Batch Production Research Articles

Targeted microbial collaboration to enhance key flavor metabolites by inoculating Clostridium tyrobutyricum and Saccharomyces cerevisiae in the strong-flavor Baijiu simulated fermentation system

Ethyl hexanoate and ethyl butyrate are indispensable flavor metabolites in strong-flavor Baijiu (SFB), but batch production instability in fermenting grains can reduce the quality of distilled Baijiu. Biofortification of the fermentation process by designing a targeted microbial collaboration pattern is an effective method to stabilize the quality of Baijiu. In this study, we explored the metabolism under co-culture liquid fermentation with Clostridium tyrobutyricum DB041 and Saccharomyces cerevisiae YS219 and investigated the effects of inoculation with two functional microorganisms on physicochemical factors, flavor metabolites, and microbial communities in solid-state simulated fermentation of SFB for the first time. The headspace solid-phase microextraction-gas chromatography-mass spectrometry results showed that ethyl butyrate and ethyl hexanoate significantly increased in fermented grain. High-throughput sequencing analysis showed that Pediococcus, Lactobacillus, Weissella, Clostridium_sensu_stricto_12, and Saccharomyces emerged as the dominant microorganisms at the end of fermentation. Co-occurrence analysis showed that ethyl hexanoate and ethyl butyrate were significantly correlated (|r| > 0.5, P < 0.05) with a cluster of interactions dominated by lactic acid bacteria (Pediococcus, Lactobacillus, Weissella, and Lactococcus), which was driven by the functional C. tyrobutyricum and S. cerevisiae. Mantel test showed that moisture and reducing sugars were the main physicochemical factor affecting microbial collaboration (|r| > 0.7, P < 0.05). Taken together, the collaborative microbial pattern of inoculation with C. tyrobutyricum and S. cerevisiae showed positive results in enhancing typical flavor metabolites and the synergistic effects of microorganisms in SFB.

KT-Biologics I (KTB1): A dynamic simulation model for continuous biologics manufacturing

The pharmaceutical industry's shift towards biological therapeutics has led to a transition from conventional batch production to continuous manufacturing. This change highlights the crucial need for effective process monitoring and control strategies to ensure consistent product quality and stability. Open-source benchmark simulation models have become essential tools for refining these processes, offering a platform for testing research hypotheses. This study uses the production of Lovastatin as a case study for continuous biopharmaceutical production. A comprehensive dynamic model covering upstream and downstream components provides an integrated perspective of the production process. The study introduces a basic control system emphasizing realistic sensor and actuator integration to enhance simulation accuracy. It assesses the benchmark through open-loop and closed-loop simulations, offering an in-depth analysis of the KTB1 model's dynamic response and functionality. KTB1 represents a model-driven decision support tool that enables the evaluation of monitoring strategies, process design, process optimization, and control for biomanufacturing.

Physiologically Based Biopharmaceutics Modeling for Gefapixant IR Formulation Development and Defining the Bioequivalence Dissolution Safe Space.

Gefapixant is a weakly basic drug which has been formulated as an immediate release tablet for oral administration. A physiologically based biopharmaceutics model (PBBM) was developed based on gefapixant physicochemical properties and clinical pharmacokinetics to aid formulation selection, bioequivalence safe space assessment and dissolution specification settings. In vitro dissolution profiles of different free base and citrate salt formulations were used as an input to the model. The model was validated against the results of independent studies, which included a bioequivalence and a relative bioavailability study, as well as a human ADME study, all meeting acceptance criteria of prediction errors ≤ 20% for both Cmax and AUC. PBBM was also applied to evaluate gastric pH-mediated drug-drug-interaction potential with co-administration of a proton pump inhibitor (PPI), omeprazole. Model results showed good agreement with clinical data in which omeprazole lowered gefapixant exposure for the free base formulation but did not significantly alter gefapixant pharmacokinetics for the citrate based commercial drug product. An extended virtual dissolution bioequivalence safe space was established. Gefapixant drug product batches are anticipated to be bioequivalent with the clinical reference batch when their dissolution is > 80% in 60 minutes. PBBM established a wide dissolution bioequivalence space as part of assuring product quality.

