The use of Raman in Bioprocess development has shown great potential for process understanding and monitoring although there are still some challenges and limitations in performance when conditions such as clone, media or scale are changed during bioprocess development. This study proposes different strategies to balance the different information content of multiple mammalian cell cultivations produced during a bioprocess development program when several conditions are investigated. The aim is to serve as a blueprint to how can PAT approaches be best developed in parallel to bioprocess development. Learn More

The Bioprocess Systems Alliance published its first component quality test matrices in 2007. The state purpose of this work was to “help guide users when making their selections and (to) facilitate qualification, validation, and use of single-use products.”
This 2015 document is an update to the original publication necessitated by the increase in the number of components the are currently incorporated into single-use assemblies as well as the introduction of new single-use products to the market. For example, single use sensors and chromatography column products were not a part of the 2007 matrices publication. This update also accounts for changes to common practices followed by single-use component and assembly providers.
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Single-use technology is fast growing in the biopharmaceutical industry.  Often, designing new single-use systems involves a long, iterative process between end-user and supplier to ensure quality, regulatory, and technical requirements are met.  Wouldn’t it be convenient if all these requirements were captured in a toolkit? BioPhorum and BPSA have created new templates aligned with industry standards (i.e. ASTM E3051) which will simplify the single-use design process.
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This white paper, The Role of Single-Use Polymeric Solutions in Enabling Cell and Gene Therapy Production:

  • Defines and maps commonalities between bioprocessing and CGT
  • Provides high level documentation to identify information gaps
  • Shares best practices to scale up and scale out
  • Identifies regulatory and technical requirements of each stage
  • Provides education around single-use technologies and what is available
  • Defines the language

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The advent of single-use bioprocess systems used for the delivery, storage or manufacture of biopharmaceuticals has introduced a new potential source for extractables and leachables (E&L) as these systems are comprised of polymeric materials. Several industry working groups, the FDA and USP have issued guidance and draft guidance on E&L analyses for a variety of applications. These documents typically indicate that mass spectrometry should be applied for discovery of E&L's but provide little guidance as to the exact analytical methodology which should be used. We investigated the extractable profiles of a model single-use bioprocessing system consisting of a single-use bioprocess bag, connector tubing, and a hydrophilic disk filter including filter housing. Extractions were performed in water, ethanol, ethanol/water (50:50) and saline solutions. Extracts were analyzed using a stepwise analytical methodology including a variety of screening and mass spectrometry methods We then used this model system to demonstrate the use of recursive feature finding to automatically detect unique extractables followed by statistical filtering to focus on differentially present extractables which were above the analytical evaluation threshold (AET). We further show the significant affects of standard selection on the number of compounds determined to be above AET when reducing liquid chromatography-mass spectrometry (LC/MS) data. A relative response factor database consisting of 14 structurally diverse commercially available polymer additives was used to arrive at an LC/MS identification threshold. The results of this study demonstrate that significant care should be taken when selecting standards for LC/MS analysis to avoid under reporting of extractables and leachables.
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Original Publication Date: 2/20/18

This review provides an overview and a critical discussion of novel possibilities of applying soft sensors for on-line monitoring and control of industrial bioprocesses. Focus is on bio-product formation in the upstream process but also the integration with other parts of the process is addressed. The term soft sensor is used for the combination of analytical hardware data (from sensors, analytical devices, instruments and actuators) with mathematical models that create new real-time information about the process. In particular, the review assesses these possibilities from an industrial perspective, including sensor performance, information value and production economy. The capabilities of existing analytical on-line techniques are scrutinized in view of their usefulness in soft sensor setups and in relation to typical needs in bioprocessing in general. The review concludes with specific recommendations for further development of soft sensors for the monitoring and control of upstream bioprocessing.
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Original Publication Date: 4/20/17

The application of PAT for in-line monitoring of biopharmaceutical manufacturing operations has a central role in developing more robust and consistent processes. Various spectroscopic techniques have been applied for collecting real-time data from cell culture processes. Among these, Raman spectroscopy has been shown to have advantages over other spectroscopic techniques, especially in aqueous culture solutions. Measurements of several process parameters such as glucose, lactate, glutamine, glutamate, ammonium, osmolality and VCD using Raman-based chemometrics models have been reported in literature. The application of Raman spectroscopy, coupled with calibration models for amino acid measurement in cell cultures, has been assessed. The developed models cover four amino acids important for cell growth and production: tyrosine, tryptophan, phenylalanine and methionine. The chemometrics models based on Raman spectroscopy data demonstrate the significant potential for the quantification of tyrosine, tryptophan and phenylalanine. The model for methionine would have to be further refined to improve quantification.
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Original Publication Date: 10/3/17

In this study, we prepared protein A grafted magnetic nanoparticles for the industrial large-scale purification of antibodies with enhancement of binding capacity and immobilization by controlled orientation with chlorophenylsilane (CPTMS) on the surface. For site-specific immobilization of protein A, genetically modified protein A with a cysteine residue was expressed in E. coli and purified by affinity chromatography. To improve the surface area to volume ratio and increase the immobilization amount of protein A, chlorophenylsilane functionalized magnetic nanoparticles (CPTMS@MNPs) were prepared, which are smaller nanoparticles with an average diameter of 20 nm compared to commercial magnetic microparticles (Dynabeads) with an average size of 2.8 μm. The CPTMS@MNPs showed the enhancement of protein A immobilization and binding capacity to antibodies, being 11.5-fold and 7-fold higher than those of commercial Dynabeads, respectively. In addition, the CPTMS@MNPs retained about 80% of the initial protein binding capacity until the third stage of recycling. Therefore, protein A grafted CPTMS@MNPs may be useful for the industrial large-scale purification of antibodies.
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Original Publication Date: 11/2/17

Stirred tank single-use bioreactors have proven their capability to successfully replace their stainless-steel counterparts in the biopharmaceutical industry. To date, however, only a five-fold volume expansion is achievable in a single-use stirred tank bioreactor, which in turn, necessitates intermediate equipment to scale up the culture to production volume. This study introduces a two-chamber single-use bioreactor that is capable of cell culture expansion from 1 to 50 L. The prototype is a proof of concept that can help users save costs of purchase and qualification of equipment, reduce factory footprint, and reduce the risk of contamination during culture transfer from one intermediate bag to another. The prototype is made of two chambers of different volumes, interconnected as a single, closed system. The design and construction of the prototype is described in detail and results from the engineering characterization (e.g., mixing time, power input per unit volume, and oxygen mass transfer coefficient) are reported for both chambers. The results are in good agreement with general criteria proposed in literature for bioreactor design and with published data for commercially available bioreactors. Further, the concept is not limited to the two-chamber design presented in this study; additional chambers can be integrated along with different volumes, geometries, mixing, sparging, and heating approaches.
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Original Publication Date: 2/15/18

