Silylacetate-promoted addition reaction of isocyanides to nitrones: effective synthesis of C(1)-carboxamide derivatives.

We report an efficient method for the synthesis of C(1)-carboxamide derivatives by adding isocyanides to 3,4-dihydroisoquinoline N-oxides and 3,4-dihydro-ß-carboline 2-oxide in the presence of TMSOAc. 3,4-Dihydroisoquinoline-1-carboxylamide derivatives and 9-dihydro-3H-pyrido[3,4-b]indole-1-carboxamide derivatives were obtained in reasonable yields. The method could be used to synthesize alangiobussine, an alkaloid, in 61% yield.

Computer-aided exploration of multiobjective optimal temperature profiles in slow freezing for human induced pluripotent stem cells.

Human induced pluripotent stem (hiPS) cells have demonstrated promising potential in regenerative medical therapeutics. After successful clinical trials, the demand for hiPS cells has steadily increased. Therefore, the optimization of hiPS cell freezing processes for storage and transportation is essential. Here, we presented a computer-aided exploration of multiobjective optimal temperature profiles in slow freezing for hiPS cells. This study was based on a model that calculates cell survival rates after thawing, and the model was extended to evaluate cell potentials until 24 h after seeding. To estimate parameter values for this extension, freezing experiments were performed using constant cooling rates. Using quality and productivity indicators, we evaluated 16,206 temperature profiles using our model, and a promising profile was obtained. Finally, an experimental investigation of the profile was undertaken, and the contribution of the temperature profile to both quality and productivity was confirmed.

Clinical Impact of Malnutrition According to the Global Leadership Initiative on Malnutrition Criteria Combined With Kidney Dysfunction to Determine Mortality in Inpatients.

OBJECTIVE: The clinical impact of malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria in patients with kidney dysfunction remains poorly understood. This study investigated the usefulness of GLIM criteria for malnutrition in predicting mortality in patients with kidney dysfunction and different clinical renal states, including no kidney disease (NKD), acute kidney injury (AKI), and chronic kidney disease (CKD). METHODS: This single-center retrospective cohort study included 6,712 patients aged ≥18 admitted between 2018 and 2019. The relationship between the estimated glomerular filtration rate (eGFR) groups, nutritional status based on the GLIM criteria, and the incidence of all-cause mortality was evaluated using a multivariate Cox proportional hazards model. Malnutrition was defined as at least one phenotype (weight loss, low body mass index, or reduced muscle mass) and one etiological criterion (reduced intake/assimilation or disease burden/inflammation). RESULTS: Multivariate Cox proportional hazards model showed that eGFR ≤29 (vs. eGFR: 60-89, adjusted hazard ratio [HR] = 1.84, 95% confidence interval [CI]: 1.52-2.22), 30-59 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.20-1.64), and ≥90 (vs. eGFR: 60-89, adjusted HR = 1.40, 95% CI: 1.14-1.71), moderate and severe malnutrition (vs. without malnutrition, adjusted HR = 1.38 [1.18-1.62] and 2.18 [1.86-2.54], respectively) were independently associated with the incidence of death. The all-cause mortality rate was higher in patients with malnutrition or eGFR ≤29 (adjusted HR, 3.31; 95% CI: 2.51-4.35) than in patients without malnutrition or eGFR 60-89. Furthermore, moderate and severe malnutrition (vs. no malnutrition) was independently associated with death in patients with NKD, AKI, and CKD. CONCLUSION: Malnutrition based on the GLIM criteria was associated with increased all-cause mortality in inpatients, and malnutrition combined with kidney dysfunction was associated with a higher risk of mortality. Furthermore, patients with NKD, AKI, and CKD showed an association between malnutrition based on GLIM criteria and mortality.

Association of alcohol consumption with the incidence of proteinuria and chronic kidney disease: a retrospective cohort study in Japan.