R2R‐Based Continuous Production of Patterned and Multilayered Elastic Substrates with Liquid Metal Wiring for Stretchable Electronics

AbstractThe roll‐to‐roll (R2R) process for fabricating elastic substrates is essential for the social implementation of next‐generation stretchable devices with soft interfaces. In recent years, there is a growing demand for soft heterostructures with multiple monolithically patterned organic materials. However, a continuous processing technique for substrates with heterostructures patterned using highly stretchable wiring has not yet been developed. Conventional manufacturing methods for stretchable electronics lack production capacity. This study introduces an R2R‐based method for the continuous production of multilayered substrates composed of various elastic materials, integrated with liquid metal (LM) wiring, suitable for stretchable electronics. Continuous fabrication of polymer films is achieved with pattern areas as small as 0.78 mm2, using three different polymers varying in hardness. The R2R coating process, paired with liquid metal wiring dispensing printing, allows for the creation of lines as fine as 140 microns. This process supports the batch production of 15 stretchable hybrid devices at a time and enables the creation of large‐area devices up to 400 cm2. The fabrication technique developed herein holds promise for the future manufacturing of not only stretchable electronics but also cutting‐edge soft electronics like smart packaging. This is expected to be a factor leading to the commercialization of stretchable electronics.

Improved Radiosynthesis and Automation of [11C]2-(2,6-Difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2) for Positron Emission Tomography of the Glutamate α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid (AMPA) Receptor.

A new automated radiosynthesis of [11C]2-(2,6-difluoro-4-((2-(N-methylphenylsulfonamido)ethyl)thio)phenoxy)acetamide ([11C]K2), a radiopharmaceutical for the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, is reported. Although manual syntheses have been described, these are unsuitable for routine production of larger batches of [11C]K2 for (pre)clinical PET imaging applications. To meet demands for the imaging agent from our functional neuroimaging collaborators, herein, we report a current good manufacturing practice (cGMP)-compliant synthesis of [11C]K2 using a commercial synthesis module. The new synthesis is fully automated and has been validated for clinical use. The total synthesis time is 33 min from end of bombardment, and the production method provides 2.66 ± 0.3 GBq (71.9 ± 8.6 mCi) of [11C]K2 in 97.7 ± 0.5% radiochemical purity and 754.1 ± 231.5 TBq/mmol (20,382.7 ± 6256.1 Ci/mmol) molar activity (n = 3). Batches passed all requisite quality control testing confirming suitability for clinical use.

Feasibility study on mass-production of oxide dispersion strengthened Cu alloys for the divertor of DEMO fusion reactor

Oxide dispersion strengthened Cu (ODS Cu) alloys possess a high potential to be used as promising heat sink materials for the divertor system in DEMO fusion reactors. Considering their future application in fusion reactor divertor systems, mass-production of ODS Cu alloys is a must. The purpose of this study is to investigate the feasibility of large-scale production of ODS Cu alloys by improving the production process based on the already established mass-production process of ODS Fe alloys in cooperation with the steel manufacturer Kobelco Research Institute. After optimization of the mechanical alloying (MA) parameters, a large-scale production of ODS Cu powders was successfully achieved with a recovery rate of over 90% and around 1Kg powder in one batch production using an industry-level attritor ball mill cooled by circulating water. The mass-produced ODS Cu alloys were comprehensively characterized, including mechanical properties, microstructure and thermal diffusivity, and a new concept of low-energy ball milling was proposed based on the results to realize the mass-production of ODS Cu alloys.

Integrated Subsystems of Materials and Information Flow for Continuous Manufacturing of Coal and Steel

Abstract With the concept of Industry 4.0 production processes are moving towards autonomy and intelligence. Technologies equipped with artificial intelligence (AI) are involved into processes that are more and more digitized. Collaborative technologies are a feature of discrete processes. The automotive industry has achieved many successes in the process innovation towards smart factories. Other plants, such as smelters or coal mining are also striving to develop smart manufacturing with integrated computer systems to support processes. A continuous production is different from a discrete or batch production. Industry 4.0 concept is focused on discrete production (with high level of automation and robotization of manufacturing) meanwhile there is a gap in implementation of these approach in the continuous production. The objective of the publication is to prepare and design the integrated computer management system based on processes realized in coal and steel manufacturing. Coal and steel production are key elements in a chain of any industrial manufacturing e.g. automotive or machinery engineering. These processes are crucial in building of smart value chain. In our paper we present the structure of processes for the continuous production. Based the processes model we proposed the next steps to build the smart manufacturing for continuous production.