In a conventional protein downstream processing (DSP) scheme, chromatography is the single most expensive step. Despite being highly effective, it often has a low process throughput due to its semibatch nature, sometimes with nonreproducible results and relatively complex process development. Hence, more work is required to develop alternative purification methods that are more cost-effective, but exhibiting nearly comparable performance. In recent years, surfactant precipitation has been heralded as a promising new method for primary protein recovery that meets these criteria and is a simple and cost-effective method that purifies and concentrates. The method requires the direct addition of a surfactant to a complex solution (e.g. a fermentation broth) containing the protein of interest, where the final surfactant concentration is maintained below its critical micelle concentration (CMC) in order to allow for electrostatic and hydrophobic interactions between the surfactant and the target protein. An insoluble (hydrophobic) protein-surfactant complex is formed and backextraction of the target protein from the precipitate into a new aqueous phase is then carried out using either solvent extraction, or addition of a counter-ionic surfactant. Importantly, as highlighted by past researchers, the recovered proteins maintain their activity and structural integrity, as determined by circular dichroism (CD). In this review, various aspects of surfactant precipitation with respect to its general methodology and process mechanism, system parameters influencing performance, protein recovery, process selectivity and process advantages will be highlighted.
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Original Publication Date: 04/21/17

Glycosylation is recognized as a Critical Quality Attribute for therapeutic glycoproteins such as monoclonal antibodies, fusion proteins and therapeutic replacement enzymes. Hence, efficient and quantitative glycan analysis techniques have been increasingly important for their discovery, development and quality control. The aim of this review is to highlight relevant and recent advances in analytical technologies for characterization of biotherapeutic glycoproteins. The review gives an overview of the glycosylation trends of biotherapeutics approved in 2016 and 2017 by FDA. It describes current and novel analytical technologies for characterization of therapeutic glycoproteins and is explored in the context of released glycan, glycopeptide or intact glycoprotein analysis. Ultra performance liquid chromatography, mass spectrometry and capillary electrophoresis technologies are explored in this context. There is a need for the biopharmaceutical industry to incorporate novel state of the art analytical technologies into existing and new therapeutic glycoprotein workflows for safer and more efficient biotherapeutics and for the improvement of future biotherapeutic design. Additionally, at present, there is no 'gold-standard' approach to address all the regulatory requirements and as such this will involve the use of orthogonal glycoanalytical technologies with a view to gain diagnostic information about the therapeutic glycoprotein.
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Original Publication Date: 11/22/17

mAbs are successful biopharmaceuticals playing an important role in the treatment of cancer, autoimmunity and inflammatory diseases. Mammalian cells are the dominant system for the recombinant production of the biopharmaceuticals due to complex protein processing machinery for proper protein folding and assembly. Like other proteins, mAbs tend to form higher molecular weight aggregates during manufacturing, which negatively influence quality, safety and efficacy of the biotherapeutics. The protein aggregates can be removed during downstream processing, but this cost-intensive step leads to a reduction of process yields. An alternative to this expensive removal of HMW species during DSP represents the reduction of protein aggregates at its origin during upstream processing using bioprocess optimization. Such bioprocess optimization has been performed mainly to improve cell growth, product yield and glycosylation instead of decreasing protein aggregation of mAbs. One reason for this is the lack of analytical methods for the upstream characterization of mAb aggregation. In order to study protein aggregation upstream several methods were established for the characterization of soluble protein aggregates and large aggregate particles in cell culture samples. Using these novel methods cell culture conditions were screened for their influence on protein aggregation in cell cultures of Chinese hamster ovary (CHO) production cell lines. After identification of the most critical factors influencing protein aggregation, conditions were found for the reduction of aggregates in the cultures of the tested cell lines. Strikingly, the aggregate reducing conditions were validated in another cell culture medium and another CHO production cell line. Furthermore, it was revealed that leachables from cell culture vessels like Bisphenol A do not influence protein aggregation during bioprocessing, but can influence cellular performance of production cell lines. Moreover, this study revealed that the production enhancer VPA increased the specific productivity of mAbs produced in CHO, but also induced protein aggregation in a concentration dependent manner and negatively influenced the glycosylation pattern.
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Original Publication Date: 02/23/17

A method for the identification of leachables in chemically defined media for CHO cell culture using dispersive liquid-liquid microextraction (DLLME) and UHPLC-MS is described. A Box-Behnken design of experiments (DoE) approach was applied to obtain the optimum extraction conditions of the target analytes. Performance of DLLME as extraction technique was studied by comparison of two commercial chemically defined media for CHO cell culture. General extraction conditions for any group of leachables, regardless of their specific chemical functionalities can be applied and similar optimum conditions were obtained with the two media. Extraction efficiency and matrix effects were determined. The method was validated using matrix-matched standard calibration followed by recovery assays with spiked samples. Finally, cell culture media was incubated in 7 single use bioreactors (SUBs) from different vendors and analysed. TBPP was not detected in any of the samples, whereas DtBP and TBPP-ox were found in all samples, with bDtBPP detected in six SUBs. This method can be used for early identification of non-satisfactory SUB films for cultivation of CHO cell lines for biopharmaceutical production.
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Original Publication Date: 08/25/17

Microbial bioprocesses need to be designed to be transferable from lab scale to production scale as well as between setups. Although substantial effort is invested to control technological parameters, usually the only true constant parameter is the actual producer of the product: the cell. Hence, instead of solely controlling technological process parameters, the focus should be increasingly laid on physiological parameters. This contribution aims at illustrating a workflow of data life cycle management with special focus on physiology. Information processing condenses the data into physiological variables, while information mining condenses the variables further into physiological descriptors. This basis facilitates data analysis for a physiological explanation for observed phenomena in productivity. Targeting transferability, we demonstrate this workflow using an industrially relevant Escherichia coli process for recombinant protein production and substantiate the following three points: (1) The postinduction phase is independent in terms of productivity and physiology from the preinduction variables specific growth rate and biomass at induction. (2) The specific substrate uptake rate during induction phase was found to significantly impact the maximum specific product titer. (3) The time point of maximum specific titer can be predicted by an easy accessible physiological variable: while the maximum specific titers were reached at different time points (19.8 ± 7.6 h), those maxima were reached all within a very narrow window of cumulatively consumed substrate dSn (3.1 ± 0.3 g/g). Concluding, this contribution provides a workflow on how to gain a physiological view on the process and illustrates potential benefits.
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Original Publication Date: 09/20/16

