Solution Alert

Adoptive T-cell Therapy is a promising area of medicine where the lymphocytes are used to induce antitumor effects in patients with haematological malignancies. Despite the recent commercial approval of chimeric antigen receptor (CAR) T-cells to treat B-cell acute lymphoblastic leukaemia and non-Hodgkin lymphoma, the design space for the manufacturing of T-cell therapies is yet to be fully characterised and optimised. High throughput systems such as micro-Matrix (Applikon Biotechnology) in combination with Design of Experiment approach is a powerful tool for screening culture conditions for manufacture of T-cells at the micro-scale.
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Today’s market demand on biologic and pharmaceutical manufacturers to develop new drugs — combined with the economic environment — is challenging bioprocessors to review their processing systems and seek ways to make them more flexible, reliable and cost effective. Increasingly, manufacturers are turning to single-use aseptic processing systems to meet or beat aggressive product-introduction time frames and control costs.
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Many readers may be familiar with Clean-In-Place (CIP) systems and the design considerations.  Clean-Out-of-Place (COP) solutions such as cabinet washers also have many design considerations that are often less known or thought about. Two Sani-Matic experts, Solo Yang, sales engineer and BPE contributing member, and Pete Barrie, senior product manager and BPE Systems Design committee member, provide a brief overview of the cabinet washer standards released in the 2016 edition of ASME BPE and the ten must-knows about them.
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A long-standing ABEC customer experienced repeated sheathing and tailing lug cracks due to extreme thermal shock. ABEC proposed installing slip jackets around the vessels as a root cause solution to the problem; however, due to time constraints, the customer elected to reinforce the cracking areas.Despite the reinforced alcoves, the doublers around the legs, and added support around the breast ring, the thermal shock continued to cause sheathing cracks. During the year-end business review, ABEC resubmitted the slip jacket proposal and provided a business case outlining the cost savings and ROI (return on investment) of the slip jacket solution versus continual sheathing crack repairs. ABEC received approval to perform the installation on two test vessels.
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There has been increasing momentum recently in the biopharmaceutical industry to transition from traditional batch processes to next‐generation integrated and continuous biomanufacturing. This transition from batch to continuous is expected to offer several advantages which, taken together, could significantly improve access to biologics drugs for patients. Despite this recent momentum, there has not been a commercial implementation of a continuous bioprocess reported in the literature. In this study, we describe a successful pilot‐scale proof‐of‐concept demonstration of an end‐to‐end integrated and continuous bioprocess for the production of a monoclonal antibody.
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The detection of biothiols has attracted extensive interest owing to their vital importance in maintaining bioprocesses. Here, we reported a fluorescent probe MANK with facile preparation and excellent water solubility, which can effectively distinguish Cys from its two analogues glutathione (GSH) and homocysteine (Hcy) with a large “turn‐on” fluorescent signal of more than 40‐fold enhancement. Importantly, during the selective detection of Cys, the large concentration differences of three biothiols in living cells had been taken into account. The maleyl group in MANK acted both as a recognition site and fluorescence quenching group. And in the presence of Cys, the thiol group of Cys reacted with maleyl group of MANK by nucleophilic addition and the resulting adduct restored fluorescence emission with a high fluorescent quantum yield of 0.40 in phosphate buffered saline (PBS). Finally, it was successfully utilized to map the endogenous Cys in living cells by confocal microscopy.
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Biochemical changes essential for cell growth occur within sub-cellular spaces, for which there are no readily available technologies to map their important ephemeral fluctuations. Fluorescent nanosensors, have the potential to address this challenge, due to their biocompatibility, ratiometric accuracy and real-time measurement capabilities. They have already demonstrated their potential to quantify pH, molecular oxygen and temperature in complex model systems, which include nematodes, fungi, stem cells and electronic devices. Therefore, these exciting findings could be readily translated to augment biomanufacturing for cell and gene therapy future pharmaceuticals.
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We present three types of optical ammonia sensors suitable for environmental, bioprocess, and reaction monitoring. A respective fluorescent BF2-chelated tetraarylazadipyrromethene dye (aza-BODIPYs) is physically entrapped in a polyurethane hydrogel (HydroMed D4) forming an emulsion system with vinyl-terminated polydimethylsiloxane (PDMS). The analyte-sensitive layer is covered by a hydrophobic membrane which excludes hydrophilic substances. Three different protection layers are tested, whereby the Teflon and the hydrophobic PES layers outperform a PDMS/TiO2 layer. 
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Enzymes production by solid-state cultivation in packed-bed bioreactor needs to be improved by mathematical modeling and also by experimentation. In this work, a mixture of sugarcane bagasse and wheat bran was used for the growth of the fungus Myceliophthora thermophila I-1D3b, able to secrete endoglucanase and xylanase, enzymes of interest in the second-generation ethanol production. Bench and pilot-scale bioreactors were used for the experiments, while critical parameters as bed porosity and airflow distribution were evaluated. Results showed enzymes with higher activities for the most porous medium, even though the less substrate amount to be cultivated.
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Ultrafiltration is a powerful method used in virtually every pharmaceutical bioprocess. Depending on the process stage, the product-to-impurity ratio differs. The impact of impurities on the process depends on various factors. Solely mechanistic models are currently not sufficient to entirely describe these complex interactions. We have established two hybrid models for predicting the flux evolution, the protein rejection factor and two components’ concentration during crossflow ultrafiltration. The hybrid models were compared to the standard mechanistic modeling approach based on the stagnant film theory. The hybrid models accurately predicted the flux and concentration over a wide range of process parameters and product-to-impurity ratios based on a minimum set of training experiments. 
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We report a mid-IR transmission setup for the analysis of the protein amide I and amide II band in aqueous solutions that achieves a limit of detection as low as 0.0025 mg mL–1 (outperforming our previous results and other state-of-the-art mid-IR-based techniques by almost an order of magnitude). This large improvement is made possible by combining the latest-generation external cavity-quantum cascade laser (EC-QCL) operated at room temperature with an optimized double-beam optical setup that adjusts the path length (26 μm) to ensure robust sample handling.
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Digital methods for process design, monitoring, and control can convert classical trial-and-error bioprocess development to a quantitative engineering approach. By interconnecting hardware, software, data, and humans currently untapped process optimization potential can be accessed. The key component within such a framework is a digital twin interacting with its physical process counterpart. In this chapter, we show how digital twin guided process development can be applied on an exemplary microbial cultivation process.
