August 1, 2009 (Vol. 29, No. 14)
Jim Furey General Manager PendoTECH
Novel Tools Focus on Critical Process Parameter Monitoring in Disposable Systems
The practice of integrating bags, tubing, and filters into preassembled, ready-to-use bioprocess solutions is optimized if noninvasive sensing of critical process parameters is part of the package. These single-use assemblies frequently require treatment for bio-burden reduction or sterilization by nonthermal methods such as gamma irradiation because of the incompatibility of most bioprocess bag materials with temperatures associated with sterilization.
The benefits of single-use technology, including its ability to focus internal resources on core activities versus ancillary tasks such as cleaning validation and the expenses associated with that activity, have been well publicized. With all of the benefits that disposable technologies offer, performance—especially the monitoring and control of process conditions—must not be sacrificed.
Critical process parameters that are often monitored include pressure, pH, dissolved oxygen, conductivity, UV absorbance, flow, and turbidity. The packages that contain the traditional technologies for monitoring these parameters are not usually compatible with or effective when integrated into single-use assemblies for many reasons: cost, cross contamination, inability to maintain a closed system, and system incompatibility with gamma irradiation.
Even though these obstacles do not always preclude the use of traditional measurement technologies, single-use solutions for monitoring process parameters eliminate the need for equipment cleaning and autoclaving small parts, reduce the risk and cost involved with making process connections, and may be more cost effective than tracking and maintaining traditional technologies. For example, a sanitary, autoclavable pressure transducer that is qualified for a certain number of autoclave cycles and requires recalibration may be more expensive to use versus a single-use pressure sensor.
As single-use sensing technologies evolve, a framework for evaluation before implementation must be determined. Key points to consider are material properties, sensor manufacturing, process compatibility, performance requirements, control system integration, compatibility with treatments before use, and regulatory requirements.
Pressure is one of the most ubiquitous process parameters. Many bioprocess unit operations are either controlled based on pressure or have significant pressure-related safety issues. When pressure monitoring is applied to single-use applications, however, it is routinely relegated to ancillary status.
Two classic examples are the bioreactor and the primary recovery process steps. Traditional stainless steel reactors are monitored and controlled for pressure, as pressure is used as a means of influencing mass transfer and mitigating contamination. In addition, a high-pressure event is a potentially hazardous situation.
Single-use bioreactor systems, on the other hand, are frequently not monitored or controlled for pressure because stainless steel pressure transducers are not compatible or cost effective when applied to disposable bioreactors. As a result, a clogged vent filter on a bioreactor can easily rupture bags, spilling the contents of the reactor and exposing the operators to unprocessed bulk.
Another application where pressure monitoring is central to process performance is depth and sterile filtration. A filter’s capacity is primarily measured by either flow decay or pressure increases, although adding reusable traditional pressure transducers to a process train defeats the purpose of a single-use process set-up. Depending on the process application, the product contact surface of a traditional device requires either sanitization or moist heat sterilization.
There are traditional devices that are compatible with steam in place, where only the product contact surface is exposed to steam, and even devices that can be placed in an autoclave where the entire device is exposed to steam. Many single-use process components, however, are not compatible with moist heat sterilization temperatures so there may be a requirement for separate sterilization of the stainless steel device and possibly nonoptimal connection to a pre-sterilized disposable assembly.
The application of piezo electric micro-electro-mechanical system (MEMs) pressure sensors with standard or braided silicone tubing mitigates the need for any batch-to-batch cleaning or any product changeover to be done.
Single-use pressure sensing allows for rapid changeover of product contact parts in both development applications and especially in early-phase clinical manufacture. Single-use pressure sensors from PendoTECH were designed to enable pressure measurement with single-use assemblies that have flexible tubing as the fluid path (Figure 1).
These single-use pressure sensors are gamma compatible (up to 50 KGy), and the fluid-path materials meet USP Class VI guidelines and are also compliant with EMEA 410 Rev 2 guidelines. The sensors are manufactured in a Class 100,000 cleanroom to minimize introduction of foreign matter, and each sensor is tested for leaks, accuracy, and electrical specification. In addition, the sensors are compatible with typical bioprocessing solvents.
On a single-use bioreactor, a sensor can be installed on a vent line to measure headspace pressure (Figure 2). Even though the sensors are qualified for use up to 75 psi, the core sensor is accurate in the low-pressure range required for a single-use bioreactor (Figure 3).
When implementing single-use technology into a process train, the measurement of key analytics is critical and should not be sacrificed or overlooked. It is incumbent upon the manufacturer, user, and quality and safety organizations to make sure the appropriate sensing technology is suitably integrated.
Jim Furey ([email protected]) is general manager at PendoTECH.