BACKGROUND: The difference in the clinical impact of alcohol consumption on kidney function based on sex remains to be elucidated. This study aimed to assess the association between the dose of alcohol consumption and the incidence of proteinuria and chronic kidney disease stratified by sex. METHODS: This retrospective cohort study included 26,788 workers (19,702 men and 7086 women) with normal renal function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2) at annual health examinations between January 2010 and March 2015 in Japan. The main exposure was alcohol consumption. The primary outcomes were the incidence of proteinuria (dipstick urinary protein ≥ 1) and incidence of low estimated glomerular filtration rate (eGFR; rate < 60 mL/min per 1.73 m2; decreased from the baseline eGFR by 25%). RESULTS: During a median observational period of 4 years (interquartile range: 2-6), 1993 (10.1%) men and 462 (6.5%) women developed proteinuria, whereas 667 (3.4%) men and 255 (3.6%) women developed low eGFR. After adjustment for clinically relevant factors using a Cox proportional hazards model, alcohol consumption of ≥ 46 g/day in females was significantly associated with the incidence of proteinuria (hazard ratio, 1.57; 95% confidence interval, 1.10-2.26) and low eGFR (hazard ratio, 1.62; 95% confidence interval, 1.04-2.53). However, no significant association between alcohol consumption and primary outcomes was observed in men. CONCLUSIONS: In conclusion, daily higher alcohol consumption was significantly associated with a higher incidence of proteinuria and low eGFR among women. Women might be prone to high alcohol consumption with kidney dysfunction.

Time to normalisation of CRP and incidence of relapse in microscopic polyangiitis: A medical records review study in Japan.

OBJECTIVES: Despite the identification of risk factors for relapses in anti-neutrophil cytoplasmic antibody-associated vasculitis, the relationship between changes in C-reactive protein levels after initial treatment and incidence of relapse remains unknown. This study aimed to assess the association between the time taken for normalisation of C-reactive protein levels and the incidence of relapse in Japanese adult patients with microscopic polyangiitis. METHODS: This study included 85 consecutive patients with newly diagnosed microscopic polyangiitis who achieved remission after six months of immunosuppressive treatment at the Aichi Medical University Hospital, between 2009 and 2017. The relationship between the time to normalisation of C-reactive protein after initial immunosuppressive treatment and relapse incidences was evaluated using multivariable Cox proportional hazard models. RESULTS: During the follow-up period, 13 (30.2%), 7 (41.2%), and 16 (64.0%) patients relapsed (P=0.025) within 1-14, 15-28, and ≥29 days of normalisation, respectively. Hazard ratios (95% confidence intervals) of the time to normalisation of C-reactive protein of 1-14, 15-28, and ≥29 days were 1.00 (reference), 2.42 (95%CI: 0.92-6.39), and 3.48 (95%CI: 1.56-7.76), respectively. CONCLUSIONS: A significant association between the time to normalisation of C-reactive protein and relapse incidence in Japanese patients with microscopic polyangiitis was observed.

Computational screening of cryoprotective agents for regenerative medical products using quantum chemistry and molecular dynamics simulations.

Cryoprotective agents (CPAs) are essential for the cryopreservation of cells. Thus far, dimethyl sulfoxide (DMSO) has been widely used as a CPA; however, DMSO is known to be toxic to cells. The damaged cells by the toxicity can present abnormal conditions, and should not be used for regenerative medical products because the cells/products are implanted directly into human bodies. With the aim of searching for an alternative CPA to DMSO, this work presents a computational screening of CPA candidate compounds using quantum chemistry and molecular dynamics (MD) simulations. Forty compounds were evaluated in regard to the solvation free energy and partition coefficient by quantum chemistry simulation and the root mean square deviation (RMSD) of a phospholipid bilayer which composes a cell membrane by MD simulation. The solvation free energy, partition coefficient, and RMSD were defined as indicators of osmoregulatory ability, affinity with a cell membrane, and ability to spread a cell membrane, respectively. The quantum chemistry simulation elucidated that the six compounds of trimethylglycine, formamide, urea, thiourea, diethylene glycol, and dulcitol were better than DMSO in either or both of the physical properties considered. This finding is based on the inherent physical property and is thus case-independent. Further characterization with the MD simulation suggested that formamide, thiourea, and urea should be the first candidates to investigate, although the result was valid only in the simulated condition. This work serves as the first step of multi-faceted computational evaluation of multiple compounds in the search for an effective CPA compound after DMSO.

Association between body mass index and severe infection in older adults with microscopic polyangiitis: a retrospective cohort in Japan.