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A high degree of charge heterogeneity is an unfavorable phenomenon commonly observed for therapeutic monoclonal antibodies (mAbs). Removal of these impurities during manufacturing often comes at the cost of impaired step yields. A wide spectrum of posttranslational and chemical modifications is known to modify mAb charge. However, a deeper understanding of underlying mechanisms triggering charged species would be beneficial for the control of mAb charge variants during bioprocessing. In this study, a comprehensive analytical investigation was carried out to define the root causes and mechanisms inducing acidic variants of an immunoglobulin G1‐derived mAb. 
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The complexity of biopharmaceutical products implies that their approval is based on a specific process. Any further change, especially in the process, requires drug validation in terms of clinical effects and biosecurity. Because changes in the processes may be unavoidable, quality assurance by inspection at the end of the process (Quality by Testing-QbT) tends to be replaced by a new quality perspective called Quality by design (QbD) which builds drug Critical Quality Attributes (CQA) controlling key Critical Process Parameters (CPP) in real-time. Consequently, the objective of this work has been to develop new methodological and experimental applications, based on in situ NIR spectroscopy, for real-time monitoring of biopharmaceutical-producing cell cultures.
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This work presents a miniaturized electrochemical sensor-integrated bioprocess monitoring pod (bPod) that wirelessly monitors local dissolved oxygen (DO) saturation within bioreactors in real-time. The system comprises a compact printed circuit board (PCB) that integrates a potentiostat analog-front-end (AFE) and a Bluetooth Low Energy (BLE) microcontroller with an electrochemical DO sensor. In situ detection of DO within the bioreactor is enabled via a 3-D printed ABS-M30i shell, representing a robust and biocompatible packaging solution for prolonged monitoring. 
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This is the first comprehensive review on methods and materials for use in optical sensing of pH values and on applications of such sensors. The Review starts with an introduction that contains subsections on the definition of the pH value, a brief look back on optical methods for sensing of pH, on the effects of ionic strength on pH values and pKa values, on the selectivity, sensitivity, precision, dynamic ranges, and temperature dependence of such sensors. Commonly used optical sensing schemes are covered in a next main chapter, with subsections on methods based on absorptiometry, reflectometry, luminescence, refractive index, surface plasmon resonance, photonic crystals, turbidity, mechanical displacement, interferometry, and solvatochromism.
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The COVID-19 pandemic has highlighted a pressing need for new analytical technologies that provide more sensitive and quantitative measures of proteins and whole viruses Virus lasers are a new class of biological laser system for biological detection in which the detection probes produce an amplified optical – rather than chemical, as in the case of PCR – signal. Ligand-binding assays based on virus lasers promise to be more rapid and precise than competing technologies. In the long-term, virus lasers will substitute antibody- based techniques in a wide range of applications, including discovery research, bioprocess analytics, clinical diagnostics, and environmental monitoring. In this project, we demonstrated the feasibility of the technology by overcoming two major technical barriers.
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This paper presents various software based approaches suitable for the design of knowledge-based monitoring of biotechnological production processes. These processes require special treatment with respect to the complexity in biochemical reactions which make the design and construction of reasonably complex and practically usable mathematical models rather difficult. Additional complexity arises from the lack of industrially viable sensors for on-line measurement of key process variables. This approach is shown in practice using two different case studies of knowledge-based software sensors.
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Pichia pastoris has emerged in the past years as a promising host for recombinant protein and biopharmaceutical production. In the establishment of high cell density fed‐batch biomanufacturing, screening phase and early bioprocess development (based on microplates and shake flasks) still represent a bottleneck due to high‐cost and time‐consuming procedures as well as low experiment complexity. In the present work, a screening protocol developed for P. pastoris clone selection is implemented in a multiplexed microfluidic device with 15 μL cultivation chambers able to operate in perfusion mode and monitor dissolved oxygen content in the culture in a non‐invasive way.
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The demand for feasible bioprocesses is continuously increasing in order to realize new production pathways, convert yet unconsidered raw materials, and allow new or advanced product portfolios. One bioprocess of major interest over the last years is the production of fuels or chemicals from biomass. One key process within this production chain is the degradation of recalcitrant cellulose to better processible soluble sugars, and cellulases are key players in the hydrolyzation of cellulose. To identify best working cellulase candidates and their production hosts a reliable screening procedure is necessary. Therefore, a robotic platform is presented, the so called “Cellulolytic RoboLector”. 
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Real-time monitoring of product titers during process development and production of biotherapeutics facilitate implementation of quality-by-design principles and enable rapid bioprocess decision and optimization of the production process. Conventional analytical methods are generally performed offline/at-line and, therefore, are not capable of generating real-time data. In this study, a novel fiber optical nanoplasmonic sensor technology was explored for rapid IgG titer measurements. The sensor combines localized surface plasmon resonance transduction and robust single use Protein A-modified sensor chips, housed in a flexible flow cell, for specific IgG detection.
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Buffer preparation and storage requires a significant facility footprint in large scale bioprocessing and together with the costs of supply chain management can have a substantial economic impact. In-line buffer mixing in chromatography is commonly performed by blending different buffer solutions using at least two pumps and a static or dynamic mixer. We developed a device for an in-line gradient delivery of buffering agents directly from solids to be applied for chromatographic separation processes. A solid feeding device with a screw conveyor and a hold tank for the solids was designed and a miniaturized system was 3D printed.
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Miniaturized stirred-tank bioreactor systems provide a scalable platform for high-throughput bioprocess development. Online measurement of process variables is a major demand to enable efficient process monitoring and control in parallel operated bioreactors. One miniaturized laser light source and two photodiodes were placed around a cylindrical disposable bioreactor made of polystyrene for individual and contact-free measurement of optical density (OD). Online OD measurements based on the transmitted light signals showed low standard deviation at low cell densities, whereas scattered light signals were more accurate at higher cell densities.
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Ultra-performance liquid chromatography is a common analysis tool, and stirring is common in many laboratory setups. Here we show a device which enables continuous stirring of samples whilst inside an ultra-performance liquid chromatography system. Utilizing standard magnetic stirring bars that fit standard vials, the device allows for the automation of experimental setups that require stirring. The device is designed such that it can replace the standard sample holder and fits in its place, while being battery operated. Design files and schematics are provided.
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Influence of Image Analysis Strategy, Cooling Rate, and Sample Volume on Apparent Protein Cloud-Point Temperature Determination

