Lauren Lavelle

Various pieces of equipment to advance upstream bioprocess have been introduced within recent months. The following products showcase a select few of those advancements.

	Sartorius Stedim Biotech introduced a new single-use vessel for the ambr 250, a modular, benchtop, automated mini-bioreactor system for biologics process optimization. The vessel was constructed for use with therapeutic cell lines for process development of cell and gene therapy applications. The vessel allows scale-up into cGMP single-use bioreactors and bags for clinical production of regenerative medicines.

	The new unbaffled vessel design with a large, pitched-blade impeller has a working volume of 100–250 mL and the ability to handle gentle agitation and mixing without sedimentation for growth of single-cell suspensions, cell aggregates, and adherent cells on microcarriers. Compared to less predictive spinners and T-flask models, the new system enhances cell-culture performance for regenerative medicines, according to a company press release.

	Additionally, the ambr 250 features a new 100–4500 rpm motor that allows lower stirrer speeds for therapeutic cell lines, including stem cells. Optional design of experiments software supports scale-up to the company’s stirred bioreactors and scale-out to the company’s rocking bags for production of autologous and allogeneic cell and gene therapies.

	Custom Single Run (CSR) Bioreactors from ABEC are designed to work with volumes up to 6000 L, an increase from the company’s 4000-L single-use bioreactor size.

	The new bioreactor is fully customizable and enhances cell culture capacity per unit of floorspace, which saves in capital, facility, and disposables cost. CSR bioreactors are designed to deliver equivalent power per volume while maintaining low shear mixing. CSR products use a non-proprietary material, instrument, and component supply chain.

	“We understand that our customers cannot compromise on scalability and cost of goods when realizing other single-use benefits such as multi-product flexibility,” said Scott Pickering, ABEC president and CEO. “In applications where single-use is preferred, with 6000-L CSR bioreactors, customers can now achieve even greater economies of scale for cell culture production.”

	INFORS HT’s updated Techfors pilot bioreactors for production-scale bioprocesses are equipped with workflow-oriented, touchscreen interfaces and a new version of the company’s eve bioprocess software to control, monitor, analyze, and document bioprocesses in a GMP-regulated environment. 

	With all the capabilities of smaller bioreactors, Techfors give users the ability to start their projects right away, without the need for familiarization or new skill learning. The bioreactors can now also be custom-made to match the customer’s requirements.

	“Besides the modern look with ergonomically arranged pumps and a tilting touch screen, we particularly focused on a consistently workflow-oriented user interface,” said Dr. Dirk Hebel, lead product manager, Bioreactors, INFORS HT.

	Watson-Marlow Fluid Technology Group expanded its range of puresu single-use assemblies for the manufacturing of biopharmaceuticals and personalized medicines. The components use an open-architecture design to allow creation of custom sterile fluid paths.

	Three new product variants include sterile claim, gamma irradiated, and non-irradiated assemblies. Sterile puresu is used as a solution for fluid path bioprocesses for customers who require contamination risk mitigation, gamma irradiated is offered for customers who manage microbial control through bioburden reduction, and non-irradiated is designed for process development activities.

	Assemblies are available with a sterility assurance level claim of 10-6 with a two-year shelf life. The company offers product traceability and documented quality systems compliant with ISO 9001.

	Tridex Protein Analyzer by IDEX Health & Science is a compact solution for real-time, at-line titer monitoring in a bioprocess environment. The device is the first protein analyzer designed specifically for bioprocess monitoring. It is designed to ensure that at-line results directly correlate to offline HPLC methodology.

	It features a trap and elute technique to monitor the titer in a bioreactor and provides users with the option to connect to an automated sampling system so the system can integrate completely into a bioprocessing environment. Additionally, the sample path is enclosed, which enables single-use capabilities. The instrument measures over a dynamic range of 0.1–10 g/L, with minimal sample manipulation and results in under five minutes.

	Cytovance Biologics will add a single-use platform for the manufacturing of plasmid DNA (pDNA) to their facilities in Oklahoma City, OK. Critical Reagent Grades and CGMP-grades will be available in lot sizes from 1 g to 50 g, and one R&D grade will be available in lot sizes from 1 g to 5 g. 

	“With this new platform, our teams will ensure high-quality, fast, and affordable plasmid development and delivery, which will be key to our clients and ultimately benefit the patients,” said Yan Wang, CEO of Cytovance Biologics.

	“Whether our clients need pDNA for early pre-clinical work or for advanced commercial efforts, our team will ensure a cost-effective and robust supply of high-quality plasmids that align with the regulatory expectations across a product’s lifecycle,” added Jesse McCool, chief technology officer of Cytovance Biologics.