Adoption of Quality by Design (QbD) principles, regulatory support of QbD, process analytical technology (PAT), and continuous manufacturing are major factors effecting new approaches to pharmaceutical manufacturing and bioprocessing. In this review, we highlight new technology developments, data analysis models, and applications of Raman spectroscopy, which have expanded the scope of Raman spectroscopy as a process analytical technology. Emerging technologies such as transmission and enhanced reflection Raman, and new approaches to using available technologies, expand the scope of Raman spectroscopy in pharmaceutical manufacturing, and now Raman spectroscopy is successfully integrated into real-time release testing, continuous manufacturing, and statistical process control. Since the last major review of Raman as a pharmaceutical PAT in 2010, many new Raman applications in bioprocessing have emerged. Exciting reports of in situ Raman spectroscopy in bioprocesses complement a growing scientific field of biological and biomedical Raman spectroscopy. Raman spectroscopy has made a positive impact as a process analytical and control tool for pharmaceutical manufacturing and bioprocessing, with demonstrated scientific and financial benefits throughout a product's lifecycle
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Original Publication Date: 01/01/17

The BPSA has debuted its new technical guide to Design, Control and Monitoring of Single-Use Systems for Integrity Assurance. The uptake of single-use technologies (SUT) in more critical good manufacturing practices (cGMP) processes and applications has made assurance of integrity a critical quality attribute for both suppliers and end-users. The document provides recommendations to both suppliers and end-users in the single-use technology industry regarding strategies, tools and procedures that can assist in providing enhanced assurance of integrity of single-use systems. It can help end-users convey their specific requirements to the supplier. In turn, suppliers can use the document to demonstrate what they can provide to the end-user.

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Undergraduate students learn about mammalian cell culture applications in introductory biology courses. However, laboratory modules are rarely designed to provide hands-on experience with mammalian cells or teach cell culture techniques, such as trypsinization and cell counting. Students are more likely to learn about cell culture using bacteria or yeast, as they are typically easier to grow, culture, and manipulate given the equipment, tools, and environment of most undergraduate biology laboratories. In contrast, the utilization of mammalian cells requires a dedicated biological safety cabinet and rigorous antiseptic techniques. For this reason, we have devised a laboratory module and method herein that familiarizes students with common cell culture procedures, without the use of a sterile hood or large cell culture facility. Students design and perform a time-efficient inquiry-based cell viability experiment using HeLa cells and tools that are readily available in an undergraduate biology laboratory. Students will become familiar with common techniques such as trypsinizing cells, cell counting with a hemocytometer, performing serial dilutions, and determining cell viability using trypan blue dye. Additionally, students will work with graphing software to analyze their data and think critically about the mechanism of death on a cellular level. Two different adaptations of this inquiry-based lab are presented—one for non-biology majors and one for biology majors. Overall, these laboratories aim to expose students to mammalian cell culture and basic techniques and help them to conceptualize their application in scientific research.
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This article discusses the status quo of the Cabilly patents, their scope of protection and the role these patents play for the therapeutic antibody industry in Europe and the US.

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A two part guide covering definitions, regulatory issues, risk assessment, program evaluation and program execution as part of process validation for implementation of single-use systems. Keywords: extractables, leachables, regulatory, compliance, CFR, FDA, 211.65, Title 21, CDER, DMF, BMF, QA,RA, environmental, control.

Author: Extractables and Leachables Subcommittee of the BPSA Technology Committee

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This work aims to evaluate the benefits of the continuous process in biopharmaceutical manufacturing of monoclonal antibodies (mAbs). An integrated continuous process is designed and built using a process simulator and compared with a fed-batch process production line. The comparisons are based on cost of goods (COG/g) calculation and sensitivity analysis. The fed-batch process results in operating COG/g of $99/g in mAbs production, whereas the continuous process accounts for $51/g. Because of the smaller footprint and fewer storage tanks required in the continuous process, the facility cost reduced by 66%, compared to the fed-batch process. Learn More

As the biopharmaceutical industry continues to grow at a rapid pace, companies are realizing that they may need to transform their biomanufacturing networks to respond to changing market dynamics and anticipate customer requirements. A major factor behind the growth of the biopharmaceutical industry has been the huge and continued success of the monoclonal antibodies segment. Within the industry, however, companies have started to diversify their pipelines, developing products such as antibody-drug conjugates, nonantibody recombinant proteins, gene therapies, and autologous and allogenic cell therapies

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Authors: Ganesh Kumar, Michael Koch, and Gerben Zijlstra, Ph.D.

Process chromatography forms the core of purification of biotherapeutics. It is typical to have three to five chromatography steps in a purification process for a biotherapeutic. Generally, these steps offer different modes of separation such as ion-exchange, reversed phase, size exclusion, and hydrophobic interaction. In the past decade, multimodal chromatography has emerged as an alternative to the traditional modes. It involves use of more than one mode of separation and typically combines ion-exchange and hydrophobic interactions to achieve selectivity and sensitivity. This review aims to present key recent developments that have occurred on this topic together with a perspective on future applications of multimodal chromatography. Learn More

Bioprocessing has been used for decades for the industrial production of beverages and for the production and preservation of food and feed ingredients. While these applications are still crucial, new ones are being added, such as the production of new food and feed additives, functional foods and various types of novel foods. Many interventions are needed to improve product characteristics, ensure consistent quality, and reduce production costs: strain engineering, optimization of process parameters, handling of difficult process conditions, and more. There are many interesting examples in the literature of how researchers tackle the challenges in food and feed applications, both old and new. In this white paper we introduce several of them that provide valuable insights and ideas.