BACKGROUND: Although previous studies have evaluated risk factors for the incidence of severe infection in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), the relationship between body mass index (BMI) and severe infection in AAV has not been elucidated. We hypothesized that older adults with AAV and a low BMI would be at a higher risk of infection. We therefore investigated the association between underweight status at AAV diagnosis and subsequent occurrence of severe infection in older adults with AAV. METHODS: This single-center retrospective cohort study included 93 consecutive older adults with microscopic polyangiitis (MPA) treated at the Aichi Medical University Hospital in Japan between 2004 and 2018. The relationships between BMI at diagnosis and subsequent first severe infection were assessed using multivariate Cox proportional hazards models. The cumulative probability of the development of the first severe infection was calculated using the Kaplan-Meier method and the log-rank test. The level of statistical significance was set at P <  0.05. RESULTS: During the median follow-up period of 19 (6-53) months, 29 (31.2%) patients developed at least one severe infection. Older age (adjusted hazard ratio [HR] = 2.02, 95% confidence interval [CI]: 1.14-3.52, per 10 years; P =  0.016), low BMI (< 18.5 kg/m2 compared with normal BMI [18.5-23.0 kg/m2], adjusted HR =  2.63, 95% CI: 1.11-6.19; P =  0.027), and use of methylprednisolone pulse therapy (adjusted HR = 2.48, 95% CI: 1.07-5.76; P =  0.034) were found to be significant predictors of severe infection. CONCLUSIONS: Low BMI was associated with a higher risk of severe infection in older adults with MPA, suggesting that careful management may be required to prevent this complication in this vulnerable group. Further studies are needed to elucidate the optimal treatment strategy for these patients.

Prediction Performance and Economic Efficiency of Soft Sensors for in-Line Water Content Monitoring in Fluidized Bed Granulation: PP-Based Model vs. NIRS-Based Model.

Soft sensors play a crucial role as process analytical technology (PAT) tools. They are classified into physical models, statistical models, and their hybrid models. In general, statistical models are better estimators than physical models. In this study, two types of standard statistical models using process parameters (PPs) and near-infrared spectroscopy (NIRS) were investigated in terms of prediction accuracy and development cost. Locally weighted partial least squares regression (LW-PLSR), a type of nonlinear regression method, was utilized. Development cost was defined as the cost of goods required to construct an accurate model of commercial-scale equipment. Eleven granulation lots consisting of three laboratory-scale, two pilot-scale, and six commercial-scale lots were prepared. Three commercial-scale granulation lots were selected as a validation dataset, and the remaining eight granulation lots were utilized as calibration datasets. The results demonstrated that the PP-based and NIRS-based LW-PLSR models achieved high prediction accuracy without using the commercial-scale data in the calibration dataset. This practical case study clarified that the construction of accurate LW-PLSR models requires the calibration samples with the following two features: 1) located near the validation samples on the subspace spanned by principal components (PCs), and 2) having a wide range of variations in PC scores. In addition, it was confirmed that the reduction in cost and mass fraction of active pharmaceutical ingredient (API) made the PP-based models more cost-effective than the NIRS-based models. The present work supports to build accurate models efficiently and save the development cost of PAT.

Approach to Establishment of Control Strategy for Oral Solid Dosage Forms Using Continuous Manufacturing.

As a result of the research activities of the Japan Agency for Medical Research and Development (AMED), this document aims to show an approach to establishing control strategy for continuous manufacturing of oral solid dosage forms. The methods of drug development, technology transfer, process control, and quality control used in the current commercial batch manufacturing would be effective also in continuous manufacturing, while there are differences in the process development using continuous manufacturing and batch manufacturing. This document introduces an example of the way of thinking for establishing a control strategy for continuous manufacturing processes.

Relationship between doses of antihypertensive drugs and left ventricular mass index changes in hemodialysis patients in a Japanese cohort.

