Question-based review for pharmaceutical development: An enhanced quality approach.

Over the last years, the pharmaceutical industry has faced real challenges regarding quality assurance. In this context, the establishment of more holistic approaches to the pharmaceutical development has been encouraged. The emergence of the Quality by Design (QbD) paradigm as systematic, scientific and risk-based methodology introduced a new concept of pharmaceutical quality. In essence, QbD can be interpreted as a strategy to maximize time and cost savings. An in-depth understanding of the formulation and manufacturing process is demanded to optimize the safety, efficacy and quality of a drug product at all stages of development. This innovative approach streamlines the pharmaceutical Research and Development (R&D) process, provides greater manufacturing flexibility and reduces regulatory burden. To assist in QbD implementation, International Conference on Harmonisation (ICH), U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) organized and launched QbD principles in their guidance for industry, identifying key concepts and tools to design and develop a high-quality drug product. Despite the undeniable advantages of the QbD approach, and the widespread information on QbD regulatory expectations, its full implementation in the pharmaceutical field is still limited. The present review aims to establish a crosswise overview on the current application status of QbD within the framework of the ICH guidelines (ICH Q8(R2) - Q14 and ICH Q2(R2)). Moreover, it outlines the way information gathered from the QbD methodology is being harmonized in Marketing Authorization Applications (MAAs) for European market approval. This work also highlights the challenges that hinder the deployment of the QbD strategy as a standard practice.

Risk assessment for biopharmaceutical single-use manufacturing: A case study of upstream continuous processing.

In the current transition to intensified upstream processing, the risks of adopting traditional single-use systems for high-titer, long-duration perfusion cultures, have thus far not been considered. This case study uses the Failure Modes and Effects Analysis (FMEA) method to evaluate the risks associated with implementing upstream single-use technology. The simulated model process was used to compare the risk level of single-use technology for a traditional fed-batch cell culture with that for perfusion culture, under the same annual protein production conditions. To provide a reasonable source of potential risk for FMEA, all single-use upstream operations for both fed-batch and perfusion processes were investigated using an analytical method developed to quantify the impact of process parameters and operating conditions on single-use system specifications and to ensure objectivity. Many of the risks and their levels, were similar in long-duration perfusion cultures and fed-batch cultures. However, differences were observed for high-risk components such as daily sampling and installation. The result of this analysis indicates that the reasons for risk are different for fed-batch cultures and perfusion cultures such as larger bioreactors in fed-batch and longer runs in perfusion, respectively. This risk assessment method could identify additional control measures and be part of a holistic contamination control strategy and help visualize their effectiveness.

[Quality control strategy of traditional Chinese medicine based on pharmaceutical product lifecycle management].

Quality control is pivotal in the research and development of traditional Chinese medicine, whose connotation is not limi-ted to the qualitative or quantitative detection of an indicator component, but extends to the establishment of a whole process quality control system from the perspective of pharmaceutical product lifecycle management. This study discussed the quality control strategy of Chinese medicine based on the concept of pharmaceutical product lifecycle management, and proposed the following suggestions:(1) to focus on the "holistic view" and "phased" characteristics of quality control and strengthen the establishment of quality control strategy based on top-level design;(2) to strengthen the research on quality control of Chinese medicine based on quality risk management, focus on the correlations of quality control indicators with the safety and effectiveness of traditional Chinese medicine, and establish a quality evaluation system consistent with the characteristics of traditional Chinese medicine;(3) to consider the characteristics of different registration classifications in the establishment of quality control strategy;(4) to highlight the quality correlation research, strengthen the quality transfer research, ensure the quality traceability, and establish a sound quality management system;(5) to strengthen the quality research on marketed drugs to achieve dynamic quality improvement.

Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy.

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits.

Regional heterogeneity and driving factors of road runoff pollution from urban areas in China.