	1. Sartorius Stedim Biotech, “New ambr 250 Modular Bioreactor Vessel Launched for Cell and Gene Therapy Applications,” Press Release, June 27, 2019.
	2. ABEC, “ABEC Advances Single-Use Bioreactor Volumes to 6,000 Liters,” Press Release, Sept. 10, 2019.
	3. INFORS HT, “INFORS HT launches new version of the Techfors pilot bioreactor,” Press Release, Oct. 3, 2019.
	4. Watson-Marlow Fluid Technology Group, “Watson-Marlow Fluid Technology Group’s puresu single-use tube assemblies offer reliable, sterile, customisable solutions for bioprocessing,” Press Release, Oct. 31, 2019
	5. IDEX Health & Science, “IDEX Health & Science, LLC Launches Dedicated Protein Analyzer for Bioprocessing: TRIDEX™,” Press Release, July 10, 2019.
	6. Cytovance Biologics, “Cytovance Biologics Introduces An Integrated Single-Use Platform For Plasmid DNA (PDNA) Manufacture,” Press Release, Oct. 21, 2019. 

Articles

The latest advances in upstream technologies include single-use equipment and a protein analyzer for titer monitoring, as well as new plasmid DNA manufacturing capability. 

What’s New in Manufacturing: Upstream Technologies

Advancements in downstream technologies are imperative to improving the reliability and capacity of biomanufacturing. The following products promise to aid the bioprocessing industry.

	Stainless steel liquid chromatography column

	DAC Ergo by Asahi Kasei Bioprocess (AKB) is a liquid chromatography (LC) column that allows stainless-steel dynamic axial compression LC columns to be unpacked, disassembled, and reassembled by a single operator using a hydraulic system in collaboration with a bottom plate-fastening approach (1).

	Unlike smaller particle chromatography devices, which are unpacked manually by removing the bottom plate from the depressurized column, the new device uses a quick-release bottom plate-fastening design and a hydraulic column lift driven by a handheld control pendant. The plate is then fastened to the bottom of the column tube using I-bars instead of traditional threaded bolts and, once the column is correctly positioned, the bars can be disengaged by hand without tools.

	 “DAC Ergo allows a single operator to disassemble the column bottom plate and unpack the column in less than 30 minutes, while the performance of the column and its flow distribution remain first-rate,” said Chris Nordhoff, president of AKB America and head of AKB’s Fluid Management business unit, in a press release. “Through both operator safety and labor savings perspectives, this new feature aligns strongly with our division slogan of ‘Pioneering Biologics Safety and Manufacturing Efficiency’.”

	The columns are available in diameters between 60 cm and 120 cm with pressure ratings up to 35 bar.

	Updated sensing and control unit for hygienic valves

	Alfa Laval introduced an updated version of its valve sensing and control unit for hygienic valves, the Alfa Laval ThinkTop. The new additions, the Alfa Laval ThinkTop V50 and V70, are the second generation of the device and now include the latest advances in technology, according to the company (2).

	The new devices are chosen based on the number of solenoid valves required and can cover all valve requirements. The V50 comes equipped with butterfly, single-seat, and double-seal valves, while the V70 comes with the same features as the V50 plus a double-seat and special valves.

	The redesigned valve sensing and control units also include a 360° LED visual status indication, a repositioned Gore Vent, an auto-setup feature for simplified commissioning, a compact industrial exterior suitable for tight installations, burst seat cleaning, and a QR code for access to support materials and direct support.

	“We have listened carefully to what customers want from a valve sensing and control unit,” said René Stietz, Product Management Valves & Automation, Hygienic Fluid Handling, Alfa Laval, in a press release. “The changes we’ve made to the ThinkTop are highly responsive to customer needs and therefore highly relevant-for instance, faster and more intuitive setup without compromising durability and reliability.”

	Wettable phase for separation and purification

	Kromasil unveiled a new wettable phase engineered for the separation and purification of biomolecules, impurity removal, and API manufacturing under aqueous conditions. The phase works in conjunction with the Kromasil 100 Å C18(w), which permits selectivity and resolution opportunities to isolate impurities and cultivate samples with amino acids and peptides (3).

	The phase is end-capped and allows for sample loading and a 100% aqueous run start. Along with this, the Kromasil 100 Å C18(w) comes with 10 µm particles as bulk and packed columns from 4.6 mm to 21.2 mm inner diameter.