The protein cloud-point temperature (TCloud) is a known representative of protein–protein interaction strength and provides valuable information during the development and characterization of protein-based products, such as biopharmaceutics. A high-throughput low volume TCloud detection method was introduced in preceding work, where it was concluded that the extracted value is an apparent TCloud (TCloud,app). As an understanding of the apparent nature is imperative to facilitate inter-study data comparability, the current work was performed to systematically evaluate the influence of 3 image analysis strategies and 2 experimental parameters (sample volume and cooling rate) on TCloud,app detection of lysozyme.
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Quality by Design Approaches to Assessing the Robustness of Tangential Flow Filtration for mAb

Quality by Design (QbD) is a modern approach for quality assurance in pharmaceutical production. This article illustrates a case study of TFF robustness performed for a process characterization of a monoclonal antibody under QbD principles by exploring functional relationships that link the process parameters to quality/process attributes with prior process knowledge, risk assessment, and multivariate experiments. In every case of quality or process attributes, all measured values were in alignment with the allowable specification range, and the developed models were non-significant and had no lack of fit, thus confirming the robustness of the TFF process within the tested ranges of process parameters.
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Pre‑Stage Perfusion and Ultra‑High Seeding Cell Density in CHO Fed‑Batch Culture: A Case Study for Process Intensification Guided
by Systems Biotechnology