Due to the multiple influences of natural and anthropogenic factors, stormwater runoff from urban roads generally presents heterogeneous pollution among cities. The identification of regional heterogeneity and related driving factors of road runoff pollution is of significance for the optimal management of road runoff pollution according to the local circumstances. In this study, the regional heterogeneity of urban road runoff pollution from fourteen representative cities in China is analyzed for four typical pollutants including total suspended solids (TSS), chemical oxygen demand (COD), total nitrogen (TN) and total phosphorus (TP). The results show wide variations in TSS, COD, TN and TP pollution among cities, with the average event mean concentrations ranging from 77.0 to 1347.9, 31.4 to 488.1, 0.81 to 8.46, 0.139 to 1.930 mg/L, respectively. One-way ANOVA analyses demonstrate significant differences in road runoff pollution among cities. The TSS pollution is significantly heavier for northern and northwestern inland cities than that for eastern and southern cities. Pearson correlation analysis and Stepwise linear regression analysis are performed to identify and rank the influence of climate, population, economy, industry structure, traffic and environmental quality. Direct relationships of road runoff pollution are detected with PM2.5, PM10, secondary industry, tertiary industry, annual rainfall, and urban green coverage, among which PM10 and urban green coverage are the most important and common factors exerting positive and negative influences on road runoff pollution, respectively. Based on the findings of this work, improvement of atmospheric particulate pollution and increase in urban greenness are recommended measures to manage the road runoff pollution. Furthermore, the traffic-related emissions accompanying the upgrading of industry structure should be effectively controlled to attenuate the TSS and COD pollution in road runoff.

Quality control strategy of traditional Chinese medicine based on pharmaceutical product lifecycle management / 中国中药杂志

Quality control is pivotal in the research and development of traditional Chinese medicine, whose connotation is not limi-ted to the qualitative or quantitative detection of an indicator component, but extends to the establishment of a whole process quality control system from the perspective of pharmaceutical product lifecycle management. This study discussed the quality control strategy of Chinese medicine based on the concept of pharmaceutical product lifecycle management, and proposed the following suggestions:(1) to focus on the "holistic view" and "phased" characteristics of quality control and strengthen the establishment of quality control strategy based on top-level design;(2) to strengthen the research on quality control of Chinese medicine based on quality risk management, focus on the correlations of quality control indicators with the safety and effectiveness of traditional Chinese medicine, and establish a quality evaluation system consistent with the characteristics of traditional Chinese medicine;(3) to consider the characteristics of different registration classifications in the establishment of quality control strategy;(4) to highlight the quality correlation research, strengthen the quality transfer research, ensure the quality traceability, and establish a sound quality management system;(5) to strengthen the quality research on marketed drugs to achieve dynamic quality improvement.

[Research status and strategy of quality control of medicinal and edible food].

As China is implementing "Healthy China" strategy, medicinal and edible food has attracted unprecedented attention due to the dual attributes of food and medicine. However, there is a lack of the quality control standard and the existing quality control research cannot fully reflect the dual attributes of medicinal and edible food, which consequently restrict the development of medicinal and edible food industry. This study reviewed the research status and proposed the strategy of quality control in line with the dual attribu-tes of medicinal and edible food, and clarified the research contents of quality control of medicinal and edible food of different types to provide references for the follow-up quality control of medicinal and edible food.

Quality by design (QbD) approach in marketing authorization procedures of Non-Biological Complex Drugs: A critical evaluation.

The emergence of innovator-driven complex drug products, such as Non-Biological Complex Drugs (NBCDs), has provided disruptive advances in the Nanotechnology and Biotechnology fields. However, the design and development of NBCDs can be particularly challenging due to some unresolved scientific and regulatory challenges associated with the pharmaceutical quality assessment. The application of a more holistic, systematic, integrated science and risk-based approach, such as Quality by Design (QbD), is essential to address key scientific, technological, and regulatory constraints in the research and development of the NBCDs. The deeper product and process understanding derived from the implementation of the QbD approach ensures consistent, reliable, and high-quality pharmaceutical products. Furthermore, this approach promotes innovation and continuous improvement in the entire product lifecycle. Regulatory authorities highly recommend QbD-based submissions to successfully translate NBCDs from laboratory-scale research to the pharmaceutical market with the required quality, safety, and efficacy standards. The main aim of this article is to obtain a comprehensive and in-depth investigation into the state of implementation of the QbD approach in the pharmaceutical development and marketing authorization of NBCDs in Europe and the United States, through the analysis of the available data from their regulatory dossiers. In addition, it aims to understand and discuss how the QbD approach is used and implemented for complex drug products in the pharmaceutical industry, highlighting the gaps and challenges involved with its implementation. An analysis is held regarding QbD's advantages in terms of knowledge growth, regulatory flexibility, and the speed of development based on big data science, along with the reduction of regulatory failures and market withdrawals.