Standardization of Phomopsis sp. extract and prediction of anti breast cancer activity from the main compound through molecular docking

Abstract Endophytic fungi isolated from Indonesian soursop (Annona muricata) leaves, which have the potential to treat breast cancer, have been successfully isolated since 2016. Identification based on the Internal Transcribed Spacer (ITS) gene revealed that fungi close to Phomopsis sp. The fungi were stored, subcultured, and extracted with ethyl acetate for in vitro and in vivo studies. To be registered as a medicinal ingredient and meet the requirements of the Indonesian Food and Drug Supervisory Agency (BPOM, Badan Pengawas Obat dan Makanan), it is necessary to ensure the standardization, safety, and quality of the Phomopsis extract. The results showed that the Phomopsis extract met the BPOM requirements for organoleptic, water, and solvent content, microbial and heavy metal contamination, total aflatoxin, and metabolite content. Analysis of the Phomopsis extract content also showed that the compounds in the two production batches were stable, with the highest relative abundance of 7-hydroxycoumarin. In silico studies with molecular docking show that the affinity energy of 7-hydroxycoumarin docking with the estrogen receptor alpha (ERα) and thymidine kinase 1 (TK1) has a lower negativity value than the comparison ligand (-6.7 and -6.8 kcal/mol).

Certificate of Analysis (CoA) and Calculations for Small-Molecule Drugs

The Certificate of Analysis (CoA) is a crucial Good Manufacturing Practice (GMP) document for a batch of drug substances or products in development or production. It contains essential quality information and a summary of specifications and testing results. This article describes the contents and associated calculations of CoAs for small-molecule drugs. It explains how these documents help to ensure drug quality in the supply chain.

Ultrafine Si evaporation control technology to inhibit the island nucleation of epitaxial graphene on SiC (000-1)

The theoretically high mobility of graphene on C-terminated face of silicon carbide (SiC (000-1)) makes it a suitable candidate for electronic devices. However, the quality of graphene grown on SiC (000-1) is always poor. In this paper, we clarify that the partial pressure of silicon is the core parameter to control the nucleation and growth of graphene on SiC (000-1). Therefore, we propose a new system with SiC cap and optimize the height between the SiC cap and the SiC sample to control the partial pressure of silicon. Finally, the high-quality graphene with almost no D peak in Raman spectrum has been obtained. The nanosized domain underlying the top graphene layer has been demonstrated as the source of the defects, which can be inhibited by high partial pressure of silicon. Herein, a special electronic detective mode of electrically biased tapping mode (eb-TM) has been successfully implemented to characterize of the nano-domains underside. Furthermore, in our system, the suitable temperature is from 1350 °C to 1500 °C and the pressure is from 750 Pa to 40 kPa. This broad growth window makes the SiC cap system has greater advantages in the large-scale and stable batch production of epitaxial graphene in the future.

Development of the technological basis for the production of aceclofenac

Aceclofenac drugs are widely used in the global therapeutic practice of inflammatory and painful conditions for the treatment of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis in various dosage forms. The basics of the technology of domestic industrial batch production of aceclofenac with a capacity of 110 t/year for the production of a number of effective medicines have been developed. A five-stage production process is proposed that will allow the production of a domestic product with a high yield (~ 91 %) from commercially available reagents. Material calculations were carried out to determine the consumption rates of raw materials. The types of equipment were selected, and the number of equipment was determined. The basic technological scheme and technological flowchart for the production of aceclofenac are proposed.

A Heuristic Robust Design Optimization Approach for Batch Production Permanent Magnet Actuator Consider Various Uncertainties and Life-Cycle Quality Loss

A Heuristic Robust Design Optimization Approach for Batch Production Permanent Magnet Actuator Consider Various Uncertainties and Life-Cycle Quality Loss

Analysis of three characterization assays reveals ddPCR of LIN28A as the most sensitive for the detection of residual pluripotent stem cells in cellular therapy products

Background aimsWith the continuous development and advancement of human pluripotent stem cell (PSC)-derived cell therapies, an ever-increasing number of clinical indications can benefit from their application. Due to the capacity for PSCs to form teratomas, safety testing is required to ensure the absence of residual PSCs in a cell product. To mitigate these limitations, in vitro analytical methods can be utilized as quality control after the production of a PSC-derived cell product. Sensitivity of these analytic methods is critical in accurately quantifying residual PSC in the final cell product. In this study, we compared the sensitivity of three in vitro assays: qPCR, ddPCR and RT-LAMP. MethodsThe spike-in samples were produced from three independent experiments, each spiked with different PSC lines (PSC1, NH50191, and WA09 referred to as H9) into a background of primary fibroblasts (Hs68). These samples were then subjected to qPCR, ddPCR and RT-LAMP to determine their detection limit in measuring a commonly used PSC marker, LIN28A. ResultsThe results indicated that the three analytic methods all exhibited consistent results across different cell-line spiked samples, with ddPCR demonstrating the highest sensitivity of the three methods. The LIN28A ddPCR assay could confidently detect 10 residual PSCs in a million fibroblasts. DiscussionIn our hand, ddPCR LIN28A assay demonstrated the highest sensitivity for detection of residual PSCs compared to the other two assays. Correlating such in vitro safety results with corresponding in vivo studies demonstrating the tumorigenicity profile of PSC-derived cell therapy could accelerate the safe clinical translation of cell therapy.