Left ventricular hypertrophy commonly occurs in dialysis patients and is associated with a risk of developing cardiovascular disease events and all-cause mortality. Although hypertension treatment reduces left ventricular mass index (LVMI) in hemodialysis patients, the relationships of prescription pattern, dose, and changes in the dose of antihypertensive drugs with LVMI have not been completely elucidated. Here, we hypothesized that volume reduction would lead to a decrease in the antihypertensive drug dose and subsequently to a reduction in LVMI; conversely, fluid retention would lead to an increase in the antihypertensive drug use and, subsequently, to LVMI progression. To assess this hypothesis, we investigated the relationship between changes in the dose of antihypertensive drugs and subsequent changes in LVMI in 240 patients who had just started hemodialysis using a retrospective hemodialysis cohort in Japan. Using multiple linear regression analysis, we assessed the association between changes in the antihypertensive drug dose over 1 year after hemodialysis initiation and changes in LVMI during this period. A decrease and an increase in the antihypertensive drug dose were significantly associated with a reduction in LVMI (vs. no change; ß  = - 17.386, p < .001) and LVMI progression (vs. no change; ß  = 16.192, p < .001), respectively. In conclusion, our findings suggested that volume reduction, leading to a decrease in the use of antihypertensive drugs, is a therapeutic strategy in patients undergoing hemodialysis to prevent LVMI progression.

[A case of stage IV b pancreatic head cancer that was resected because of a good response to chemotherapy].

The prognosis of Stage IV b pancreatic cancer is extremely poor; the mean survival time is 2-4 months. However, new anticancer agents can improve the outcome of advanced pancreatic cancer. We present the case of a 50-year-old female patient with Stage IV b pancreatic head cancer with invasion to the superior mesenteric vein(SMV)and multiple liver metastases. The patient received S-1 as first-line chemotherapy. Three months later, a further CT scan showed reduction of the pancreatic tumor, disappearance of the liver metastases, and reduction in SMV invasion. Therefore, a subtotal stomach-preserving pancreatoduodenectomy with partial SMV resection was performed. Following surgery, the patient received S-1 chemotherapy again. However, lung metastasis appeared. Despite the initiation of gemcitabine(GEM)treatment, the patient developed metastases in other parts of the lung and the abdominal wall. She died 46 months after surgery, but it is noteworthy that the liver metastases were manageable. The combination of chemotherapy and surgery was effective in prolonging survival in this patient with Stage IV b pancreatic head cancer.

Interaction of Necl-4/CADM4 with ErbB3 and integrin α6 ß4 and inhibition of ErbB2/ErbB3 signaling and hemidesmosome disassembly.

Nectin-like molecule 4 (Necl-4)/CADM4, a transmembrane cell-cell adhesion molecule with three Ig-like domains, was shown to serve as a tumor suppressor, but its mode of action has not been elucidated. In this study, we showed that Necl-4 interacted in cis with ErbB3 through their extracellular regions, recruited PTPN13 and inhibited the heregulin-induced activation of the ErbB2/ErbB3 signaling. In addition, we extended our previous finding that Necl-4 interacts in cis with integrin α6 ß4 through their extracellular regions and found that Necl-4 inhibited the phorbol ester-induced disassembly of hemidesmosomes. These results indicate that Necl-4 serves as a tumor suppressor by inhibiting the ErbB2/ErbB3 signaling and hemidesmosome disassembly.

Modeling of cell cultivation for monoclonal antibody production processes considering lactate metabolic shifts.

Demand for monoclonal antibodies (mAbs) is rapidly increasing. To achieve higher productivity, there have been improvements to cell lines, operating modes, media, and cultivation conditions. Representative mathematical models are needed to narrow down the growing number of process alternatives. Previous studies have proposed mechanistic models to depict cell metabolic shifts (e.g., lactate production to consumption). However, the impacts of variations of some operating conditions have not yet been fully incorporated in such models. This paper offers a new mechanistic model considering variations in dissolved oxygen and glutamine depletion on cell metabolism applied to a novel Chinese hamster ovary (CHO) cell line. Expressions for the specific rates of lactate production, glutamine consumption, and mAb production were formulated for stirred and shaken-tank reactors. A deeper understanding of lactate metabolic shifts was obtained under different combinations of experimental conditions. Lactate consumption was more pronounced in conditions with higher DO and low glutamine concentrations. The model offers mechanistic insights that are useful for designing advanced operation strategies. It can be used in design space generation and process optimization for better productivity and product quality.

Lymphopenia is a risk factor for severe infections in older patients with microscopic polyangiitis: a retrospective cohort study in Japan.