How should designated COVID-19 hospitals in megacities implement a precise management strategy in response to Omicron?

As a new variant of COVID-19 with varied mutations, Omicron is more transmissible, more rapidly contagious, and has a greater risk of reinfection. Given those facts, a precise manage strategy needs to be formulated and implemented in designated megacities. Here, the precise COVID-19 prevention and control strategy for a designated hospital in Shenzhen, China is summarized, including implementation of a two-wing "On duty/On standby" approach based on busy and calm periods, an identification, classification, and grading system for the occupational exposure risks of medical staff, classification of patient transmission risks, separate admission, and an innovative treatment (nasal irrigation). The strategy has enabled the efficient and orderly integration of resources, it has resulted in zero infections among medical staff even during the peak hours of the pandemic at the hospital (1,930 patients admitted to both wings in a single day), and it has significantly reduced the initial period of no virus detection when patients infected with Omicron received saline nasal irrigation (P < 0.001). This strategy has provided evidence of precise prevention and control in a hospital, infection control, and efficient patient treatment in an era when Omicron is widespread.

Holistic analytical characterization and risk assessment of residual host cell protein impurities in an active pharmaceutical ingredient synthesized by biocatalysts.

Host cell proteins (HCPs) are a significant class of process-related impurities commonly associated with the manufacturing of biopharmaceuticals. However, due to the increased use of crude enzymes as biocatalysts for modern organic synthesis, HCPs can also be introduced as a new class of impurities in chemical drugs. In both cases, residual HCPs need to be adequately controlled to ensure product purity, quality, and patient safety. Although a lot of attentions have been focused on defining a universally acceptable limit for such impurities, the risks associated with residual HCPs on product quality, safety, and efficacy often need to be determined on a case-by-case basis taking into consideration the residual HCP profile in the product, the dose, dosage form, administration route, and so forth. Here we describe the unique challenges for residual HCP control presented by the biocatalytic synthesis of an investigational stimulator of interferon genes protein agonist, MK-1454, which is a cyclic dinucleotide synthesized using Escherichia coli cell lysate overexpressing cyclic GMP-AMP synthase as a biocatalyst. In this study, a holistic characterization of residual protein impurities using a variety of analytical tools including nanoscale liquid chromatography coupled to tandem mass spectrometry, together with in silico immunogenicity prediction of identified proteins, facilitated risk assessment and guided process development to achieve adequate removal of residual protein impurities in MK-1454 active pharmaceutical ingredient.

Model predictive control in pharmaceutical continuous manufacturing: A review from a user's perspective.

Pharmaceutical continuous manufacturing is considered as an emerging technology by the regulatory agencies, which have defined a framework guided by an effective quality risk management. With the understanding of process dynamics and the appropriate control strategy, pharmaceutical continuous manufacturing is able to tackle the Quality-by-Design paradigm that paves the way to the future smart manufacturing described by Quality-by-Control. The introduction of soft sensors seems to be a helpful tool to reach smart manufacturing. In fact, soft sensors have the ability to keep the quality attributes of the final drug product as close as possible to their references set by regulatory agencies and to mitigate the undesired events by potentially discard out of specification products. Within this review, challenges related to implementing these technologies are discussed. Then, automation control strategies for pharmaceutical continuous manufacturing are presented and discussed: current control tools such as the proportional integral derivative controllers are compared to advanced control techniques like model predictive control, which holds promise to be an advanced automation concept for pharmaceutical continuous manufacturing. Finally, industrial applications of model predictive control in pharmaceutical continuous manufacturing are outlined. Simulations studies as well as real implementation on pharmaceutical plant are gathered from the control of one single operation unit such as the tablet press to the control of a full direct compaction line. Model predictive control is a key to enable the industrial revolution or Industry 4.0.