The Impact of Serialisation on Operational Efficiency and Productivity in Irish Pharmaceutical Sites

Technology enabling drug serialisation technology was introduced by regulators to enhance security in pharmaceutical supply chain and protect drugs from infiltration by falsified and substandard medicines. The introduction of systems for serialisation required huge financial outlays manufacturers of pharmaceuticals. This study investigated the impact of serialisation on the operational efficiency and productivity in Irish pharmaceutical sites. A qualitative study was conducted with 11 manufacturing sites in Ireland. The participating companies operated a total of 114 pack-lines, representing approximately 65% of the automated packing lines in the country. The study found that serialisation had a negative effect on packaging production line OEE and line availability and on the individuals cost per unit of packaged pharmaceuticals. The research results estimated that the capital costs of serialisation were four times greater than those estimated by the regulators. There was a 4.1 cents average cost per pack for serialisation with high volume sites reporting an annual cost of serialisation of up to €4.5 m per annum and a 2.7% increase in the average cost of goods sold. A pattern whereby where many pharmaceutical manufacturers are transitioning from smaller batch production and moving toward larger batch production sizes in order to increases efficiencies was identified. The research also proposed the use of a serialisation depreciation factor as a method to determine the impact of serialisation on the cost of goods sold. This is the first study of its kind into the cost of serialisation from a manufacturer’s viewpoint and studying the effects of serialisation on productivity, line availability and operational efficiency.

Distance-based quantitative determination of pyrophosphate ions with a Haus-made microfluidic paper-based device using the metal–organic framework NH2-MIL-88 (Fe)

This study initially reports a distance-based quantitative assay of pyrophosphate ion (PPi) based on analyte-triggered decomposition of metal–organic framework (MOF) in microfluidic paper-based analytical devices (µPADs). The µPADs were created using a mini-cutter machine and a home-use hot-pressing machine for loading one type of MOF of NH2-MIL-88 (Fe) prepared with Fe3+ and fluorescent ligand of 2-aminoterephthalic acid (NH2-BDC). Upon sample introduction, the PPi could compete with NH2-BDC to bind Fe3+, leading to disintegration of the MOF and releasing of the fluorescent ligand in paper channel. The length (distance) of the NH2-BDC’s flow trace, when irradiated by a money tester pen, is proportional to the PPi level. The results show that the developed method only requires a ruler to linearly quantify PPi in a concentration range of 0–1000 μM, with a limit estimated to be ∼0.25 μM. Furthermore, recovery of PPi in orange juice and human urine was between 95.72 and 108.11 %, further validating its high detection accuracy. The fabrication method for µPADs offers many attractive advantages kike simplicity, batch production capability and low cost. Moreover, to our knowledge, this may be the first report of a portable quantitative MOF-based PPi assay with distance-based readout in µPADs.

An improved skip-lot sampling scheme with resampling mechanism using an advanced capability index

In today’s competitive market, product quality holds significant importance for consumers, motivating companies to prioritise high-quality product development and enhance their competitiveness. Acceptance sampling plans have proven to be indispensable tools in quality control practices, enabling producers and consumers to protect their interests by establishing evaluation rules for product batches. As defective rates decrease in modern manufacturing, skip-lot sampling plans (SkSP) have emerged as a suitable way for lots exhibiting stable and excellent product quality. Additionally, repetitive group sampling plan (RGSP) offers a cost-effective way to maintain desired protection for both parties, especially in costly or destructive inspection scenarios. Therefore, this study integrates the benefits of process capability indices, SkSP, and RGSP to develop a new variables SkSP with RGSP as its reference plan based on an advanced capability index Cpmk (called Cpmk -based SkSP-RGSP). The proposed plan achieves comparable discriminatory power to traditional sampling plans while significantly reducing the required sample size. Detailed tables of plan parameters are given to facilitate effective implementation for practitioners.