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PAREXEL International is a global consulting company specializing in pharmaceuticals and medical devices. From strategy to condition of clinical trials to post-release marketing, for over 30 years, PAREXEL has helped pharmaceutical companies get critical drugs into the hands of consumers as quickly, safely, and cost-effectively as possible. Typically, it takes a drug manufacturer an average of 10 years from the time of discovery to bring a drug to market. One of the most complex and expensive aspects of this 10-year process is clinical trials, a period when patient participation and adherence is imperative to success. To increase the success rates of clinical trials, PAREXEL turned to the combination of wearable devices and the OSIsoft PI System.

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For many of us, wearable devices are now a way of life. Our wristbands or smart watches can track how many steps we take on a daily basis, how much we sleep (or don't!) and even things like calorie intake or blood pressure. That data provides valuable information about our fitness progress and goals and even our overall health. While that data paints a helpful picture for the individuals with wearable devices, it also has the potential to change an entire industry.

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Original Publication Date: December 18, 2017

Biogen is a leading developer of drug therapies for neurological and neurodegenerative diseases. Headquartered in Cambridge, MA, for nearly 40 years, the Biogen team has worked to combat the effects of diseases such as MS, Alzheimer's and spinal muscular atrophy. Biogen is in the process of rolling out its Aducanumab drug, which is designed to treat the symptoms of Alzheimer's. Phase 1b results noted that the drug significantly slowed the decline in Alzheimer's patients, giving hope to the over 25 million people around the world who suffer from the disease.

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In heavily-regulated industries, the path of least resistance often means that processes stay the same, and the pharmaceutical industry is no exception. Between red tape and high-margin drugs that are brought to market under short-term patents, pharmaceutical companies must quickly recoup research and development costs while mitigating risk, leaving little incentive to proactively rework supply chain processes.

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Original Publication Date: August 31, 2017

In pharmaceutical and biotech industry there is an increasing interest in gene therapy-based applications. This leads to an increasing demand in scalable production systems for viral vectors. Cell culture in suspension instead of monolayer culture simplifies scale-up, because it allows bioprocessing in scalable, stirred-tank bioreactors. Researchers at Cevec Pharmaceuticals adapted the small scale shake flasks rAAV production process to stirred-tank bioreactors and scaled it up in BioBLU Single-Use Vessels from a working volume of 2 L to 10 L. Scale-up in bioreactors was based on constant power input/volume. It led to comparable cell growth and virus production at both scales and to the original shake flask process.

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Original Publication Date: December 2018

Vero cells are anchorage-dependent cells that are used widely as a platform for viral vaccine production (1). In stirred-tank bioreactors, they are grown ordinarily on microcarriers. Fibra-Cel disks are an alternative attachment matrix because they provide a three-dimensional environment that protects cells from damaging shear forces. However, such disks have not been tested for the cultivation of Vero cells. We tested whether benchtop single-use and glass bioreactors with a packed bed made of Fibra-Cel disks would be suitable for cultivation of Vero cells. To monitor the culture, we quantified glucose and lactate concentrations in the medium daily and inferred from those parameters about cell growth. We concluded that the cells multiplied efficiently in the packed-bed bioreactors. Cell yields in the glass and single-use bioreactors were equivalent. Our results suggest that benchtop, packed-bed bioreactors filled with Fibra-Cel disks are well suited for the cultivation of the Vero cell line — and hence vaccine production — in small batch sizes.

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Original Publication Date: March 2018

Authors: Joseph Duffy, Shannon Guertin, Chris Bellerive, Dan Mardirosian, Ma Sha, and Kamal Rashid.

Baffles are internals, generally flat plates, used in agitated vessels to optimize and stabilize the mixing flow pattern and minimize variation in agitator power draw. Baffle recommendations are part of the agitator vendor's scope although the baffles are designed and fabricated by others. Proper baffle implementation dramatically impacts process results. Learn More

For biopharm manufacturers the challenge is clear: quickly and efficiently transfer materials aseptically from one physical area to another, while minimizing the risk of contamination and maximizing efficiency and cost effectiveness. This is especially true for cGMP facilities adapting single-use technology as an operating platform over traditional stainless steel piping systems.

Pharmaceutical and biopharma manufacturers need to move fluids from one cleanroom to another quickly with maximum productivity and minimal effort and expense. Incorporating Single-Use/disposable equipment and practices can help speed and streamline operations while maintaining isolated environments. This report explains how a wall pass-through system that incorporates Single-Use components can reduce contamination risks and the use of valuable resources.
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Original Publication Date:

Author: Tony Butler, ASQ CSSBB Manager, Single-Use Systems AdvantaPure®

Both qualitative and quantitative measures of mixing can be used to characterize performance of mixing systems, allowing comparison among designs and confirmation of equipment performance. In addition, these data can be used to more fully understand the process space and allow parameters to be adjusted to achieve optimal performance in areas such as mixing efficiency, limitation of shear, or limitation of foaming. In addition, documentation of the mixing data can create a record for process development and regulatory demands. The ability to quantify the mixing process allows development of better equipment and processes.

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Acid precipitation has been demonstrated as a clarification method for cell culture supernatant (CCS) pretreatment during Immunoglobulin G (IgG) purification. In this study, the responses of IgG, non-histone host cell protein (n-hHCP), histone, and DNA to different pHs in the presence of salt (NaCl) at various concentrations were systematically studied. IgG loss was closely associated with the precipitation of chromatin heteroaggregates, in which DNA/histone showed significant decreases along with the acidification of buffer environment. In addition, DNA showed full recovery after pH neutralization, while the low pH treatment induced histone precipitation was permanent and could not be reverted upon pH increase. Learn More

A mathematical mass-transfer model was developed based on the mass balance of gas exchange in cell culture bioreactors. The model combines the bioreactor mass transfer properties and mammalian cell metabolic parameters to predict the cell culture process oxygen demands and carbon dioxide accumulation in bioreactors. With the guidance of the mass-transfer model, a CHO cell culture process to produce a therapeutic antibody was successfully scaled up from 2-L to 1500-L bioreactor directly without intermediate steps. The process performances and product quality attributes demonstrate good robustness and consistency between small and large scales. This mass-transfer model provides a more systematic and reliable approach for mammalian cell culture bioreactor scaling up. Learn More