Process intensification strategies are needed in the field of therapeutic protein production for higher productivities, lower cost of goods and improved facility utilization. This work describes an intensification approach, which connects a tangential-flowfiltration (TFF) based pre-stage perfusion process with a concentrated fed-batch production culture inoculated with an ultrahigh seeding density (uHSD). This strategy shifted biomass production towards the pre-stage, reaching up to 45 × 106 cells/mL in perfusion mode. Subsequently, production in the intensified fed-batch started immediately and the product titer was almost doubled (1.9-fold) in an equivalent runtime and with comparable product quality compared to low-seeded cultures. Overall, we showed that the described intensification strategy yielded in a higher volumetric productivity and is applicable for existing or already approved molecules in common, commercial fed-batch facilities.
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Virus Harvesting in Perfusion Culture: Choosing the Right Type of Hollow Fiber Membrane

The use of bioreactors coupled to membrane‐based perfusion systems enables very high cell and product concentrations in vaccine and viral vector manufacturing. Many virus particles, however, are not stable and either lose their infectivity or physically degrade resulting in significant product losses if not harvested continuously. Even hollow fiber membranes with a nominal pore size of 0.2 µm can retain much smaller virions within a bioreactor. Here, we report on a systematic study to characterize structural and physicochemical membrane properties with respect to filter fouling and harvesting of yellow fever virus (YFV; ~50 nm). In tangential flow filtration perfusion experiments, we observed that YFV retention was only marginally determined by nominal but by effective pore sizes depending on filter fouling. Evaluation of scanning electron microscope images indicated that filter fouling can be reduced significantly by choosing membranes with certain characteristics.
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Modulation of Transmembrane Pressure in Manufacturing Scale Tangential Flow Filtration N‐1 Perfusion Seed Culture

A high‐density culture was used to inoculate the production stage of a biomanufacturing process. At constant permeate flux operation, increased transmembrane pressures (TMPs) were observed on the final day of the manufacturing batches. Small scale studies suggested that the filters were not irreversibly fouled, but rather exposed to membrane concentration polarization that could be relieved by tangential sweeping of the hollow fibers. Studies were undertaken to analyze parameters that influence the hydrodynamic profile within hollow fibers; including filter area, cell density, recirculation flow rate, and permeate flow rate. Results indicated that permeate flow rate had the greatest influence on modulating TMP. Further evaluation showed a significant decrease in TMP when permeate flow was reduced, and this occurred without any negative effect on cell growth or viability. 
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Wide‐Surface Pore Microfiltration Membrane Drastically Improves Sieving Decay in TFF‐Based Perfusion Cell Culture and Streamline Chromatography Integration for Continuous Bioprocessing

Although several compelling benefits for bioprocess intensification have been reported, the need for a streamlined integration of perfusion cultures with capture chromatography still remains unmet. Here, a robust solution is established by conducting tangential flow filtration‐based perfusion with a wide‐surface pore microfiltration membrane. The resulting integrated continuous bioprocess demonstrated negligible retention of antibody, DNA, and host cell proteins in the bioreactor with average sieving coefficients of 98 ± 1%, 124 ± 28%, and 109 ± 27%, respectively. Further discussion regarding the potential membrane fouling mechanisms is also provided by comparing two membranes with different surface pore structures and the same hollow fiber length, total membrane area, and chemistry.
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Development of Redox Potential-Driven Fermentation Process for Recombinant Protein Expression
A redox potential-driven fermentation, maintaining dissolved oxygen at a prescribed level while simultaneously monitoring the changes of fermentation redox potential, was developed to guide the cultivation progress of recombinant protein expression. A recombinant E. coli harboring prolinase-expressing plasmid (pKK-PepR2) was cultivated using the developed process. Two distinct ORP valleys were noticeable based on recorded profile. The first ORP valley is equivalent to the timing for the addition of inducing agent, and the second ORP valley serves to guide the timing for cell harvesting. The final prolinase activity is 0.172 μmol/mg/min as compared to that of 0.154 μmol/mg/min where the optical density was employed to guide the timing of inducer addition and an empirically determined length of the cultivation.
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Process Adapted Calibration Improves Fluorometric pH Sensor Precision in Sophisticated Fermentation Processes
In order to develop an accurate scale‐down model for bioprocess screening and optimization, small‐scale bioreactors must be able to accurately reproduce complex process designs. Monitoring methods, such as fluorometric‐based pH sensors, provide elegant solutions for the miniaturization of bioreactors, however, previous research suggests that the intrinsic fluorescence of biomass alters the sigmoidal calibration curve of fluorometric pH sensors, leading to inaccurate pH control. In this article, we present results investigating the impact of biomass on the accuracy of a commercially available fluorometric pH sensor. Subsequently, we present our calibration methodology for more precise online measurement and provide recommendations for improved pH control in sophisticated fermentation processes.
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In this thesis, we present the case for the use of mathematical optimization of mechanistic models to accurately describe cell culture processes and augment their behavior. We first outline recent advances in understanding of metabolic regulation and homeostasis. Cell signaling and metabolic networks interact over multiple time-scales and through multiple means, resulting in cell metabolism with nonlinear behavior that is consequently context-dependent. In the following sections of this work, we then develop an optimization framework which can efficiently be used for the design of experiments to rewire cellular metabolism through metabolic engineering, or to otherwise understand the biological requirements of different metabolic phenomena.
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To improve the purification of monoclonal antibodies (mAbs) produced by mammalian cell culture, lipid removal by lipase addition was evaluated. A workflow was developed that combined ultra-scale down centrifuge and filtration with design of experiments to screen, solids remaining, lipid concentration and depth filter capacity according to the viability of the cell culture, the enzyme addition and the equivalent flow rate to centrifuge. Results showed a statistically significant impact of lipase treatment on clarification, when CHO cell broth with low viability and high concentration of lipids was exposed to high shear forces. This shows proof of concept of the auto-lipolytic chassis as means to improve manufacturability in mAb processing.
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Real-Time Characterization of Mammalian Cell Culture Bioprocesses by Magnetic Sector MS

