Shaken cultures of suspension-adapted animal cell lines are still the method of choice for screening and small-scale culture experiments due to their easy handling, the simple and fast implementation in almost any laboratory environment and the possibility of cost-effective parallelization. However, on closer inspection, there are a few points that need to be considered and which play a major role in successful cultivation. Learn More

In this poster an economic analysis employing modified peptide/oligo/RNA purification approach indicates a savings for an annual production amount of 10 kg peptide (synthesis, chromatography, and re-chromatography) from US$ 0.6 million to US$ 2.1 million expected, in comparison to the conventional reference process. Learn More

Protein freeze-thawing is frequently used to stabilize and store recombinantly produced proteins after different unit operations in upstream and downstream processing. However, freeze-thawing is often accompanied by product damage and, hence, loss of product. Different effects are responsible, including cold denaturation, aggregation effects, which are caused by inhomogeneities in protein concentration, as well as pH and buffer ingredients, especially during the freeze cycle. In this study, we tested a commercially available small-scale protein freezing unit using immunoglobin G (IgG) as monoclonal antibody in a typical formulation buffer containing sodium phosphate, sodium chloride, and Tween 80... Learn More

Critical process parameters (CPPs) are the key variables in the pharmaceutical manufacturing process that are most likely to affect the quality attributes of a biological product. CPPs must be monitored and controlled throughout the various stages of production. The most common CPPs measured are pH, dissolved oxygen, conductivity, capacitance, and biomass. In this white paper from CPC, the authors discuss the role of traditional sensors in single-use systems including the benefits they offer, their associated challenges and the solutions available for their successful use. Learn More

Biomanufacturing relies on numerous pieces of equipment working in concert to produce life-altering therapeutics. The equipment relies on various subsystems to achieve the desired results. In a bioreactor, one of the most essential subsystems provides gas management for the gases necessary for cellular metabolism. At the heart of the gas management subsystem is the thermal mass flow controller (MFC), a component that precisely measures and controls the delivery of gases to the bioprocess. Learn More

The development of bioreactor processes for cGMP monoclonal antibody (mAb) manufacturing requires reliable, accurate, and timely in-process analytical data to guide process development decisions. The measurement of IgG expression level or titer is a key upstream process output that can present challenges for the rapid and systematic optimization of robust, scalable process. This study compares Protein A HPLC with the Roche Cedex Bio instrument for profiling the expression of multiple antibody products generated from CHO cell bioreactor culture. Considerations of comparative instrument performance, accuracy, economics, and versatility are presented in the context of accelerating development timelines from bench scale development to manufacturing clinical antibody supply. Learn More

In this application note, published by ForteBio, the analytical group at Boehringer Ingelheim, Fremont, USA illustrates how they needed a robust assay to measure the biological activity of an antibody fragment (Fab) molecule for in-process testing as well as stability and lot release testing in their Quality Control (QC) department. The group was able to develop a working Fab activity assay on the Octet® RED system in less than a week. Learn More

The economically competitive bioproduction of specialty chemicals using microbial cultures often demands the use of complex feedstocks that have undergone minimal processing and purification. Such feedstocks may be high in cellulosic content, have dark color, contain a wide mixture of particle sizes, and exhibit substantial batch-to-batch variation. The real-time monitoring of cell density (or cell biomass) is essential to maintaining the health of the microbial culture and for optimizing the yield of bioproducts, but has been a long-standing challenge within such complex feedstocks. Learn More

The economically competitive bioproduction of specialty chemicals using microbial cultures often demands the use of complex feedstocks that have undergone minimal processing and purification. Such feedstocks may be high in cellulosic content, have dark color, contain a wide mixture of particle sizes, and exhibit substantial batch-to-batch variation. The real-time monitoring of cell density (or cell biomass) is essential to maintaining the health of the microbial culture and for optimizing the yield of bioproducts, but has been a long-standing challenge within such complex feedstocks. Learn More