Strategy for treating vascular emergencies during the COVID-19 pandemic in China.

Coronavirus-caused pneumonia (COVID-19) broke out in December 2019. The virus soon proved to be extremely contagious and caused an international pandemic. Clinicians treating COVID-19 patients face considerable danger of occupational exposure because of the highly infectious nature of the virus, and precautions must be taken to prevent medical staff infections. This article lists important measures that may save the lives of patients and medical staff during the COVID-19 pandemic and help stop the transmission of COVID-19 on hospital grounds. The suggestions include establishing detailed infection control and prevention protocols in the operating room; expediting testing procedures and patient screening for COVID-19; using case-specific treatment planning for vascular patients with COVID-19, favoring minimally invasive methods; and establishing and reinforcing protective awareness of medical personnel.

The development of an herbal material quality control strategy considering the effects of manufacturing processes.

BACKGROUND: Quality by design (QbD) is an advanced drug quality control concept that has been gradually implemented in the optimization of manufacturing processes of Chinese medicines. However, the variation of Chinese medicinal material quality has rarely been considered in published works. Because manufacturing processes may lower the variation introduced through different batches of materials, a material quality control strategy should be developed considering the influences of manufacturing processes. METHODS: In this work, the processes of extraction, concentration, water precipitation, and chromatography for notoginseng total saponin (NTS) production were investigated while considering Panax notoginseng quality variation as a sample. Ten process parameters were studied simultaneously using a definitive screening design. After the process critical quality attributes (CQAs) were determined, critical process parameters (CPPs) and critical material attributes (CMAs) were identified simultaneously. Then, models utilizing the CMAs, CPPs, and process CQAs were developed. The design space was then calculated using a Monte Carlo simulation method with an acceptable probability of 0.90. A material quality control strategy considering the influences of manufacturing processes was proposed. RESULTS: The ginsenoside Rd purity and total saponin purity in the eluate were identified as process CQAs. The ethanol solution concentration used for extraction, the ethanol solution concentration used for elution, and elution time were identified as CPPs. The extractable dry matter content of Panax notoginseng was one of the CMAs. The extractable contents of notoginsenoside R1, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rd were the other CMAs. The inequalities implemented to discriminate the high quality and low quality of Panax notoginseng were developed according to the NTS standard of the Xuesaitong injection. Low quality Panax notoginseng should not be released for NTS production. High quality Panax notoginseng can be treated with feasible manufacturing processing parameters. Verification experiments were carried out successfully for 2 batches of high quality Panax notoginseng. CONCLUSIONS: In this work, a quality control strategy for herbal materials was developed considering the matching of process characteristics and material quality attributes. This strategy is promising for application to other Chinese medicines.

An influent responsive control strategy with machine learning: Q-learning based optimization method for a biological phosphorus removal system.

Biological phosphorus removal (BPR) is an economical and sustainable processes for the removal of phosphorus (P) from wastewater, achieved by recirculating activated sludge through anaerobic and aerobic (An/Ae) processes. However, few studies have systematically analyzed the optimal hydraulic retention times (HRTs) in anaerobic and aerobic reactions, or whether these are the most appropriate control strategies. In this study, a novel optimization methodology using an improved Q-learning (QL) algorithm was developed, to optimize An/Ae HRTs in a BPR system. A framework for QL-based BPR control strategies was established and the improved Q function, Qt+1(st,st+1)=Qt(st,st+1)+k·[R(st,st+1)+γ·maxatQt(st,st+1)-Qt(st,st+1)] was derived. Based on the improved Q function and the state transition matrices obtained under different HRT step-lengths, the optimum combinations of HRTs in An/Ae processes in any BPR system could be obtained, in terms of the ordered pair combinations of the . Model verification was performed by applying six different influent chemical oxygen demand (COD) concentrations, varying from 150 to 600 mg L-1 and influent P concentrations, varying from 12 to 30 mg L-1. Superior and stable effluent qualities were observed with the optimal control strategies. This indicates that the proposed novel QL-based BPR model performed properly and the derived Q functions successfully realized real-time modelling, with stable optimal control strategies under fluctuant influent loads during wastewater treatment processes.