Objective: Previous studies have identified the predictors of severe infections in ANCA-associated vasculitis. However, lymphopenia has not been fully evaluated as a predictor of subsequent severe infections in patients with microscopic polyangiitis (MPA). The aim of this study was to assess the association between lymphopenia and severe infections requiring hospitalization after receiving immunosuppressive therapy for MPA. Methods: This single-centre retrospective cohort study included 130 consecutive patients with newly diagnosed MPA from Aichi Medical University Hospital, Japan, who received immunosuppressive therapy between March 2004 and December 2020. The relationship between lymphopenia and subsequent severe infections was assessed using time-dependent multivariate Cox proportional hazard models adjusted for clinically relevant factors. Results: During the follow-up period (median: 38 months; interquartile range: 15-63 months), 56 severe infectious episodes occurred in 51 patients (39.2%). Time-dependent multivariate Cox proportional hazard analyses identified older age [adjusted hazard ratio (HR) = 1.74 per 10 years, 95% CI: 1.13, 2.67], methylprednisolone pulse therapy (adjusted HR = 2.04, 95% CI: 1.03, 4.02), moderate lymphopenia (vs normal, adjusted HR = 7.17, 95% CI: 3.10, 16.6) and severe lymphopenia (vs normal, adjusted HR = 36.1, 95% CI: 11.8, 110.9) as significant predictors of severe infection. Conclusion: Lymphopenia is a predictor of subsequent severe infections in patients with MPA who receive immunosuppressive therapy. These results suggest the importance of sustained infection surveillance, particularly in older patients who develop lymphopenia during strong immunosuppressive therapy.

A case of 2,8-DHA crystalline nephropathy caused by adenine phosphoribosyltransferase deficiency: diagnosis and treatment.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that leads to the accumulation of poorly soluble 2,8-dihydroxyadenine (DHA) in the kidneys, resulting in a variety of renal presentations including nephrolithiasis, acute kidney injury, and chronic kidney disease (CKD) caused by crystal nephropathy. Here, we report a case of a 43-year-old man with 2,8-DHA crystalline nephropathy caused by APRT deficiency strongly suspected by renal biopsy results and definitively diagnosed by a urine gas chromatography-mass spectrometry (GC/MS)-based plasma metabolomic assessment. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition and its progression to CKD, which can be prevented by the early administration of xanthine oxidoreductase inhibitors.

Mepolizumab administration for eosinophilic granulomatosis with polyangiitis in an elderly patient with an abrupt onset of limb ischaemia and peripheral neuropathy: A case-based literature review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of anti-neutrophil cytoplasmic antibody-associated vasculitis characterised by small- to medium-sized vessel vasculitis and is typically associated with eosinophilic granulomatous inflammation. EGPA can affect any organ system, most commonly the lungs, skin, and the nervous system. However, limb ulcers are rare complications and have only been described in few case reports. Furthermore, no documented cases of EGPA have been treated with mepolizumab. Herein, we report a case of an 86-year-old Japanese woman with anti-neutrophil cytoplasmic antibody-negative EGPA, who had an abrupt onset of upper limb ulcers and bilateral foot drop due to multiple mononeuropathy. Clinicopathological sural nerve biopsy showed eosinophil-associated vascular damage. The patient was administered steroids, intravenous immunoglobulin, vasodilators, and mepolizumab; this resulted in clinical improvement of her finger ulcers and peripheral neuropathy without any adverse effects. In cases of an abrupt onset of limb ischaemia and peripheral neuropathy, physicians should consider the possibility of EGPA as a differential diagnosis. Furthermore, the early administration of mepolizumab might yield better outcomes in terms of improving limb ischaemia and peripheral neuropathy.

Malnutrition according to the GLIM criteria with kidney dysfunction is associated with increased mortality in hospitalized patients with cardiovascular disease: A retrospective cohort study.