On-line parameters like pH and dissolved oxygen are commonly used to optimize process yield. Further optimization is now possible with a new breed of sensors for on-line measurement of viable and total cell density. Data from traditional off-line measurements is limited and time consuming to obtain. The off-line results are delayed, and process adjustments are manual. Real-time measurement and control based on cell density is a critical consideration for any modern automated control strategy. Learn More

In this project, oxygen mass transfer in liquids through the use of different bubble generation equipment is examined. The purpose of this project is to first investigate the bubble formation through different type of spargers made from different materials and different governing oxygen transfer phenomena. Based on the analysis of the investigations, equipment weaknesses that might be crucial for some applications are identified and finally, an equipment design, which eliminates the identified weaknesses, is proposed and validated. Learn More

This new eBook, published by industry leader Brooks Instrument, takes you through the key steps to ensure your approach to calibrating bioreactor MFCs is accurate and on target. Understanding the role calibration plays in long-term MFC performance - and what steps you should take to ensure proper calibration - can help sustain bioprocessing results. Learn More

In the first installment of this three part interview series produced by Aber Instruments, Dr Aditya Bhat interviews Dr Sven Ansorge, exploring Sven's background, his experience and Sven's insights on the development of capacitance technology over the years, looking at it's adoption within the bioprocess industry and how capacitance has evolved to become a useful tool for monitoring biomass and controlling critical parameters, relating to the PAT initiative from the FDA. Learn More

The mass transfer coefficient (kL)and the value of the interfacial area (a) is used to characterize bioreactor systems for their oxygen transfer capability. The kLa value and the mixing time are amongst the most important performance indicators for bioreactors. Their calculation and modeling is extremely complex in highly aerated systems. This paper describes a new methodology for measuring the kLa value to accurately determine the coefficient. The valuable insights obtained allow for improved bioreactor characterization, thus, making it easier to meet regulatory requirements. Furthermore, examples outlining the benefits in the practical application of the new methodology are presented. Learn More

This case study, authored by AdvantaPure, illustrates the performance of their custom BioClosure systems for bulk drug substance. The primary objective of the customer was to develop a closed system that was leak proof under operating conditions and maintained container closure integrity during storage at -70oC. Additionally, the customer was concerned about foaming that occurred when filling the container. AdvantaPure's engineering team worked with the customer to design a custom system for their production needs. Learn More

What would it take to rapidly manufacture 3 metric tonnes and then 10 metric tonnes of a mAb? Optimized product development procedures to speed up the transition of a discovered mAb into clinic and into commercialization have been discussed in an excellent article by Brian Kelley. What about subsequent commercial manufacturing capacity? According to Ecker and Seymour, 23 metric tons of approved biologics were produced in 2018, with 65% of that capacity controlled by 10 companies. Squeezing an extra 10% of the global capacity out of the network seems achievable, particularly if these top 10 companies are involved. We used Biosolve Process to estimate the current manufacturing capacity and timeframes for production of these products. Learn More

Continuous processing is already well accepted on the upstream processing side, since perfusion mode culture has been in use for decades at an industrial scale.Justifications for switching from batch to continuous chromatography are numerous. Besides, the rising demand of biologics suggests reduced processing and labor costs, footprint reduction, flexibility increase, more stringent requirements for controlled, more consistent and improved quality; and most importantly, the requirement for higher productivity and therefore overall manufacturing cost reduction. This white paper, authored by Novasep, highlights why and how to intensify your bioprocess. Learn More

In this technical note, produced by Sonotec, the often asked question regarding the real world impact of placing an ultrasonic flow sensor calibrated for one type of tubing onto a different type of tubing without recalibration is addressed. Learn More

This white paper, authored by Nordson Medical, explains the role these new manifolds play in simplifying processing applications by offering companies an option that reduces the number of connections, shut-offs, and disconnections needed in typical production processes. The new component replaces older assemblies like ganged stopcocks and multiple leg manifold arrangements of fittings and pinch clamps. Learn More