Hybrid cell lines arise through intentional or non- intentional fusion of somatic cells having different origins. Hybrid cell lines can pose a problem for authentication testing to confirm cell line identity, since the results obtained may not conform to the results expected for the two parental cell types. Thus, depending on the identity testing methodology, a hybrid cell may display characteristics of one of the parental cell type or of both. In some instances, the hybrid cell line may display characteristics that are different from those displayed by either parental cell type; these differences may not necessarily indicate cellular cross-contamination... Learn More

Perfusion processes typically require removal of a continuous or semi-continuous volume of cell culture in order to maintain a desired target cell density. For fast growing cell lines, the product loss from this stream can be upwards of 35%, significantly reducing the overall process yield. As volume removed is directly proportional to cell growth, the ability to modulate growth during perfusion cell culture production thus becomes crucial. Leveraging existing media components to achieve such control without introducing additional supplements is most desirable because it decreases process complexity and eliminates safety and clearance concerns. Here, the impact of extracellular concentrations of sodium (Na) and potassium (K) on cell growth and productivity is explored. Learn More

A current challenge in bioprocessing is the ability to analyse critical quality attributes such as aggregation without prior purification. This study evaluated the use of fluorescent dyes (Bis-ANS, SYPRO Orange, Thioflavin T and ProteoStat) to characterise mAb aggregates in Chinese hamster ovary clarified cultures. The null and mAb culture supernatants showed an increase in fluorescence intensity over the duration of the culture. The null cultures on day 14 saw a rapid increase in fluorescence intensity; day 10 to day 14, Bis-ANS and Thioflavin T had average increases of 21% and 48%, respectively, whereas ProteoStat and SYPRO Orange showed an average increase of 60%. Higher fluorescence intensity on day 14 with the null cultures, also correlated with loss of viability. Learn More

With approximately half of bioprocessing industry professionals choosing aseptic connectors and the other half choosing tube welders, how do you know which connection type is right for you? Read our tech guide to learn more about key factors to consider when comparing tube welders and aseptic connectors, so you can make the correct choice for your needs.

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Just days after the U.S. FDA joined the EMA and Health Canada in announcing a second impurity, called NDEA, has been found in valsartan manufactured by Zhejiang Huahai Pharmaceuticals the FDA has released a third Form 483 to the company. Following inspections in July and August, the FDA issued the 483 with 11 observations, with perhaps not surprisingly specific issues raised about the firm's quality unit. The FDA also found the firm's change control system, designed to evaluate all changes that may affect production to be inadequate. Learn More

Capacitance has been used to monitor "biomass" in cell culture and fermentation processes for several decades. The present work explored various ways to support GMP use and create robust methods that would assure proper performance of capacitance equipment. The first goal was to develop a method for measuring at-line capacitance that could serve to correct or confirm online measurements from bioreactors. With appropriate control of culture temperature, vessel geometry, mixing, and timing; an at-line system was developed that consistently predicted online capacitance outputs. The at-line method yielded values that differed systematically from online values... Learn More

In this study, we investigated the effects of ATF cell separation on high-density perfusion cultures. We have developed methods to estimate theoretical residence times of cells in the ATF system and discovered that long residence times (above 75 seconds) correlate with decreased growth, metabolism and productivity. We have calculated energy dissipation rates in the ATF transfer line and filter and empirically studied the impacts of increased exchange rates on cell culture, determining that increased hydrodynamic stress can lead to decreased cell size, lactate production and specific productivity. Finally, we have conducted experiment... Learn More

A universal flu vaccine that protects people against most influenza strains is one step closer to reality, with a study from the Perelman School of Medicine at the University of Pennsylvania. The candidate vaccine, described in Nature Communications this week, elicited a strong antibody response to a structure on the surface of flu viruses, called the hemagglutinin (HA) stalk. It protected mice from infection by various flu strains. "This vaccine was able to do something that most other candidate flu vaccines have not been able to do," said study co-senior author Drew Weissman, MD, PhD, a professor of Infectious Diseases. "It was able to elicit protective responses against a conserved region that offers broad protection." Learn More

Research led by a Salk Institute scientist suggests why, at a cellular level, this might be true. The team reports that brief exposures to stressors can be beneficial by prompting the cell to trigger sustained production of antioxidants, molecules that help get rid of toxic cellular buildup related to normal metabolism. The research, which appeared in the journal Cell Metabolism this week, also revealed that short-term stress to cells leads to remodeling mitochondria, the powerhouses of the cell that deteriorate with age, so they generate fewer toxic byproducts. The findings could lead to new approaches to counter the cellular effects of aging, possibly even extending lifespan. Learn More

A critical quality attribute of therapeutic monoclonal antibodies (mAbs) is the terminal sugar molecules of the N-linked glycan attached to the fragment crystalizable (Fc) region. There exists naturally-occurring heterogeneity in the N-linked glycan structure of mAbs, and such heterogeneity has a significant influence on the clinical safety and efficacy of mAb drugs. We previously proposed a constraint-based modeling method called glycosylation flux analysis (GFA) to characterize the rates (fluxes) of intracellular glycosylation reactions and applied the method to examine the N-linked glycosylation of immunoglobulin G (IgG) in fed-batch Chinese hamster ovary (CHO) fed-batch cultivations. Learn More

Yes. Recently a single-use manifold for fluid transfer was introduced to our community 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.

Nordson CYLINDRAFlow™ Manifolds

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Recently, the importance of biopharmaceuticals in medical treatments has been increasing, and effective protein purification methods are strongly required for their production. In the present study, a temperature-responsive solid-phase extraction (SPE) column was developed for the purification of proteins without affecting their bioactivity. A temperature-responsive polymer hydrogel-modified stationary phase was prepared by coating aminopropyl silica beads with poly(N-isopropylacrylamide) (PNIPAAm)-based thermoresponsive hydrogels.n-Butyl methacrylate and acrylic acid were copolymerized with PNIPAAm as hydrophobic and anionic monomers, respectively. Learn More

A new integrated continuous biomanufacturing platform for continuous production of antibodies at fixed cell volumes and cell concentrations for extended periods with immediate capture is presented. Upstream antibody production has reached technological maturity, however, the bottleneck for continuous biomanufacturing remains the efficient and cost-effective capture of therapeutic antibodies in an initial chromatography step. In this study, the first successful attempt at using one-column continuous chromatography (OCC) for the continuous capture of therapeutic antibodies produced through alternating tangential flow perfusion is presented... Learn More