Performance and stability of a dynamically controlled EBPR anaerobic/aerobic granular sludge reactor.

Treatment of rapidly varying wastewaters in anaerobic/aerobic aerobic granular sludge (AGS) systems remains problematic. This study investigated AGS formation and the impact of varying COD and phosphorus concentrations on an enhanced biological phosphorus removal (EBPR) AGS SBR with a conductivity based anaerobic and OUR based aerobic dynamically controlled step. Phase 1 investigated the development of AGS. Phase 2 examined the flexibility of the dynamic control strategy and AGS efficiency while rapidly altering the influent composition. AGS was formed successfully in phase 1: the DV50 increased to 285 µm, and the SVI5 and SVI30 decreased to 51 and 40 ml/g respectively. In phase 2 the effluent COD and PO4-P concentration remained low at respectively 58 ±â€¯27 mg/L and 0.53 ±â€¯0.77 mg/L. With an anaerobic DOC uptake efficiency of 98.4 ±â€¯0.9%.

Analytical quality by design: Development and control strategy for a LC method to evaluate the cannabinoids content in cannabis olive oil extracts.

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) are considered as the most interesting cannabinoids in Cannabis sativa L. for the clinical practice. Since 2013, the Italian law allows pharmacists to prepare and dispense cannabis extracts to patients under medical prescription, and requires the evaluation of CBD and Δ9-THC content in cannabis extracts before sale. Cannabis olive oil extracts are prepared from dried female cannabis inflorescences, but a standard protocol is still missing. In this study, a fast RP-HPLC/UV method has been developed to quantify CBD and Δ9-THC in cannabis olive oil extracts. The analytical quality by design strategy has been applied to the method development, setting critical resolution and total analysis time as critical method attributes (CMAs), and selecting column temperature, buffer pH and flow rate as critical method parameters. Information from Doehlert Design in response surface methodology combined to Monte-Carlo simulations led to draw the risk of failure maps and to identify the method operable design region. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines and then implemented in routine analysis. A control strategy based on system control charts was planned to monitor the developed method performances. Evaluation data were recorded over a period of one year of routine use, and both the CMAs showed values within the specifications in every analysis performed. Hence, a new risk evaluation for the future performances of the method was achieved by using a Bayesian approach based on the routine use data, computing the future distribution of the two CMAs. Finally, a study focusing on the monitoring of CBD and Δ9-THC concentrations in cannabis olive oil extracts was carried out. The developed method was applied to 459 extracts. The statistical analysis of the obtained results highlighted a wide variability in terms of concentrations among different samples from the same starting typology of cannabis, underlining the compelling need of a standardised procedure to harmonise the preparation of the extracts.

[Application of feedforward control strategy based on spectra of raw materials to optimize alcohol extraction process of Panax notoginseng].

In this work, we obtained the quality information of Panax notoginseng with near infrared spectroscopy in an efficient way. By combining the quality information of raw materials with process parameters in experimental design, quantitative relationship models were established between material quality information, process parameters and product quality of P. notoginseng, thus realizing the feedforward control of the alcohol extraction process. The quantitative models established have high robustness and satisfactory forecasting ability. With new batches of P. notoginseng introduced for the alcohol extraction process, the quality information of raw materials was rapidly obtained. Based on the established models, the process parameters were optimized according to the expected critical quality attributes (CQA), thereby reducing the fluctuation of product quality caused by raw material variation.

Study on the stability control strategy of Triphala solution based on the balance of physical stability and chemical stabilities.