Purification of enveloped viruses and virus-like particles presents several challenges due to their large size and complexity. Here we present a case study about resin screening, process development, and scale-up purification of a retrovirus-like particle. The resulting cGMP- compatible process required approximately 4 hours to purify 240 L of nuclease-treated bioreactor harvest and resulted in a 99% reduction in process volume and up to 65% recovery of virus particles with a final purity consistent with requirements for clinical trials. This protocol is readily scalable, fast, low cost, simple, and cGMP-compatible and can be used for the capture step in clinical-grade manufacture of retrovirus vectors. Learn More

This handbook, created by Cytiva, describes the use of size exclusion chromatography (SEC) for the purification and separation of biomolecules, with focus on practical information for optimized results. Since the introduction of the first SEC resin, Sephadex in 1959, SEC has played a key role in the purification of proteins and enzymes, polysaccharides, nucleic acids, and other biological macromolecules. Learn More

In this well written article from PharmTech, the author explores how modular manufacturing is being increasingly used in the biopharma industry where flexibility and low-cost manufacturing systems are sought out. The design of a modular system in biopharma processing can involve breaking down a manufacturing facility into smaller functional building blocks, also known as modules. Learn More

Conventional techniques for mammalian virus purification produce variable quality, quantity, and significant loss of particle infectivity. Here, we propose the chromatographic separation of viral particles of diverse sizes and from different families, such as dengue, Japanese encephalitis, influenza, mouse hepatitis, adenovirus, poliovirus, and feline calicivirus, using CHTTM Ceramic Hydroxyapatite Media (Resin). The separation of viral particles from impurities in at least one case was best observed on CHT Ceramic Hydroxyapatite Type II Media when compared to three other apatite media, suggesting the importance of determining which media works best for a specific virus. Learn More

This guide, produced by Pall Biotech, provides insights and recommendations for applying QbD principles for sterility assurance during aseptic processing. Learn More

Integrated data collection has been established from simple to complex analyzers within pharma bioprocesses including pH meters. Cedex Analyzers, microscale bioreactors, particle counters, or mass spectrometry. These data feed into (meta)data integration layers to enable deep learning and agile process development. The talk describes how Roche Pharma Penzberg, Singapore, and Basel use Sm@rtLine Data Cockpit middleware to support this approach. Learn More

This article, authored by Sonotec, addresses the ever growing role of non-invasive flow sensors in both traditional upstream and downstream bioprocessing applications as well as their adoption to the rapidly evolving applications in continuous bioprocessing. Learn More

In recent years, adoptive T-cell therapy (ACT) has emerged as a promising way to treat systemic cancers such as Acute Lymphoblastic Leukemia. However, robustness and reproducibility of the manufacturing process remain challenging and it is therefore pivotal to understand the effect that cell culture conditions have on the expansion and differentiation of T-cells. This work investigates the effect of CO2 on the expansion of T-cells using the bioreactor AppliFlex ST due the advantages of this single-use system such as lower initial investments, faster setup and reduced cross-contamination risks. The influence of CO2 is of particular interest with regards to potential allogeneic T-cell therapies and the associated cultivation at the large scale, where CO2-removal may become insufficient. Learn More

What is big data? What is Bioprocess 4.0? How do you leverage data to make better informed decisions? This video, produced by MilliporeSigma, explores the role data plays in biopharma scale-up and manufacturing. Learn More

It is the most crucial question in bulk drug substance management: How can product loss can be avoided or at least decreased? A global Contract Manufacturing Organization (CMO) produces different drug substances of highly valuables mABs. At the fill & finish site, the BDS is thawed. The customer compared available solutions to reduce the breakage rates of the frozen and shipped single-use bags. But the CMO experienced a high loss rate of 0,5% to 5% due to their sensitivity at sub-zero temperatures. Therefore, the goal was to significantly reduce the current product loss. This case study discloses how the implementation of Single Use Support products had an impact on the risk of product loss caused by bag breakages and how the most crucial question could be answered. Learn More