Analysis of selected quality parameters of dried herbs available on the European market

Abstract International trade in herbs and spices is showing steady growth. This may contribute to the deterioration of their quality (complex supply chains) and the search for alternative, cheaper sources (adulteration). This paper presents the results of quality control of culinary herbs available on the European markets. Eight spices were evaluated: savory, lovage, basil, thyme, marjoram, oregano, fennel, mustard. The tests were performed (from January 2022 till January 2023) for three production batches from five different suppliers, and analyzed such parameters as aroma, overall appearance, impurity content, net weight, moisture content, ash content and essential oils. The analyzed parameters are the basic quality characteristics controlled by institutions overseeing the quality of foodstuffs. The determinations were made on the basis of European standards. The results show deviations from the standards especially in the content of essential oils. Slight exceedances of the standards were also recorded for water and total ash content. On the other hand, for such parameters as net weight, impurity content, general appearance or odor, no overstepping of acceptable standards was recorded.

The Power Board of the KM3NeT Digital Optical Module: Design, Upgrade, and Production

The KM3NeT Collaboration is building an underwater neutrino observatory at the bottom of the Mediterranean Sea, consisting of two neutrino telescopes, both composed of a three-dimensional array of light detectors, known as digital optical modules. Each digital optical module contains a set of 31 three-inch photomultiplier tubes distributed over the surface of a 0.44 m diameter pressure-resistant glass sphere. The module also includes calibration instruments and electronics for power, readout, and data acquisition. The power board was developed to supply power to all the elements of the digital optical module. The design of the power board began in 2013, and ten prototypes were produced and tested. After an exhaustive validation process in various laboratories within the KM3NeT Collaboration, a mass production batch began, resulting in the construction of over 1200 power boards so far. These boards were integrated in the digital optical modules that have already been produced and deployed, which total 828 as of October 2023. In 2017, an upgrade of the power board, to increase reliability and efficiency, was initiated. The validation of a pre-production series has been completed, and a production batch of 800 upgraded boards is currently underway. This paper describes the design, architecture, upgrade, validation, and production of the power board, including the reliability studies and tests conducted to ensure safe operation at the bottom of the Mediterranean Sea throughout the observatory’s lifespan.

Development of sensory tools for green rooibos (Aspalathus linearis (Burm.f.) R.Dahlgren) and changes in quality attributes during shelf-life storage.

Green rooibos (Aspalathus linearis (Burm.f.) R.Dahlgren) herbal tea is popular due to its health-promoting properties. Information on its characteristic sensory profile is scarce and sensory tools to define product variation are needed. The storage conditions and time during its shelf-life are hypothesized to affect the product quality. Production batches from two producers spanning 5 years (n = 57) were analyzed using descriptive sensory analysis. Primary attributes (>30 median intensity; 100% occurrence frequency) included 'hay/dried grass', 'cooked oats', 'tobacco', 'honey' and 'caramel' aromas, and astringent mouthfeel. 'Cooked vegetables', 'green grass', 'stewed fruit', 'rooibos-woody', 'marmalade' and 'cardboard' aromas, sweet taste and bitter taste were secondary attributes (10-20 median intensity; 100% occurrence frequency). The same flavor attributes were present, except for sweet-associated and fruity notes. A sensory lexicon and sensory wheels for aroma and palate attributes were constructed from the data. The shelf-life stability of green rooibos was evaluated in moisture-impermeable (pouches) and moisture-permeable (sachets) packaging at 25 and 40 °C at 60% relative humidity over 24 weeks. Green rooibos samples stored in pouches at 4 °C were also evaluated. Storage in sachets led to moisture uptake (~10 g (100 g)-1 dry basis) and an increase in water activity (>0.6), causing degradation of chlorophyll and dihydrochalcones. Changes in color and sensory profile (decreased vegetal, cereal and cardboard aromas and increased sweet-associated and fruity aromas) were evident and more pronounced at the higher storage temperature. Storage at ≤25 °C in moisture-impermeable packaging material is recommended for green rooibos herbal tea. © 2024 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Batch production of centimeter-scale monolayer MoS2 with low nucleation by face-to-face metal precursor supply

Transition-metal dichalcogenides (TMDs) show great potential for next-generation semiconductor due to its atomic level thickness, tunable band gap and high carrier mobility. However, high-quality monolayer MoS2 (ML-MoS2) films require stringent growth conditions during preparation. Here, we report a face-to-face metal precursor supply approach during chemical vapor deposition (CVD) to batch production of uniform ML-MoS2 films. Mo foils provide a stable concentration of metal precursors leading to uniform film generation with low nucleation. Comprehensive characterization techniques, including spectroscopic, surface topography and atomic scale analysis confirm the centimeter-scale homogeneity and high crystallographic quality of the monolayer films. Back-gate field effect transistors (FET) fabricated by ML-MoS2 exhibit excellent electrical performance. This methodology provides a pathway for the growth of TMDs, which should promote their applications in high-performance electronics or other fields.