the difference of the dorsal vertebral body height minus pedicle height, demonstrates for most levels, and either sex, an insignificant negative secular trend. Neither stature nor skeletal robustness vary significantly through time within this particular sample. The results of this study, despite obvious inadequacies of methods used, exclude secular narrowing of the "maximum intervertebral foramen width" as the only cause of radiculopathy or spinal stenosis. Furthermore, we found a mild insignificant decrease of the clinically more relevant "intervertebral foramen height." Nevertheless, the detected short-time variability of the bony intervertebral foramen, independent of individual stature, skeletal robustness or age, argues for an enhanced focus on the understanding of clinically relevant changes of spinal morphology from generation to generation