In the latest white paper presented by the National Institute of Bioprocessing Research and Training and Watson-Marlow Fluid Technology Group, 'The quest for efficiency-moving toward continuous processing', we explore the advantages of continuous processing in pharmaceutical manufacturing. Through insight into the advancement of continuous processing techniques, you will explore how new technology and production techniques can enable you to meet regulatory and quality assurance challenges whilst simplifying the management of your supply chain. Learn More

This White Paper, published by MilliporeSigma, discusseshow current trends in the biopharmaceutical industry are driving the implementation of high capacity processes capable of reducing costs and footprint without sacrificing manufacturing efficiency and product quality. A step in the biomanufacturing process that enables such convenience is ultrafiltration with single-pass tangential flow filtration (single-pass TFF). Learn More

Continuous monitoring of processes is one of the key aspects when trying to optimize and increase process reliability and efficiency. Amongst other measurement equipment, the choice of a highly precise flow sensor is of utmost importance when shifting biomanufacturing and pharmaceutical production towards the use of single-use disposables. Here, non-invasive ultrasonic sensors can provide high accuracy, combined with maximum flexibility and usability. Learn More

A typical challenge of upstream processes are variations in the growth behaviour of cultures. This can result in batch to batch variations of the cell density at the time of subculture. These variations can cause problems with further scheduling of the upstream cascade. As a solution for operational practice, a cell number control system was developed on the basis of the temperature dependence of the growth rate. The system can readily be implemented in existing production units. To our knowledge, this is the first report of such a controller for mammalian cell cultures. Learn More

This whitepaper, produced by Novasep, addresses the numerous justifications for switching from batch to continuous chromatography. Among them, the rising demand of biologics suggests reduced processing and labor costs, footprint reduction, flexibility increase, more stringent requirements for controlled, more consistent and improved quality; and most importantly, the requirement for higher productivity and therefore overall manufacturing cost reduction. Learn More

Over the past 40 years, drug development costs have been increasing exponentially and the return on investment within pharmaceutical companies has come under pressure. Fast time-to-market is essential in order to be competitive and moreover to serve today's patients with the best possible medicines available. V-Control is a process control platform that has been developed as a 'one common-platform' solution from Discovery up to Production. The seamless technology transfer of modules from R&D to production systems and the scalable data transfer result in optimal bioprocess control with shorter lead times and lower development costs. Learn More

Continuous culture is best explained by discussing the basic components of the process. The theory is well known and simple to understand: Medium is both added and removed throughout much of the fermentation in order to keep cell numbers in balance. Actual execution can be difficult for starters, as there are more pumps, tubes and considerations than a simple batch fermentation.

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Driven by epidemic events and by governmental vaccination programs, there is a rising demand for development of new vaccines and the industry is growing at a double-digit rate. The vaccine industry is facing the challenge of developing new products to serve so far unmet needs and fulfilling the demands on dose numbers, both in an economically viable way. Upstream bioprocessing is an important piece of the puzzle. High titer, robustness of the process, constant product quality, fast turn-around times, and scalability are some of the success factors.  

With this ebook we would like to share expert views and case studies on some of the hot topics in vaccine bioprocess development. We hope the information on viral vector production, continuous bioprocessing, and process scale-up will prove useful for your development projects.

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Sensors are essential devices that can be used for most, if not all, typical biopharmaceutical development and manufacturing processes to monitor fundamental process parameters such as flow, temperature, pH, and dissolved oxygen throughout all process stages. As the bioindustry progresses toward automation, digitalization, and other "Manufacturing 4.0" concepts, robust single-use and smart sensors for bioprocess monitoring will be needed. Read this BPI eBook to garner valuable perspectives on both of these types of sensors. Discussions herein focus on smart sensor capabilities, applications, and validation. Learn More

