May 9, 2019

What’s New in Upstream Technologies

Recent upstream processing innovations include enhanced sensor technology, single-use bioreactors, and automated cell culture systems.

By Amber Lowry 

cell culture


In recent months, a range of instruments and equipment have been introduced to advance upstream bioprocesses. The following is an assortment of such products.

Bench-scale automated cell culture system

The scale-X carbo, from Univercells, is a bench-scale automated cell culture system for the expression and concentration of viral drug substance suited for R&D activities and clinical material production (1). The system features a modular, scalable, fixed-bed bioreactor for enhanced upstream processing of viral products, including viral vaccines, viral vectors, and oncolytic viruses. The low-footprint integrated system delivers high cell densities and viral titers as well as homogeneous cell distribution throughout the fixed-bed.

According to the company, the bioreactor offers an increase of the surface/volume ratio compared to conventional technologies, with 10 m2 growth surface in 1.8-L working volume and 30 m2 growth surface in 4.2-L working volume.

Single-use sensor and adapter

Emerson’s Rosemount 550pH sensor and Rosemount 550DW dissolved oxygen (DO) sensor adapter provide improved sensor stability for single-use bioreactors and are suited to deliver the same standard of stability and performance as the company’s stainless-steel sensors (2).

The 550pH sensor is an electrochemical, fully disposable device with sensor stability of less than 0.005 pH change per day, which was verified by company testing. The device provides up to 10 times enhanced stability and requires no maintenance or calibration after initial one-point standardization, according to the company. The device can be stored wet for immediate verification and standardization, eliminating the initial stabilization process. The sensor is packaged with its own calibration fluid, which gives it a two-year shelf life. Wet, one-point standardization before startup allows for the sensor’s characteristics and functionality to be verified before any solutions or buffers are added to the bioreactor bag. The standardization also enables the verified sensor to begin measuring immediately after being introduced into the bag.

The DO sensor adapter is compatible with standard stainless-steel DO sensors and enables placement into the bioreactor single-use bag. Only the gamma-irradiated adapter touches the process solution, which allows for the sensor to be reused for multiple batches. The sensor can be air-calibrated prior to startup to verify functionality with no fill product needed in the bioreactor.

Both the sensor and the sensor adapter operate with the company’s Rosemount liquid analytical 56 transmitter. Additionally, the new sensor technologies and the transmitter are fully compatible with the Emerson DeltaV control system.

Buffer delivery component

MilliporeSigma’s BioContinuum Buffer Delivery Platform, a new component in the company’s BioContinuum Platform for next-generation bioprocessing, offers a way to streamline buffer management (3). The platform offers “contiGuous” manufacturing, which is phrasing the company uses to describe the orchestration and management of all the processing steps (materials, production, testing, and analytics) with a streamlined and optimized approach.

The platform is an integrated solution for more efficient buffer delivery that is tailored to provide a high level of accuracy and precision in buffer preparation and management. According to MilliporeSigma’s internal market research, the launch of the platform is timely because industry adoption of liquid buffers is expected to expand from 7–56%.

The company has obtained certain exclusive rights to sell the buffer dilution system developed by LEWA-Nikkiso America (now a part of YMC), a manufacturer of pumps and systems for fluid metering, for customers involved in the development or production of diagnostics and biopharmaceuticals. This buffer dilution system offers the highest accuracy available for dilution of highly concentrated buffer, as stated by MilliporeSigma. The company also reports that it supplies process buffers at a fraction of the resources and facility space, resulting in a more streamlined buffer suite and a more efficient manufacturing process. The buffer platform is configurable and includes four components: a selection of distinct buffer concentrates; Mobius Select single-use assemblies; an automated, accurate, and precise buffer dilution system; and tailored system services.

Integrated online biomass measurement

Sartorius Stedim Biotech (SSB) added an integrated online biomass measurement to its ambr 15 fermentation and ambr 250 high throughput systems for microbial applications (4). The fermentation and high throughput systems operate up to 24 single-use stirred bioreactor cultures in parallel, and with the integration of online biomass measurement, SSB has addressed the bottleneck associated with offline sampling.

The new online biomass capability features non-invasive reflectance measurement and enables scientists to rapidly obtain detailed process understanding and control over their microbial cultures. The reflectance-based technology means that sampling is not required. Instead, the product uses lasers to transmit light through the base of each bioreactor and microprocessors to translate this into a reflectance measurement.

The biomass capacity offers a broad measurement range and bubble correction factors for gas bubble density and enables reliable online measurements in high aeration and agitation environments. Online reflectance can be displayed through a user calibration process as online optical density, wet cell weight, or dry cell weight. SSB reports that the online biomass measurement has been successfully tested with different organisms, including Escherichia coli, Pichia pastoris, Saccharomyces cerevisiae, Streptomyces spp., and Corynebacterium spp.

“By integrating innovative biomass monitoring technology into our ambr systems for microbial applications, we enable real-time growth data to be used for more advanced process control,” said Alison Rees-Manley, product manager at Sartorius Stedim Biotech, in a March 27, 2019 press statement. “We’re confident that these ambr systems will help scientists by reducing the burden of offline sampling … providing better process understanding and greater control of microbial cultures. This will result in more accurate and predictive data for cost-efficient protein production.”

Dual impeller single-use bioreactor

Laboratory testing instruments manufacturer Distek developed a dual impeller single-use bioreactor (SUB) system as part of the company’s BIOne portfolio (5). The new SUB increases mixing efficiency within the bioreactor, resulting in an increased mass transfer coefficient (kLa) while maintaining the same rate of agitation.

“Optimized mammalian processes are yielding higher cell densities and more product than ever,” said Cristy Botens, product manager of Bioprocessing, Distek, in a March 21, 2019 company press release. “We’ve developed a dual impeller SUB configuration to improve mixing efficiency and provide higher kLa values to support our customers as they develop tomorrow’s medicines and cures.”


1. Univercells, “Introducing the scale-X carbo Bioreactor System,” Press Release, April 10, 2019.
2. Emerson, “New Sensor Technology Fills Speed and Stability Gap for Single-use Bioreactors,” Press Release, April 3, 2019.
3. MilliporeSigma, “MilliporeSigma Elevates its BioContinuum Platform Strategy to Deliver ‘ContiGuous’ Bioprocessing,” Press Release, April 2, 2019.
4. Sartorius Stedim Biotech, “ambr Now Available with Integrated Online Biomass Measurement,” Press Release, March 27, 2019.
5. Distek, “Distek, Inc. Releases Dual Impeller BIOne Single-Use Bioreactor System,” Press Release, March 21, 2019.

Tags: cell culture, bioreactors, sensor technology, upstream, single-use