	The BioContinuum Buffer Delivery Platform from Millipore Sigma is a new element in the BioContinuum Platform for next-generation bioprocessing, which includes the company’s “contiGuous” bioprocessing (4).

	The delivery platform is comprised of a selection of distinct buffer concentrates, Mobius Select single-use assemblies, and an automated buffer dilution system with tailored system services. It also produces process buffers with less resources and facility space, which provides a streamlined buffer suite and an easier manufacturing process.

	Using the contiGuous processing element, the platform will handle the materials, production, testing, and analytics elements of the processing techniques.

	“MilliporeSigma’s vision goes beyond continuous manufacturing and will deliver contiGuous bioprocessing-a seamless confluence of digital and intensified bioprocessing building blocks,” said Andrew Bulpin, head of Process Solutions at MilliporeSigma, in a press release. “Our BioContinuum Buffer Delivery Platform is a perfect example of the high degree of connectivity that contiGuous biomanufacturing can achieve.”

	Sartorius Stedim Biotech announced the launch of the new Sartocheck 5 Plus to its current line of Sartocheck integrity testers (5). The new device improves the detectability of operator errors, improper test set-ups, and out-of-tolerance environmental conditions. Advanced functions ensure data integrity and compliance with future requirements of quality risk management, such as the upcoming Annex 1 of the European Medicines Agency.

	Compared to other filter testers with limited flow measurement capabilities, the Sartocheck 5 Plus covers a range of integrity testing from small syringe filters up to large, multi-round housings and crossflow cassettes, with diffusion rates of up to thousands of milliliters per minute. An automatic test-time feature for diffusion and water intrusion, along with accelerated bubble point testing, reduces overall test time, and parallel bubble-point testing enables up to 10 small filters to be checked with one filter tester. A 12-inch screen has an ergonomic interface, easy-to-clean design, and inherent virus protection.

	1. Asahi Kasei Bioprocess, “Asahi Kasei Bioprocess Launches DAC Ergo, an Innovative Large-Scale Chromatography Column Design,” Press Release, July 24, 2019.
	2. Alfa Laval, “Introducing Alfa Laval ThinkTop V50 and V70,” Press Release, June 20, 2019.
	3. Kromasil, “The New Kromasil Wettable Phase,” Press Release, Sept. 2019.
	4. MilliporeSigma, “MilliporeSigma Elevates its BioContinuum Platform Strategy to Deliver ‘ContiGuous’ Bioprocessing,” Press Release, April 2, 2019.
	5. Sartorius Stedim Biotech, “Sartorius Stedim Biotech Launches New Sartocheck 5 Plus Filter Tester,” Press Release, Oct. 21, 2019. 


	Vol. 32, No. 11
	November 2019
	Pages: 48-49

	When referring to this article, please cite it as L. Lavelle, “What’s New in Manufacturing: Downstream Technologies,” 

The latest advances in downstream technologies include stainless-steel liquid chromatography columns, sensing and control units for hygienic valves, a wettable phase for separation and purification, a buffer delivery platform, and a new filter integrity tester. 

What’s New in Manufacturing: Downstream Technologies

Advances in process chromatography are necessary for accuracy and productivity in biologics manufacturing. The following products promise to improve and enhance the reliability of process chromatography.

	The ReadyToProcess chromatography column with 600 mm inner diameter is the latest addition to the ReadyToProcess chromatography column line from GE Healthcare. The pre-packed, ready-to-use column offers enhanced flexibility and productivity in clinical and commercial manufacturing by eliminating the need for column preparation, packing, and validation procedures, according to the company.

	Introduced to the market in July 2019, the ReadyToProcess 600 mm inner diameter chromatography column comes equipped with bed heights of 100–250 mm. The column is compatible with a variety of chromatography resins including those used for monoclonal antibody (mAb) purification, viral vectors, plasmids, recombinant proteins, and more.

	Validation columns from GE Healthcare involve pre-packed scale down Tricorn 10/200 columns for process development and process validation. The columns can be run on chromatographic systems, including the company’s own ÄKTA chromatography systems, and are prepacked to save time, improve reproducibility, and eliminate the need for packing expertise, the company says.

	The columns come equipped with a bed height of 20 cm and an inner diameter of 10 mm. MabSelect PrismA, MabSelect SuRe, MabSelect SuRe LX, Capto S ImpAct, Capto Q, Capto SP ImpRes, and Capto Adhere prepacked resins are available for use with these columns.