Mammalian cell culture processes were characterized upon the analysis of the exhaust-gas composition achieved through the on-line integration of a magnetic sector MS analyzer with benchtop bioreactors. The non-invasive configuration of the magnetic sector MS provided continuous evaluation of the bioreactor's exhaust gas filter integrity and facilitated the accurate quantification of O2 and CO2 levels in the off-gas stream which ensured preserved bioreactor sterility prior to cell inoculation and provided evidence of the ongoing cellular respiratory activity throughout the cultures. Real-time determination of process parameters such as the Respiratory Quotient (RQ) allowed for precise pin-pointing of the occurrence of shifts in cellular metabolism which were correlated to depletion of key nutrients in the growth medium, demonstrating the suitability of this technology for tracking cell culture process performance.
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Effect of Sialic Acid on Mammalian Cell Culture and Protein Expression: A Potential Productivity Enhancer for Biopharmaceutical Cell Culture Processes Improved productivity of the two most commonly used cell lines in the biopharmaceutical industry, such as human embryonic kidney 293 (HEK293) and Chinese hamster ovary (CHO), could reduce production costs and increase manufacturing capacity. One method for increasing protein productivity is the addition of antioxidants during the cell culture process. In this study, we examined the effect of sialic acid (SA) on one HEK293 cell line and two CHO cell lines. The addition of SA to HEK293 cell led to a higher viable cell density (VCD), viability (Via), and a lower lactate content in the later stage of cultures. Further results showed that SA reduced the reactive oxygen species (ROS), improved cell viability, reduced lactate production, and increased antibody expression by more than 20% in the later stage of the two CHO cell lines cultures.
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Control of IgG glycosylation in CHO cell perfusion cultures by GReBA mathematical model supported by a novel targeted feed, TAFE
The N-linked glycosylation pattern is an important quality attribute of therapeutic glycoproteins. It has been reported by our group and by others that different carbon sources, such as glucose, mannose and galactose, can differently impact the glycosylation profile of glycoproteins in mammalian cell culture. Acting on the sugar feeding is thus an attractive strategy to tune the glycan pattern. However, in case of feeding of more than one carbon source simultaneously, the cells give priority to the one with the highest uptake rate, which limits the usage of this tuning, e.g. the cells favor consuming glucose in comparison to galactose. We present here a new feeding strategy (named ‘TAFE’ for targeted feeding) for perfusion culture to adjust the concentrations of fed sugars influencing the glycosylation.
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Far from being a concept, it is my understanding that the folks at G-Con have made it a reality. The way it was explained to me is that they take one of their proven LabPOD products and actually mount it on a trailer designed to be hauled by a semi-truck. This has the result of giving the lab complete mobility. Learn More

It is my understanding that this event had some technical issues surrounding live presentations. However, it appears that Sani-Matic has you covered. Here is an "instant replay" of their presentation where you can learn about how you can reduce COP part cleaning labor with automated cabinet washers. Learn More

I took a look at our event calendar and I think I found it. The title was “Online Monitoring and Control of Upstream Titer, Product Quality and Amino Acid Content Using 2D-LC with SegFlow Interface”. Although the live webinar took place several weeks ago, I was able to identify an On-Demand link which is provided below

Agilent 2D-LC with Segflow Interface

I think the product you are looking for is the recently launched CultureOne from Alfa Laval. It features a replaceable insert that includes Alfa Laval’s fully hermetic design and UniDisc technology. It is being presented as the first premium separator for single-use bioprocessing. Here is a link to more information;