Triphala is a well-known prescription in Indian Ayurveda and TCM medicine for its great effect on gingivitis and hyperlipidemia. However, its solution is unstable for the containing of excessive polyphenol, leading to the production of sediment in the short term and the decrease of efficacy. Based on the analysis of sediment formation, a novel control strategy is proposed. To conduct the analysis, the sediment formation was recorded for a consecutive five days. The changes in the composition of the supernatant and the sediment were studied by the HPLC profile analysis. The main components of the sediment were identified as corilagin, ellagic acid and gallic acid, and the amount of ellagic acid sediment increased with the storage time. Then, with a series of pH status adjustments of the Triphala solution, the physical and chemical stabilities were acquired by Turbiscan and HPLC respectively. The results showed that as the pH value increased, so did the physical stability, but the particle size and TSI of the association decreased. While the fingerprint of chemical profile similarity decreased, so did the chemical stability. Combining physical and chemical stability parameters, an equilibrium point was found out. When the pH value was adjusted to 5.0, both the physical and chemical stabilities were better: the verification test showed that the sedimentation inhibition rates on the 3rd, 5th,10th and15th days were 41%, 55%, 41%, and 23%, respectively. This manuscript provided a new control strategy that will pique pharmaceutical and food development engineers' interest and trigger research ideas controlling the quality of decoction.

[Influence of Moxa Smoke on Indoor Air Quality and Strategies for Its Control].

Moxibustion is an effective therapy for treatment of a lot of clinical problems, but the ignited moxa-induced smoke containing harmful substances may bring about indoor air pollution to affect both patients' and medical workers' health. However, there is no standards about controlling indoor air quality (IAQ) for moxibustion rooms in China. In the present study, the authors reviewed newly-published articles about some substances released from moxa smoke as inhalable particles (PM 10 and PM 2.5), formaldehyde, benzene, methylbenzene, xylene, bene[α]pyrene, total volatile organic compounds, CO, CO2, NO, SO2, NH3, O3, etc. some of which affect IAQ. On this account, the authors put forward some strategies for controlling IAQ in moxibustion clinics including setting united safe standards, enhancing ventilation, controlling moxibustion material quality and strengthening scientific research on the safety of moxa smoke control, fully playing the superiority of moxibustion therapy and reducing its unfavorable aspects in clinical practice in the future.

Enhanced isopropanol-butanol-ethanol mixture production through manipulation of intracellular NAD(P)H level in the recombinant Clostridium acetobutylicum XY16.

BACKGROUND: The formation of by-products, mainly acetone in acetone-butanol-ethanol (ABE) fermentation, significantly affects the solvent yield and downstream separation process. In this study, we genetically engineered Clostridium acetobutylicum XY16 isolated by our lab to eliminate acetone production and altered ABE to isopropanol-butanol-ethanol (IBE). Meanwhile, process optimization under pH control strategies and supplementation of calcium carbonate were adopted to investigate the interaction between the reducing force of the metabolic networks and IBE production. RESULTS: After successful introduction of secondary alcohol dehydrogenase into C. acetobutylicum XY16, the recombinant XY16 harboring pSADH could completely eliminate acetone production and convert it into isopropanol, indicating great potential for large-scale production of IBE mixtures. Especially, pH could significantly improve final solvent titer through regulation of NADH and NADPH levels in vivo. Under the optimal pH level of 4.8, the total IBE production was significantly increased from 3.88 to 16.09 g/L with final 9.97, 4.98 and 1.14 g/L of butanol, isopropanol, and ethanol. Meanwhile, NADH and NADPH levels were maintained at optimal levels for IBE formation compared to the control one without pH adjustment. Furthermore, calcium carbonate could play dual roles as both buffering agency and activator for NAD kinase (NADK), and supplementation of 10 g/L calcium carbonate could finally improve the IBE production to 17.77 g/L with 10.51, 6.02, and 1.24 g/L of butanol, isopropanol, and ethanol. CONCLUSION: The complete conversion of acetone into isopropanol in the recombinant C. acetobutylicum XY16 harboring pSADH could alter ABE to IBE. pH control strategies and supplementation of calcium carbonate were effective in obtaining high IBE titer with high isopropanol production. The analysis of redox cofactor perturbation indicates that the availability of NAD(P)H is the main driving force for the improvement of IBE production.