In an achievement that has significant implications for research, medicine, and industry, UC San Francisco scientists have genetically reprogrammed the human immune cells known as T cells without using viruses to insert DNA. The researchers said they expect their technique -- a rapid, versatile, and economical approach employing CRISPR gene-editing technology -- to be widely adopted in the burgeoning field of cell therapy, accelerating the development of new and safer treatments for cancer, autoimmunity, and other diseases, including rare inherited disorders. The new method, described in the July 11, 2018 issue of Nature, relies on electroporation. Learn More

Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the FIRC Institute of Molecular Oncology (IFOM) in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification, this is accomplished by confining them to a defined geometric space for an extended period of time. "Our breakthrough findings will usher in a new generation of stem cell technologies for tissue engineering and regenerative medicine that may overcome the negative effects of geonomic manipulation," said Prof Shivashankar.
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The U.S. FDA this week published a warning letter sent to China based Zhuhai United Laboratories for significant deviations from CGMP for API. The FDA inspectors found the manufacturer lacked adequate procedures for investigating, and scientific justification to invalidate, out-of-specification (OOS) results.The warning letter also cites the API manufacturer for failing to adequately investigate findings from a February 2015 retrospective review of analytical chromatography data irregularities. FDA inspectors also found additional examples of incomplete data relating to Zhuhai's sterile manufacturing operations evaluated as part of FDA's pre-approval inspection. Learn More

The measurement of the flow of liquids associated with bioprocessing has long been sought, and largely addressed, for the most part. The exception being the accurate and reliable measurement of liquid at ultra-low flow. However, this is fast becoming recognized by our industry as an exception no more. The Sonoflow IL sensors have proven capable of delivering the precise measurement (+/- 1%) of flow ranges below 10ml/min. These sensors accomplish this while complying with the first rule of bioprocessing when it comes to the cells, "do no harm". Learn More

The applications of mass spectrometry in the pharmaceutical industry have long been established. Mass spectrometers are highly versatile and commonly used to identify reagents, products, contaminants, and impurities from samples in drug research and development, scale-up, and high volume manufacturing lines. However, the instruments are normally large, power demanding, and expensive pieces of equipment operated in centralized laboratories by MS specialists. The new demands of bioprocessing, used to make biologics, means that there is a need for analytical instruments, such as mass spectrometers, to provide real-time information (on-line and at-line) at the point-of-need. Learn More

The U.S. FDA this week finalized its guidance to help sponsors understand how the review goals established as part of the Generic Drug User Fee Amendments Reauthorization of 2017 (GDUFA II) apply to amendments to either abbreviated new drug applications (ANDAs) or prior approval supplements (PASs). The 32-page final guidance contains clarifications to the draft guidance of the same title that published in October 2017, the agency says. The GDUFA II Commitment Letter includes changes in the classification of and review goals for amendments to ANDAs and PASs under GDUFA I, when amendments got classified into a Tier-based system. Learn More

The effectiveness of antibiotics can be altered by combining them with each other, non-antibiotic drugs or even with food additives. Depending on the bacterial species, some combinations stop antibiotics from working to their full potential whilst others begin to defeat antibiotic resistance, report EMBL researchers and collaborators in Nature on July 4th, 2018. In the first large-scale screening of its kind, scientists profiled almost 3000 drug combinations on three different disease-causing bacteria. The research was led by EMBL group leader Nassos Typas. Learn More

Mylan's manufacturing facility in Morgantown, WV, has received an FDA Form 483 listing inspectional observations, some of which were due to failures of its quality control unit.
Agency investigators who visited the firm during a 12-day site inspection earlier this year, noted 13 situations of noncompliance to good manufacturing practices in the 32-page Form 483. From a lack of appropriate oversight and documentation on written procedures changes to an inadequately validated cleaning process and established time limits on drug products, seven observations described the firm's quality control unit. Learn More

In a hard hitting article published in ProPublica this week, the author argues that with biopharma underwriting roughly 75% of the FDA's budget for scientific reviews, it is perhaps not a coincidence that the agency is increasingly fast-tracking expensive drugs with significant side effects and unproven health benefits. She notes that once widely assailed for moving slowly, today the FDA reviews and approves drugs faster than any other regulatory agency in the world. Between 2011 and 2015, the FDA reviewed NDA's more than 60 days faster on average than did its couterparets at the EMA. Learn More

Viral inactivation plays a critical role in assuring the safety of mAb therapeutics. Traditional viral inactivation involves large holding tanks in which product is maintained at a target low pH for a defined hold time, typically 30-60 minutes. The drive toward continuous and improved facility utilization has provided motivation for development of a continuous viral inactivation process. To this end, a lab-scale prototype viral inactivation system was designed, built, and characterized. Multiple incubation chamber designs are evaluated to identify the optimal design that enables narrow residence time distributions in continuous flow systems... Learn More

This work is a proof of concept of how a sequence of industrial batch separation steps together are used to form an integrated autonomous downstream process. The sequence in this case study consisted of an anion chromatography step, virus inactivation and finally a hydrophobic chromatography step. Moving from batch to integrated separation minimizes hold-up times, storage tanks, and required equipment. The conversion from batch to integrated mode is achieved by extracting operating points and separation data from batch chromatograms. The integrated separation process is realized on an ÄKTA Pure controlled by an open research software... Learn More

Researchers at the Harvard John A. Paulson School of Engineering and Applied Sciences have developed an oral delivery method that could dramatically transform the way in which diabetics keep their blood sugar levels in check. By encapsulating the insulin-ionic liquid formulation in an enteric coating, the team overcame the challenge of resisting a breakdown by gastric acids in the gut. This polymer coating dissolves when it reaches a more alkaline environment in the small intestine, where the ionic liquid carrying insulin is released. The research was published in the Proceedings of the National Academy of Sciences. Learn More

The U.S. FDA has warned Chinese API manufacturer Henan Lihua Pharmaceutical Co. Ltd. for good manufacturing practice (GMP) violations stemming from an inspection last December. During the inspection, the FDA says its on-site investigators observed lapses in oversight by the company's quality unit and deviations related to record keeping at the Henan province-based facility. These issues resulted in the agency placing the company on import alert in March. The FDA also says the company rubber stamped manufacturing records and did not control access to those forms or the stamps. Learn More