Alfa Laval CultureOne

The virtual environment you are looking for is actually free standing and available in two parts; the first being a Cleanroom and the second being a QC Lab. Among the products featured are particle counters, TOC analyzers, and cell counting/viability analyzers to name just a few. Here is a link to more information and access to the environment; 

Beckman Coulter

We are going to have to get back into the DeLorean for this one. I took a look at their website and the folks at Broadley James still offer a DO membrane cartridge tester. It is a simple device that allows you to check your membranes for leaks before use. You did not mention whose DO probes you are using but if memory serves this solution works on most if not all of them, provided they are 25 mm. Here is a link to more information;

DO Membrane Cartridge Tester

I'm glad you specified plastic as the preferred material for your fabrication, otherwise we would be looking at a lot of metal benders. That being said, I would recommend you take a look at Non-Metallic Solutions. While I have not done any work with them directly, I know several folks like yourself who have and say the experience was very positive. Here is a link to more information;

Non-Metallic Solutions

This is an increasingly common challenge that I'm pleased to get a chance to address. While most clamp-on flow sensors will make a claim to suitability for applications requiring braid reinforced tubing, few can deliver. That being said, I would recommend you take a look at the offering from Sonotec. I have actually heard first-hand from end users like yourself that their flow sensors work well with reinforced tubing. Here is a link to more information;

Sonotec Sonoflow

With all that has been going on I was wondering how long it would take for this question to come my way. With that in mind, I cheated and have been doing some research. What I came up with is a product called "Tandem" from a firm called Apprentice. It is a really cool solution that allows you to bring the knowledge currently outside your bioprocess suite into the suite, while remaining remote. You will find a link below where you can learn more about this enabling technology.

Apprentice Tandem

While I have not had first-hand experience with the product yet, there is an electromagnetic flowmeter that features a disposable flow tube designed specifically for single use bioprocessing applications. The flowmeter is manufactured by the German firm Krohne, whose other products for flow and level measurement I have had success with over the years. Here is a link to more information;

Flexmag 4050

To be honest, I was not aware that this was a bioprocess challenge needing to be addressed. However, I did a bit of research and found that the use of "pulsation dampeners" has been explored in bioprocess applications downstream, specifically TFF and Chromatography. As the name implies their purpose is to mitigate the possible adverse effects of pressure and flow pulsations potentially associated with positive displacement pumps. Here is a link to more information;

Single-Use Pulsation Dampener

I would strongly recommend you take a look at the "Digital Instruments & Protocols" document that Brooks Instrument published earlier this year. It addresses the advantages to be realized from a digital solution as well as a number of the considerations for each of the most widely utilized protocols. Here is a link to more information;

Digital Instruments & Protocols

While a good problem to have, it is still a problem. I would suggest you take a look at the ArcAir software that is actually available from the supplier of the pH and DO sensors that came with those new bioreactors you mentioned. Here is a link to more information;


I have to admit that at first I thought this was going to be nearly impossible, then I noticed your application. While close, I think the product you are looking for is not the Echo but instead the Ekko. It is a scalable acoustic cell processing tool developed by FloDesign Sonics which is now part of Millipore Sigma. Here is a link to more information;


Not that long ago I would have been hard pressed for such a solution, thankfully things have changed. In recent years we have seen the introduction of single-use solutions for most, if not all, bioprocessing applications and sample valves are no exception. The folks at FluidLine Technology have introduced a line of disposable sampling valves that can be either Single-Use (3 cleaning cycles) or Limited Use (12 cleaning cycles). Here is a link to more information;

Fluidline Technology

The virtual environment you are looking for is actually free standing and available in two parts; the first being a Cleanroom and the second being a QC Lab. Among the products featured are particle counters, TOC analyzers, and cell counting/viability analyzers to name just a few. Here is a link to more information and access to the environment;

Beckman Coulter Virtual Experience

It took a bit of doing but I was able to find a small peristaltic pump that meets the requirements you mention. It features independent control of 2, 3 or 4 channels and supports serial communication. I had hoped to offer you more options, but the combination of independent control of 4 channels and serial communication proved a limiting factor for many. Here is a link to more information;

Ismatec Reglo

I'm pleased to report that there are no fewer than 3 company's making spare parts for BioNet bioreactors such as the ones you purchased. They are Applikon, Chemglass and Broadley James. A quick review of their websites indicates that all three have the parts you need. Here are links to more information;

Broadley James

I think the product you are looking for is the recently launched CultureOne from Alfa Laval. It features a replaceable insert that includes Alfa Laval's fully hermetic design and UniDisc technology. It is being presented as the first premium separator for single-use bioprocessing. Here is a link to more information;

