In a multiproduct cGMP clinical manufacturing facility, flexibility and short processing times are important operating attributes. A critical aspect of a multi-product facility is the procedures used to minimize product cross-contamination. Single-use (SU) technology enables flexibility, short process times, and limited chances for cross-contamination. An SU tangential flow filtration (TFF) system was implemented in a cGMP clinical manufacturing facility. In this article, we evaluate the performance, control of operation, productivity, and overall cost savings of the system.
Improving the time it takes to bring new drugs to the market continues to be an important goal for pharmaceutical companies. There are several approaches that are taken with the overall goal of bringing more drugs into commercialization phase.1 Single-use (SU) technology is one of the strategies being adopted to reduce overall drug development time. SU technology brings significant advantages of reduced capital costs, faster construction and installation, reduced processing cycle times, and elimination of the need for post-use equipment cleaning and verification.2,5
Starting with the use of plasticware such as pipettes, petri dishes, and t-flasks, disposable components are being increasingly incorporated in the laboratory environment. With the development of SU bioreactors at the 2,000 L scale (Xcellerex XDR), chromatography systems (GE ReadytoProcess), and systems for micro- and ultrafiltration, disposable equipment continues to replace fixed stainless steel equipment in manufacturing plants.
Demonstrating that process equipment is adequately cleaned is a critical aspect of any pharmaceutical plant operation. Following some type of post-use cleaning, the presence of residual protein and cleaning agent is typically assessed by subjecting equipment rinse solutions and swab samples to test methods including pH, conductivity, and fluorescamine. These procedures are time consuming and reduce equipment utilization. In a multiproduct facility, when equipment is shared between products with high and low potency, meeting the low acceptance criteria for residual protein can be very challenging.
(JOHNSON & JOHNSON)
To meet the demand of reducing production cycle time and improving productivity, a general downstream production process review was performed to identify the bottlenecks that affect the overall process efficiency. This process review identified that an existing stainless steel (SS) ultrafiltration–dialfiltration (UF–DF) system used for an intermediate UF–DF process in the facility was a bottleneck and presented an opportunity to evaluate an SU UF–DF system. The SS UF–DF system was designed for process development and scale-up rather than GMP production and had a limited retentate tank capacity (25 L). Additionaly, the clean-in-place (CIP) and post-CIP swabbing of the SS UF–DF system are very complex and time-consuming.
Criteria for Evaluating SU UF–DF Systems
Currently there are several SU UF/DF systems available. An evaluation was made to choose an appropriate system based on GMP production requirements, operational needs, budget, and timeline. These criteria included:
Operation: The system should have the capacity to handle 5 m2 membrane size, 10–50 L retentate tank working volume, >80 L/h/m2
(LHM) feeding flux, and differential pressure (ΔP) and transmembrane pressure (TMP) controls at 0–20 psi. The retentate tank should have a mixing device to avoid localized concentration during the operation.
Process monitoring, control, and data management: The process should be able to be controlled by constant TMP and ΔP. The pressures, flow rates, process phases, and other process parameters should be able to be monitored and recorded in real time. Data management should meet 21 CFR Part 11 compliance.
Disposable parts: There should be no or a limited number of bio-compatibility issues for any disposable parts that contact product and process buffers. The levels of leachables and extractables should be in the acceptable safety range for clinical drug substances.
Equipment availability and vendor support: The product should be readily available. An integrated and off-the-shelf system is preferred because it saves time on equipment validation and meets short project timelines. The manufacturer should have a good record for on-time equipment delivery and reliable technical support. The manufacturer should have the capability to consistently supply high quality accessories and consumable items.
Cost: The price of the equipment and disposable items should be reasonable to reduce the overall cost of production when implementing a new UF–DF system in a GMP production facility.
The Millipore SU Mobius FlexReady Solution for TFF model TF2 system was selected after comparing three different SU UF–DF systems that are currently on the market. An ultrasonic permeate flow meter and a retentate pressure control valve (PCV) were included to enhance process control. The length of the rods on the cassette holder was extended to increase the holder capacity from 2.5 to 5 m2 of membrane.