The technology used in the continuous process can pose a challenge. With this white paper a comparison of the peristaltic performance of three TPE tubing materials provides powerful insights into the effectiveness of different products. Drug manufacturers are increasingly adopting continuous bioprocessing to manufacture biologics as efficiently as possible. A key consequence of continuous bioprocessing is that single-use components and assemblies must maintain integrity for process cycle times of up to 90 days. Learn More

Changes to bioprocessing in the biopharmaceutical industry are driven by the need for increased speed, lower cost of goods (CoG), and greater flexibility. To meet these challenges, the industry is adopting strategies that include intensified processing. That requires screening large numbers of clones and then further testing the most promising ones in benchtop bioreactors. The need to perform large numbers of time-consuming, resource-intensive experiments has led to development of micro- and mini-scale bioreactor systems that offer a small-scale, high-throughput (HT) solution for accelerating clone/media selection and process development. Learn More

In this complimentary ebook, the flow experts at Brooks Instrument explain how the data available from digital mass flow controllers (MFCs), when coupled with the capabilities of Ethernet based communications, can enable significant improvements to the management of your bioprocess gases.

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In this Ebook Single Use Support discusses the role their BULK.STREAM® solution plays in closing the gap between Downstream and Fill & Finish by offering biopharma companies access to a new and almost 100% secure management process for liquids on the basis of single use bags. The technologies increase patient safety and minimize the risk of bio contamination and product loss towards 0%. The process enables the storage and shipment of high-quality substances in a faster and more secure manner, and at a lower loading volume than to date.
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In this white paper, Watson-Marlow Fluid Technology Group (WMFTG), fluid path solutions provider of peristaltic pumps and single-use components, outlines the results of a study which makes comparisons between the semi volatiles extractables pro­file of post-cured and non post-cured samples of its Pumpsil platinum-cured silicone tubing. The study concludes that drug manufacturers must embrace the arguments for post-cured silicone tubing which can significantly reduce the amount of cyclosiloxanes that are present after tubing manufacturing. 

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An ever-decreasing sample volume required for analysis is allowing more and more cell and microbial cultures to be downscaled from Erlenmeyer flasks to microwell plates. Due to the standardized SBS-format of microwell plates automation solutions can be implemented, greatly expanding the possibilities of fast screening and optimization studies. Learn More

In a recent typical experiment, eight bioreactors were sampled three times per day with feedback control for multiple separate nutrient feed solutions per vessel, based upon independent metabolite triggers. Over the course of the run each vessel was triggered feeds 35-40 times with feed volumes ranging from 2 to 40 mL for over 300 automated feeds across the eight vessels. Refined data extraction templates streamlined data imports and the electronic notebook system, and PI integration can enable remote monitoring. The enhanced system capabilities are being increasingly leveraged to support ongoing process development efforts.

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Althea, an industry leading CMO specialized in cGMP manufacturing, analytical development, aseptic filling and protein delivery technologies was looking to evaluate flow systems for multiple applications throughout their facilities. One of the main issues looking to be addressed was the replacement of weigh scales for volume measurement with flow sensors. To that end, three competing flow sensor set-ups were configured and tested for both their measuring performance and suitability as a viable solution for the application.

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Microbial contamination monitoring for process control in the pharmaceutical industry in water for injection (WFI) or pure water (PW) has relied on laboratory-based methods developed a hundred years ago. This laboratory-based approach has a number of potential sources of contamination, even when handled by highly skilled personnel, including the sample port, sampling container and testing procedure.

In this case study we discuss how a leading biopharma company in France observed positive results on its laboratory-based testing method for microbial monitoring, leading to suspicion of microbial contamination in the water system. As a root cause analysis was being conducted, the company suspected that biofilm was forming in the system, leading to positive test results. The plant turned to the Mettler Toledo Thornton 7000RMS Microbial Detection Analyzer to provide real-time analysis of their water system for process control and to immediately identify any out of specification events.