Alfa Laval CultureOne

Not that long ago I would have been hard pressed for such a solution, thankfully things have changed. In recent years we have seen the introduction of single-use solutions for most, if not all, bioprocessing applications and sample valves are no exception. The folks at FluidLine Technology have introduced a line of disposable sampling valves that can be either Single-Use (3 cleaning cycles) or Limited Use (12 cleaning cycles). Here is a link to more information;

FluidLine Technology

I must admit that when I first saw this question, I concluded there simply was not enough space in the Alert for all the "next generation" bioprocess controllers that cross my path. However, after reading the question again and noting the term "Fix", I concluded one of two things were at work. Either you were looking for the "iFix" product from GE by way of Intellution, which has not been called "next generation" in a long, long time or you were referring to the PHIXED platform. I suspect it is the latter. Although there is not much publicly available to go on, you can use the link below to learn more;


Actually, it is my understanding that what was once in development has now been commercialized in the form of the "Breez" bioreactor from erbi. It is a cassette-based mL scale bioreactor platform enabled with mixing and closed loop pH, DO, Temperature CO2 and Cell Density. I have not had first-hand experience with it yet but people I trust who are affiliated with the platform have good things to say. Use the link below to learn more;


I would take a look at the products offered by the folks at BlueSens, specifically their BlueInOne Cell. It is a compact gas analyzer capable of measuring in parallel both carbon dioxide and oxygen online as well as in real-time. They are a German firm with a rather long history of addressing bioprocessing applications specifically. Here is the link to more information;

BlueInOne Cell

I would urge you to take a look at the RoSS product from Single Use Support. More than just a stackable container, it offers a number of engineered features designed for optimum storage of both your single use bags as well as the associated connectors and hoses. I have included a link below for your reference;


You definitely know what you want, or don't want as the case may be, and I think I have found it. A 202-page doctoral of engineering thesis prepared at University College London with the support not of the manufacturer but of no less an independent source than Eli Lilly. Complete with chapters dedicated to fluid mixing, mass transfer and so much more. Here is a link to more information;

Engineering Characterization of a Rocked Bag Bioreactor for Improved Process development and Scale-Up

Based on my experience, if you are looking for a benchtop instrument dedicated to the accurate and reliable measurement of Osmo then your best bet is the benchtop solution from Advanced Instruments. They are arguably the gold standard for osmolality measurement in our industry. Having enabled some of the most well-known stand alone and integrated bioprocessing solutions. Here is a link to more information;

Advanced Instruments

While I have not had first-hand experience with the product yet, there is an electromagnetic flowmeter that features a disposable flow tube designed specifically for single use bioprocessing applications. The flowmeter is manufactured by the German firm Krohne, whose other products for flow and level measurement I have had success with over the years. Here is a link to learn more;

Flexmag 4050

While in principle it sounds simple enough, moving a bioprocess liquid from one location to another in a manner that is at once fast, reliable and sterile, the practice has proven anything but simple. The products noted below are proven solutions for automating the collection of a sample and delivering it to a bioprocess analyzer.

Flownamics Seg-Flow

Lonza MAST

Nova BioProfile

Securecell Numera

Now this is a classic, from the reference to a 25mm threaded port, to the fact that the port in question is referred to as an 'ingold'. In this case, one classic solution deserves another. I would recommend the Keofitt sampling valve, which is fast approaching its 40th birthday and still going strong with 350,000+ valves rumored to be in operation. Also, since you did not mention if the port on your vessel is the standard or safety design, be sure to double check as this will determine which Keofitt valve length you need for a correct o-ring placement.


Based on your description, I think it is safe to say you saw the orbital shaken bioreactor system from Kuhner. I too have seen these systems in operation at conferences and the novel way in which they agitate. The system you describe as being benchtop is likely their SB10 which has a working volume of 3L to 12L. I understand there is also an SB50 and SB200 which will take you all the way up to 200L working volume to ensure scalability. Here is a link to more information; 

Kuhner SB10

With all that has been going on I was wondering how long it would take for this question to come my way. With that in mind, I cheated and have been doing some research. What I came up with is a product called "Tandem" from a firm called Apprentice. It is a really cool solution that allows you to bring the knowledge currently outside your bioprocess suite into the suite, while remaining remote. You will find a link below where you can learn more about this enabling technology.

Apprentice Tandem

While there have been several attempts at a glassless solid-state pH electrode, most notably those based on ISFET technology, their adoption by our community has been less than stellar so we will set those aside. Which brings us to the Diamond FET pH sensor understood to be in development at Yokogawa. As the name implies, it utilizes a semiconductive diamond that delivers both physical robustness and chemical stability. I have included a link to a paper discussing the development of this pH sensor below for your reference. There are other solid-state pH sensors in development, most notable the one out of UC Davis, but Yokogawas' effort best matches your question.