Cancer researchers at KU Leuven in Belgium have shown that some patients with T-cell leukemia produce too much of the BCL-2 protein. The overproduction of the BCL-2 protein is due to a defect in the ribosome, the protein factory of the cell. This defect is found in 10% of the pediatric patients with T-cell leukemia. Cancer cells take advantage of this 'survival protein' which allows them to escape chemotherapy. The impact of this ribosome defect on T-cell leukemia has never been elucidated before. A drug suppressing this BCL-2 shows promising results. Learn More

The U.S. FDA this week approved the country's first drug derived from marijuana, a medication that treats two rare and devastating forms of epilepsy. The drug, GW Pharmaceuticals' Epidiolex, is made of cannabidiol, or CBD, a component of marijuana that does not give users a high. It is given as an oil, and in clinical trials, it was shown to reduce the number of seizures by about 40 percent in patients with Dravet or Lennox-Gastaut syndromes. The FDA's decision was expected after an advisory panel had unanimously recommended it. Learn More

The Trump administration has proposed a fundamental change to the mission of the U.S. Food and Drug Administration, one that would transfer most of the responsibility for regulating food safety to the Department of Agriculture and rename the FDA the "Federal Drug Administration." The idea of changing a key mission of the FDA comes amid a turf war between the FDA and the USDA. The two agencies have recently battled over who gets to regulate lab-grown meat, Politico reported last week. And in May, FDA Commissioner Scott Gottlieb spoke about the importance of his agency regulating genetically engineered animals. Learn More

In response to industry concerns, the U.S. FDA this week announced it has withdrawn its draft guidance on evaluating studies used to demonstrate analytical similarity between a biosimilar and reference biologic.The FDA says it plans to reissue the draft guidance after considering changes to the document that will "promote a more efficient pathway for the development of biosimilar products."To date, the FDA has approved 11 biosimilars to eight reference biologics since approving its first biosimilar in 2015. However, only a fraction of those biosimilars are available on the market, with legal challenges often adding years between approval and commercial launch. Learn More

Herein, we showed for the first time that exosomes, which are nano-sized extracellular vesicles, derived from CHO cells inhibited apoptosis in CHO cell culture when supplemented to the culture medium. Flow cytometric and microscopic analyses revealed that substantial amounts of exosomes were delivered to CHO cells. Higher cell viability after staurosporine treatment was observed by exosome supplementation (67.3%) as compared to control (41.1%). Furthermore, exosomes prevented the mitochondrial membrane potential loss and caspase-3 activation, meaning that the exosomes enhanced cellular activities under pro-apoptotic condition... Learn More

To date, integrated continuous bioprocessing has not been realized as enabling technologies are nascent. In this work, a fully integrated continuous process is successfully demonstrated from pilot scale bioreactor to drug substance. Comparable product quality is observed between the continuous process and a 500 liter fed-batch conventional process. A throughput analysis shows that a fed-batch facility with four x twelve five hundred liter liter stainless steel bioreactors and purification train of the corresponding scale can be replaced by a continuous facility consisting of five x two thousand liter single use bioreactors and smaller purification train, with a cost reduction of 15%. Learn More

Ziopharm Oncology has announced that the U.S. FDA has placed a clinical hold on a Phase 1 trial to evaluate CD19-specific CAR-T therapies manufactured under point-of-care and requested additional information in support of the investigational new drug (IND) application for the trial. The FDA has requested additional information relative to Chemistry, Manufacturing and Controls. Ziopharm and its partners will address the FDA's requests, and the initiation of this trial may be delayed. Learn More

Researchers at Columbia University Irving Medical Center (CUIMC) have developed a highly innovative computational framework that can support personalized cancer treatment by matching individual tumors with the drugs or drug combinations that are most likely to kill them. The study, published this week on Nature Genetics, by Dr. Andrea Califano of Columbia University Irving Medical Center and Dr. Irvin Modlin of Yale University and Wren Laboratories LLC, co-senior author on the study, with collaborators from 17 research centers worldwide, details a proof of concept for a novel analytical platform applicable to any cancer type.
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With the publication of a final guidance, the U.S. FDA has adopted the International Council for Harmonization's (ICH) questions and answers guideline on the nonclinical evaluation of drugs intended to treat cancer.The final guidance comes less than two months after ICH advanced the document for international implementation in late April. The guideline, which contains 41 questions and answers aimed at providing additional clarity about oncology drug development, is meant to be read alongside ICH's 2009 guideline S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. Learn More

Biologic manufacturing processes typically employ clarification technologies like depth filtration to remove insoluble and soluble impurities. Conventional depth filtration media used in these processes contain naturally-derived components like diatomaceous earth and cellulose. These components may introduce performance variability and contribute extractable/leachable components like beta-glucans that could interfere with limulus amebocyte lysate endotoxin assays. Recently a novel, all-synthetic depth filtration media is developed (Millistak+® HC Pro X0SP) that may improve process consistency, efficiency, and drug substance product quality by reducing soluble process impurities... Learn More

San Carlos city officials this week approved a developer's proposal to update designs for two buildings currently under construction on the city's east side. Previously dubbed Meridian 25, the project involves a proposal to build a 530,000-square-foot office complex at Industrial and Bransten roads. Sold to Alexandria Real Estate Equities in 2017, the property has been slated for the real estate company's specialty in life sciences but required officials' approval to make changes to the previously-approved design and accommodate biotech R&D there, according to Community Development Director Al Savay. Learn More

A grand jury has indicted CEO Elizabeth Holmes and her former No. 2 Sunny Balwani for alleged fraud at Theranos, the disgraced Silicon Valley company that once promised to revolutionize blood testing in a pitch that was too good to be true. The criminal charges filed by federal prosecutors allege that Holmes and Balwani bilked investors out of hundreds of millions of dollars while also defrauding doctors and patients through years of lies that put thousands of people in personal danger. Holmes is also out as CEO, the company announced in a statement. David Taylor, the company's general counsel, will take over as CEO. Holmes remains chairman of the company's board. Learn More

To fight cancer, researchers increasingly use vaccines that stimulate the immune system to identify and destroy tumor cells. However, the desired immune response is is not always guaranteed. In order to strengthen the efficacy of vaccines on the immune system -- and in particular on T lymphocytes, specialized in the detection of cancer cells -- researchers from the universities of Geneva (UNIGE), Freiburg (UNIFR), Munich, and Bayreuth, in collaboration with the German company AMSilk, have developed spider silk microcapsules capable of delivering the vaccine directly to the heart of immune cells. This process, published in the journal Biomaterials, could also be applied to preventive vaccines... Learn More