BACKGROUND & AIMS: Cardiovascular disease (CVD) is a significant cause of mortality and rising healthcare costs, involving numerous chronic and nutritional risk. Although several studies have reported that malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria is associated with mortality in patients with CVD, they have not evaluated this association in terms of malnutrition severity (moderate or severe). Furthermore, the relationship between malnutrition combined with renal dysfunction, a risk factor for death in CVD patients, and mortality has not been previously evaluated. Thus, we aimed to assess the association between malnutrition severity and mortality, as well as malnutrition status stratified by kidney function and mortality, in patients hospitalized due to CVD events. METHODS: This single-centre, retrospective cohort study included 621 patients with CVD aged ≥18 years admitted to Aichi Medical University between 2019 and 2020. The relationship between nutritional status based on the GLIM criteria (without malnutrition, moderate malnutrition, or severe malnutrition) and the incidence of all-cause mortality was evaluated by multivariable Cox proportional hazards models. RESULTS: Patients with moderate and severe malnutrition were significantly more prone to mortality than those without malnutrition (adjusted hazard ratio [HR] of patients without, with moderate, and with severe malnutrition: 1.00 [reference], 1.94 [1.12-3.35], and 2.63 [1.53-4.50], respectively). Furthermore, we found the highest all-cause mortality rate in patients with malnutrition and a lower estimated glomerular filtration rate (eGFR <30 mL/min/1.73 m2) (adjusted HR, 10.1; confidence interval, 3.90-26.4) than in patients without malnutrition and normal eGFR (eGFR ≥60 mL/min/1.73 m2). CONCLUSIONS: The present study indicated that malnutrition according to the GLIM criteria was associated with increased all-cause mortality in patients with CVD, and malnutrition associated with kidney dysfunction was associated with a higher risk of mortality. These findings provide clinically relevant information to identify high mortality risk in patients with CVD and highlight the need for giving careful attention to malnutrition with kidney dysfunction among patients with CVD.

Association between reduced left ventricular ejection fraction and peritoneal dialysis related peritonitis: a single center retrospective cohort study in Japan.

We present a single-center retrospective analysis of 228 Japanese patients with peritoneal dialysis, in which we examined whether reduced left ventricular ejection fraction (LVEF) is a risk factor for peritonitis development. Time-dependent multivariable-adjusted Cox proportional hazards models revealed that reduced LVEF (LVEF < 50% vs. preserved LVEF ≥ 50%, hazard ratio (HR) 2.10; 95% confidence interval (CI) 1.16-3.82) was associated with peritonitis. Qualitatively, similar associations with reduced LVEF (< 50%) were observed for enteric peritonitis (adjusted HR 7.68; 95% CI 2.51-23.5) but not for non-enteric peritonitis (adjusted HR 1.15; 95% CI 0.54-2.44). Reduced LVEF is associated with a significantly higher risk of subsequent peritonitis, particularly enteric peritonitis. These results indicate that patients with reduced LVEF may be at risk of enteric peritonitis from bowel sources caused by intestinal involvement due to cardiac dysfunction.

Data-Driven Approach toward Long-Term Equipment Condition Assessment in Sterile Drug Product Manufacturing.

A two-stage data-driven methodology for long-term equipment condition assessment in drug product manufacturing is presented with a case study for a commercially operating aseptic filling line. The methodology leverages process monitoring data. Sensor measurements are partitioned using process information and maintenance schedules that are available on different databases. Data is processed to tackle heterogeneity in sources and formats. The data is cleaned to remove the effects of short-term variabilities and to enhance underlying long-term trends. Two approaches are presented for data analysis: first, anomaly detection using independent component analysis (ICA), where clusters of outliers are identified. The frequency and timing of such outliers yield important insights regarding maintenance schedules and actions. The second approach enables condition monitoring using principal component analysis (PCA). Long-term operational baselines are identified and shifts therein are linked with different process and equipment faults. This approach highlights the impact of equipment deterioration on shifting operational data baselines and shows the potential for the combined application of ICA and PCA for equipment condition monitoring. It can be applied within predictive maintenance applications where the installation of new specialized sensors is difficult, like in the pharmaceutical industry.

Digital models in biotechnology: Towards multi-scale integration and implementation.

Industrial biotechnology encompasses a large area of multi-scale and multi-disciplinary research activities. With the recent megatrend of digitalization sweeping across all industries, there is an increased focus in the biotechnology industry on developing, integrating and applying digital models to improve all aspects of industrial biotechnology. Given the rapid development of this field, we systematically classify the state-of-art modelling concepts applied at different scales in industrial biotechnology and critically discuss their current usage, advantages and limitations. Further, we critically analyzed current strategies to couple cell models with computational fluid dynamics to study the performance of industrial microorganisms in large-scale bioprocesses, which is of crucial importance for the bio-based production industries. One of the most challenging aspects in this context is gathering intracellular data under industrially relevant conditions. Towards comprehensive models, we discuss how different scale-down concepts combined with appropriate analytical tools can capture intracellular states of single cells. We finally illustrated how the efforts could be used to develop digitals models suitable for both cell factory design and process optimization at industrial scales in the future.