	Chromatography process characterization kit 

	GE Healthcare also introduced Process Characterization Kits to its catalog in July 2019. The kits provide access to knowledge from resin development projects, enable risk assessments and process characterization of resin variability, and interplay with process parameter impact on process performance and critical quality attributes. According to the company, this aids in the understanding of process parameters and raw material attributes, which are key to developing successful control strategies and
	productive processes.

	The kits come with three lots of a given resin with different ligand densities (high, center, and low) and are available for Capto S ImpAct, Capto SP ImpRes, Capto adhere, Capto adhere Impres, Capto MMC, Capto MMC ImpRes, Capto Phenyl, Capto Phenyl ImpRes, and Capto Butyl ImpRes resins. 

	Soon-to-be-released chromatography products 

	ÄKTA go is GE Healthcare’s most recent addition to the ÄKTA chromatography systems portfolio. Developed for automated chromatography descended from fast protein liquid chromatography (FPLC) technology, the system supports routine lab-scale protein purification for affinity, size exclusion, and ion
	exchange chromatography.

	With a flow rate range of 0.01 to 25 mL/min, an operating pressure of 0 to 5 MPa (50 bar, 725 psi), pressure, ultraviolet, conductivity, and pH monitors, and dimensions of 335 × 482 × 464 mm without accessories, the ÄKTA go is designed to simplify method creation, achieve desired purity with ease, and make the most of bench space in crowded laboratories. The company plans to introduce the system to the market in October 2019. 

	Similarly, Repligen will introduce a new proprietary method of packing ceramic hydroxyapatite resin in its OPUS pre-packed columns in September 2019. The columns will be ≤45 cm in diameter with a range of configurable bed heights (5–30cm) and standard OPUS pre-packed column lead times will apply, according to the company.

	Originally introduced in 2016, the next generation of Pall Biotech’s CMM HyperCel mixed-mode resin is designed for large-scale drug manufacturing. The resin works to separate proteins with similar isoelectric points and hydrophobicity in broad conditions while using a pH from five to eight and conductivity up to 50 ms/cm.

	The product is made up of a cellulosic matrix on which amino benzoic acid provides the ionic charge and hydrophobicity attached to it. It aids in process and product-related impurity removal and is particularly suitable for new engineered modality of monoclonal antibodies (mAbs) that are difficult to purify or recombinant proteins. The resin is also able to work from low to high conductivity and avoid the dilution needs required with cation exchange conditions.

	The rebooted resin has an applied flow rate allowing three-to-four-minute residence time, a binding capacity of 100 mg/mL immunoglobulin G (IgG) at pH 5, 12 ms/cm, and > 60 mg/ml mAb at 25 ms/cm efficient ion exchange at high conductivity with no need for dilution or defiltration, the company states.

	The Eshmuno CPS Resin from MilliporeSigma is a cation exchange resin that combines high dynamic binding capacity and separation efficiency in high-salt purification processes. According to the company, the resin’s salt tolerance allows for direct loading of high conductivity feed streams, which reduces costs, time, and manufacturing. It also features easy process development capabilities with bind and elute conditions and selection of process parameters.

	The resin is composed of a base matrix, hydrophilic polyvinylether polymer, and a sulfonate cation exchanger. It also has a capture and intermediate polishing step of recombinant proteins, enzymes, antibody fragments, growth factors, etc. The product has a linear flow rate up to 500 cm/h (<3.0 bar net pressure) and a binding capacity of approximately 160 mg lysozyme/mL of gel.

	GE Healthcare’s high resolution Capto HiRes Q and Capto HiRes S ion exchange chromatography columns are designed for high resolution separation for protein and nucleic acid purification or analysis. Prepacked in a Tricorn high-performance column, the resins are based on high-flow agarose with a particle size of 8 um.

	The resins come with bed heights of 50 mm (5/50 column) and 100 mm (10/100 column); column inner diameters of 5 mm (5/50 column) and 10 mm (10/100 column); maximum pressure over a packed bed of 4.0 MPa; and an ionic capacity/ml packed resin of ~0.23 mmolCl-/mL resin for the Capto HiResQ and ~0.12 mmol H+/mL resin for the Capto HiRes S. 


	Vol. 32, No. 9
	September 2019
	Pages: 47-48

	When referring to this article, please cite it as L. Lavelle, "What's New in Manufacturing: Process Chromatography," 

The latest advances in process chromatography include pre-packed chromatography columns, process characterization kits, fast protein liquid chromatography systems, and mixed-mode chromatography resins. 

Author | Lauren Lavelle

Articles

What’s New in Manufacturing: Upstream Technologies

What’s New in Manufacturing: Downstream Technologies

What’s New in Manufacturing: Process Chromatography