Protein biologics have emerged as a safe and effective group of drug products that can be used in a variety of medical disorders and clinical settings, including treatment of orphan diseases, personalized medicine, and point-of-care applications. However, the full potential of protein biologics for such applications will not be realized until there are methods available for rapid and cost-effective production of small scale products for individual needs. Here, we describe a modular and scalable method for rapid and adaptable production of protein-based medical products at small doses. The method includes cell-free synthesis of the protein target in a reactor module... Learn More

Mylan has announced that the U.S. FDA will issue a Complete Response Letter for the drugmaker's generic version of GlaxoSmithKline's Advair Diskus on June 27th, 2018. The generic drugmaker said the agency "identified minor deficiencies" that will be communicated in the CRL. Once the official rejection is received, Mylan will determine what impact it will have on its financial outlook for the year. Mylan was quick to point out the abbreviated New Drug Application for the generic asthma drug had a priority review and could be approved ahead of the 90-day period typical after a response to a CRL, suggesting the generic could still be approved this year. Learn More

The New Jersey Economic Development Authority has approved a 10-year, $40 million tax savings incentive package for Teva Pharmaceuticals to move its domestic headquarters to Parsippany, NJ from Pennsylvania. The tax credits would be conditional upon the company preserving 1,000 jobs via a combination of new hires and retention of existing jobs. The move is expected to bring 843 jobs to New Jersey, while keeping 232 the company already has in Parsippany. Teva is considering moving into a 345,000-square-foot space at 400 Interpace Parkway and out of its current space in Frazer, a town just outside of Philadelphia.
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As part of an effort spur the development of new antimicrobial drugs intended for limited patient populations, the U.S. FDA this week issued a draft guidance with recommendations for demonstrating the safety and effectiveness of such drugs. In recent years, the U.S. Congress has attempted to address shortfalls in the development of new antimicrobial drugs as resistance to existing drugs mounts and questions about the economic viability of new antimicrobial drugs loom."...there has unfortunately been an overall decline in antibiotic drug research driven largely by the significant obstacles to developing innovations in this category," FDA Commissioner Scott Gottlieb said. Learn More

Eisai has announced that it will close its existing site in Andover in early 2019 and launch the Eisai Center for Genetics Guided Dementia Discovery in Cambridge, Massachusetts. The Center will be located in a new, dedicated state-of-the-art facility and be funded by a $100 million investment over the first three years. This will be followed by what the company anticipates to be substantially increased funding requirements as its pipeline develops with a new drug expected to have been discovered at the Center by 2020. The new 50,000-square-foot facility is being constructed in the Alewife Research Center. Learn More

The prominent cancer biologist Inder Verma, a researcher at the Salk Institute for Biological Studies in San Diego since 1974, has unconditionally resigned and his resignation accepted. This comes after Salk hired a leading San Diego employment law firm earlier this year to investigate reports of several allegations of sexual harassment against Verma, 70, a pioneer in gene therapy and oncogene research. It was later learned that no fewer than eight women, six of them affiliated with Salk, had reported incidents of harassment spanning 40 years. For his part, Verma has denied the allegations in a written statement. Learn More

Editing cells' genomes with CRISPR-Cas9 might increase the risk that the altered cells, intended to treat disease, will trigger cancer, two studies published this week warn - a potential game-changer for the companies developing CRISPR-based therapies. In the studies, published in Nature Medicine, scientists found that cells whose genomes are successfully edited by CRISPR-Cas9 have the potential to seed tumors inside a patient. That could make some CRISPR'd cells ticking time bombs, according to researchers from Sweden's Karolinska Institute and, separately, Novartis. Learn More

The Scottish government has dismissed the possibility of using compulsory licensing to get a copy of Roche's breast cancer drug Perjeta to patients. A politician floated the idea of enacting a Crown use licence to bypass the pricing impasse that is stopping HER2-positive secondary breast cancer patients from accessing the biologic but has struggled to garner support at the top. Roche tried to secure reimbursement for the drug last year but the Scottish Medicines Consortium (SMC) ruled it was "very expensive" and a poor use of limited healthcare resources. Since then, Roche has met with Scottish officials with a view to coming to an agreement but is yet to file a new submission. Learn More

To meet the ever-growing demand for effective, safe, and affordable protein therapeutics, decades of intense efforts have aimed to maximize the quantity and quality of recombinant proteins produced in CHO cells. Bioprocessing innovations and cell engineering efforts have improved product titer; however, uncharacterized cellular processes and gene regulatory mechanisms still hinder cell growth, specific productivity, and protein quality. Herein, we summarize recent advances in systems biology and data-driven approaches aiming to unravel how molecular pathways, cellular processes, and extrinsic factors (e.g. media supplementation) influence recombinant protein production... Learn More

Roche has been given fast-track review by the U.S. FDA this week for its Hemlibra treatment for people with a form of haemophilia. The Basel company said the FDA has granted priority review for the drug for children and adults with hemophilia A without factor VIII inhibitors, with a decision on approval expected on October 4, 2018. Hemlibra had already received breakthrough therapy designation for the medicine to be used in people who have not yet developed resistance to conventional treatments, called inhibitors, Roche said in April. Learn More


Investors shaved billions off Nektar Therapeutics' valuation this week on news of disappointing data in its latest clinical trial update. The latest trial data suggests that melanoma patients aren't responding to the experimental treatment as well as an earlier batch of patients did. That glowing initial data revealed last fall helped propel Nektar to a market value that topped $15 billion just last week. Alert readers will recall that Nektar signed a research partnership earlier this year with Bristol-Myers that netted the startup a whopping nearly $2 billion upfront payment. Learn More

The U.S. FDA this week approved its 11th biosimilar, the first competition for Amgen's Neulasta, and known as Mylan's Fulphila. Also this week, the FDA released a new draft guidance on formal meetings between biosimilar sponsors and the agency, replacing a previous guidance from November 2015.The 21-page draft, completed as part of the second iteration of the biosimilar user fee goals, features sections on the four types of biosimilar biological product development (BPD) meetings - biosimilar initial advisory (BIA), Type 1, Type 2, Type 3 and Type 4. Learn More