Glassless Solid-State pH Sensor

While there are a number of highly qualified proven solutions for the measurement of individual elements of a bioprocess, the ability to monitor multiple elements of a bioprocess continuously in real-time is currently the role of only two core principles; Raman and Near-Infrared (NIR). However, from my experience, the better solution of the two for bioprocessing is the Raman. Here is a link to the specific platform I would suggest you take a look at;

Kaiser Optical RamanRxn2

Recognizing that your PD scale application will inevitably need the flexibility of scaling-up, and having had first hand positive experiences with many of the folks behind the system, past and present, the Xcell ATF System from Repligen is the way to go. It is truly scalable to your bioprocess, has a proven history of favorable performance and is available in a single-use version if you are interested.

Xcell ATF System

For your application, two single-use pressure sensors immediately come to mind. The first being the PendoTech offering which has a proven history of excellence and with which I have first-hand experience. The second offering being from Parker, which I knew more personally when they were SciLog, and also enjoys a history of excellence. I would urge you to take a look at both and see which best meets your needs.



The folks at Meissner have published a tech bulletin that speaks specifically to achieving a homogenous solution in one of their single-use containers that might meet your needs. The paper documents in great detail the methodology they used to identify the best practice and is supported by a substantial amount of data.

Conductivity Testing of Mixing Systems

This past December Nova Biomedical introduced their on-line auto sampling solution for the BioProfile Flex 2 known as the OLS. You would likely have seen this solution featured at numerous industry events in recent months if not for the challenges posed by COVID-19. While several firms offer a solution for automated sampling from the Flex 2, the OLS is the only sampling solution that is native to Nova. I have provided a link below to more information.

FLEX2 On-Line Autosampler (OLS)

While there are a host of bioprocess suppliers who provide flow cells, most all of which being commercial off the shelf (COTS), the sensors you mention needing to support made all the difference. I would recommend you take a look at the Hamilton offering of flow cells. I have provided a link where you can learn more.

Hamilton Flow Cells

Not that long ago such a question would have me reaching for the name of a good machine shop. One capable not only of machining the 316 S.S., complete with ports and requisite threads, but of getting the Ra finish on the wetted surface just right, but not today. Instead, I'm going to recommend an industry leading manufacturer of benchtop bioreactors with decades of experience in the design and manufacture of traditional bioreactor headplates, ports and associated accessories. That just so happens to now have the ability to manufacture fully customizable headplates, ports and the like by utilizing 3D printing technology.

AppliFlex ST

With all that has been going on I was wondering how long it would take for this question to come my way. With that in mind, I cheated and have been doing some research. What I came up with is a product called "Tandem" from a firm called Apprentice. It is a really cool solution that allows you to bring the knowledge currently outside your bioprocess suite into the suite, while remaining remote. You will find a link below where you can learn more about this enabling technology. 

Apprentice Tandem

Just when you think you're out, they pull you back in. All kidding aside, it sounds like you should take a look at the Finesse (now Thermo) TruFlow. It is a compact manifold solution designed specifically to address the challenges associated with bioprocess gas management. Per your requirements, it manages up to 6 gases and can direct gases to headspace or sparge. Bonus fact, it was known as the "Zola" during it development. I cannot speak to whether the system is available individually or must be part of a Thermo solution. The link below will provide you with more information.


To answer this question effectively I'm going to have to make the assumption that your application is a bioreactor of some scale. That being said, I would strongly suggest utilizing the FISP product from the folks at Flownamics. It is a proven solution for cell free sampling in bioreactors and fermentors at scales ranging from PD thru Pilot and Large Scale Manufacturing.


Yes. There is a single-use manifold for fluid transfer that was introduced to our community in the last couple of years that in itself does not require the use of Y connectors, stopcocks and the like. It fits 3/8" tubing ID's and is capable of a max pressure of 15 psi. No word yet if there are plans to accommodate different tubing ID's or if an automated version is in the works. I have provided a link below to more information.

Nordson CYLINDRAFlow Manifolds

This one took some real digging, but I think I found it, a 2015 patent filing from StemBioSys. The patent was for an extracellular matrix derived from human stem cells. If this sounds right to you, then I'm pleased to say that the product has been commercialized as the Cellvo Matrix Plus from StemBioSys. It is described as a novel extracellular matrix derived from human cells that improves relevancy of cell culture studies by recreating the biologically relevant microenvironment to which cells are accustomed. I have provided a link to more information below.

CELLvo Matrix Plus

With all that has been going on I was wondering how long it would take for this question to come my way. With that in mind I cheated and have been doing some research. What I came up with is a product called "Tandem" from a firm called Apprentice. It is a really cool solution that allows you to bring the knowledge currently outside your bioprocess suite into the suite, while remaining remote. You will find a link below where you can learn more about this enabling technology and the company's successful initiative to rapidly deploy it to ensure demand is met.

Apprentice Tandem