Regulatory Green Light
“FDA has looked at single-use manufacturing and does not see the need for any new regulations or guidance to cover it,” says Martin. In fact, disposables offer advantages from a regulatory perspective; they represent single-use, dedicated equipment, providing better containment, minimizing the risk of batch-to-batch contamination, and eliminating the need for cleaning and cleaning validation. In fact, an FDA guidance that favors single-use equipment for producing clinical batches “has been very enabling for CMOs,” Martin says.
Regulatory acceptance has been accompanied by heightened activity in testing to detect and measure potential extractables and leachables from the plastic materials used to make disposable products.
Pall’s Allegro™ line of disposable products for small- to large-scale processing includes Kleenpak™ Nova capsule filters. Single-use Kleenpak Connectors, each composed of a male and a female connector, are used to link two separate presterilized fluid pathways. The company’s Allegro 2-D biocontainers range in size from 50 mL to 50 L, while Allegro 3-D biocontainers and accompanying front-loading stainless steel totes are available in 100 L, 200 L, and 500 L sizes and contain a sampling port and two inlet top ports.
These disposable biocontainers are made of a polyethylene film that is both clear and low in extractables and leachables, according to Martin. The Allegro 2-D biocontainers feature rounded corners to minimize product loss. The company designed a tapered manifold to connect the plastic sheets to incoming and outgoing tubing to reduce the chance of leaking.
Sartorius Stedim Biotech recently added to its BioStat® CultiBag family of products, introducing three new products, including the CultiBag RM 600, a 600 L disposable bioreactor with a 300 L working volume. The CultiBag RM relies on the motion created by a rocking platform for mixing. It is designed for seed production or GMP manufacturing in batch or fed-batch mode. The 3-dimensional bag contains optical chemical sensors for pH and dissolved oxygen in the form of immobilized, disposable sensor patches. Also new from Sartorius is the CultiBag RM Twin-Rocker, which consists of two rocker units that can be controlled independently by a single BioStat RM Control Tower.
With the introduction of the CultiBag STR, Sartorius Stedim Biotech brings to the market a single-use stirred tank bioreactor. This new product line debuts with a disposable bioreactor chamber that has a maximum working volume of 200 L. The chamber sits inside a stainless steel support housing; the system includes a controller and disposable sensors.
Holger Bromm, director of marketing and product management for filtration and fermentation technologies at Sartorius Stedim Biotech, identifies the major benefit of this reactor type. “It is as close as possible to a stainless steel reactor, with identical control, agitation, sparking, and design.” The company plans to introduce models with working volumes of 50 L, 500 L, and 1,000 L within the next 6–12 months.
The Hydrocyclone from Sartorius Stedim Biotech is a perfusion device for cell separation designed for use in combination with a large-scale disposable bioreactor being operated in continuous product collection mode. It functions as an inverted fixed-wall centrifuge without rotating parts.
Hydrodynamic energy-driven centrifugal forces move cells downward, while smaller particles, dead cells, and cell debris are driven toward an exit port at the top by a countercurrent inner secondary vortex. The Hydrocyclone has a maximum perfusion performance of up to 720 L/day; larger-scale perfusion can be achieved by operating multiple systems in parallel.
Other new disposable offerings from Sartorius Stedim Biotech include Sartoclear L-Drums for large-scale cell harvesting, which are an extension of the Sartoclear P product family. Composed of a double layer of cellulose-based depth filters, the Sartoclear drum can be used singly for cell clarification after centrifugation, or two drums can be used in series for cell harvesting, eliminating the need for centrifugation or spin filters, the company reports. The L-Drum will initially be available in four different multilayer combinations of filters, each with a surface area of 2 m2.
For single-use filtration applications, Sartorius Stedim Biotech completed its Sartopore® 2 polyethersulfone (PES) membrane filter product portfolio with the launch of the Sartopore 2 XLG MidiCaps and MaxiCaps disposable capsules for sterile filtration. The XLG and existing XLI versions of the MidiCaps and MaxiCaps exceed the total throughput performance of most commercially available PES filter membranes by 80–100% in application such as media filtration, sterile filtration after cell harvest, and filtration of downstream intermediates, according to Bromm.
Applikon’s AppliFlex single-use bioreactor is made of JMS Flex Film. The Appliflex product range has built-in fluorophor sensors for pH and dissolved oxygen; these parameters can also be controlled using classical pH, dissolved oxygen, and temperature sensors. The AppliFlex Rocker ensures reliable mixing.
Next to join the Appliflex product range later this year will be a new single-use bioreactor system being developed by Applikon in cooperation with Millipore.
SAFC offers a family of single-use products for cell culture and bioprocessing under the BIOEAZE™ trade name. The company’s ethyl vinyl acetate bags, polyethylene bags, sterile tank liners, EZ Top and asceptic connecting devices, and disposable tubing can be purchased separately or as an assembled, customized bioprocessing system.