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The Bio-Process Systems Alliance (BPSA) has published a 20-page Market Data Report - A Data-Driven Assessment of Single-Use System Reliability: 2016-2018. The report, funded and overseen by members of BPSA, used a confidential third-party to undertake this priority project that now allows SUS end-users to quantitatively assess the overall performance of SUS in order to make comprehensive business decisions. Additionally, this initiative allows each SUS supplier to benchmark their own performance against industry averages. Both end-users and suppliers can then target improvement initiatives toward complaint rate categories that align with their specific business or quality goals. Learn More

In today's state-of-the-art bioprocessing systems, one of the most essential subsystems provides gas management for the gases necessary for cellular metabolism. At the heart of the gas management subsystem is the thermal mass flow controller (MFC), advanced digital technology that precisely measures and controls process gas delivery. This new white paper describes the inner workings of digital MFCs with an emphasis on their robust ability to gather, generate and communicate a broad range of process data. The white paper focuses on practical ways to utilize MFC device data to improve process control, system uptime, diagnostics, preventive maintenance and, ultimately, bioprocessing yields. Learn More

G-CON Manufacturing and Vanrx Pharmasystems have collaborated on the development of the Microcell POD. A fully integrated, pre-qualified, pre-installed aseptic filling facility comprised of Vanrx's Microcell Vial Filler installed inside G-CON's prefabricated cleanroom POD. The first of its kind offering requires a lead time of just 3 months and is able to be shipped globally. The Microcell POD is seen as ideal for drug development, and the manufacturing of personalized medicines and clinical trial supplies. Learn More

This technical note, authored by IDEX Health & Science, describes a novel, compact device, the Tridex Protein Analyzer, capable of rapid, automated at-line measurement of antibody titers from stirred bioreactors using an aseptic sampling device. Assay linearity and accuracy were evaluated over a measurement range of 0.1 to 6.5 g/L using a simulated cell culture titer curve spiked with bovine serum albumin (BSA) and human IgG. Manual and automated aseptic sampling measurements using the Tridex analyzer compared very favorably with a commercial Protein A HPLC system. Excellent intra-assay precision (CV < 3%) was demonstrated for both off-line and at-line measurements with the Tridex analyzer. Learn More

This article explores some of the advantages a QbD approach can bring to drug development programs and how it can ensure more robust commercial manufacturing methods for consistent production of quality medications. Quality by Design (QbD) brings a systematic approach to drug development that aims to ensure quality by applying analytical and risk-management methodologies to the design, development and manufacturing of new medications. At its core, the approach looks to design quality into workflows up front. Learn More

This 20-page white paper provides a comprehensive,
but accessible, overview of requirements and recommendations related to the U.S. FDA's Process Analytical Technology (PAT) initiative for the biopharmaceutical industry.

• Understand critical process parameters (CPPs), critical quality attributes (CQAs), and key performance indicators (KPIs) for fermentation control in the bioreactor.
• Know which CPPs and KPIs are the most reliable to efficiently monitor your process.
• See the most recent examples of PAT applied in the biopharma industry and R&D.

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The titer of an antibody being expressed in a stirred bioreactor is usually measured offline using a process that involves removing an aliquot aseptically from the bioreactor, centrifuging the aliquot, and analyzing the resulting supernatant. The supernatant is analyzed either by bio-layer interferometry (BLI), Protein A HPLC, or ELISA. Such an approach may limit throughput, workflow, and efficiency. Aragen evaluated a prototype chromatography-based device that is directly connected to a bioreactor. Learn More

The logistics of decoupling drug substance manufacturing from final drug product formulation is now possible using integrated single-use freeze-thaw assemblies which incorporate reliable components. In this white paper we will explore how freezing the biological material in single-use assemblies has been enabling technology for managing the logistics. Learn More

In this white paper, Colder shares how t he logistics of decoupling drug substance manufacturing from final drug product formulation is now possible using integrated single-use freeze-thaw assemblies which incorporate reliable components. They explore how freezing the biological material in single-use assemblies has been enabling technology for managing the logistics. Learn More