Single-use equipment and its support of QbD

QbD has found success within pharmaceutical processes and gained momentum in the production of biologics (2). Knowing the quality attributes and properties of a product creates the opportunity to design quality into the process with process analytical technology (PAT) tools. The very well-known saying, "to design quality into a process instead of testing it in" and Janet Woodcock's statement, "a maximally efficient, agile, flexible pharmaceutical-manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight" (10) are very much supported by single-use technologies, especially interconnected unit operations.

Once the critical quality attributes are known, process-development activities can include small-scale, single-use process steps to evaluate the reliability of the equipment and its potential effect on the product. Furthermore, single-use sensor technologies can be deployed to allow for process controls, creating a dependable and robust output. Such small-scale systems, however, must be scalable to avoid surprises in process scale.

Single-use process steps are unfolded at POU and interconnected aseptically by validated-connection systems. Any designs within a hardware system might be complex to disassemble, clean, and then reassemble. An interconnected single-use operation is less complex because the end-user does not have to assemble multiple components. Such design benefits and ever-advancing, single-use sensor technologies create opportunities to support QbD initiatives with PAT.

A PAT approach must take into account any out-of-specification situation within a process step. Sensor technologies in single-use format include pressure, pH, conductivity, dissolved oxygen, and temperature sensors (7). However, more needs to be done within the sensor-technology field. The qualification documentation, which commonly goes together with any single-use components or assemblies, can be used to determine any obstacles to critical quality attributes and potential influences on product quality. Vendors of single-use technologies have a thorough understanding of their raw material, finished goods, and assemblies. Furthermore, they support validation requirements with their service organization. End-user process-development resources should exploit service support opportunities by vendors to establish appropriate qualification and validation activities.

Process and facility designs

Biopharmaceutical manufacturing typically involves numerous process steps. The sequence, number, or size os steps differs by application and individual bioprocesses (8). To reduce the time and engineering effort required during the design and construction of production facilities, process platforms are increasingly used to define cost-effective solutions.

Process platforms are well-defined sequences of processes or process steps, which enable progress in biopharmaceutical development and production as they expedite time-to-market. Significant benefits associated with process platforms include efficient-engineering workflows and more precise cost determinations and cost allocations, particularly in the early design phases. Furthermore, projects can be implemented faster and investment decisions can be postponed until the drug candidate shows positive results.The use of process platforms also offers potential for process optimization, implementation support of QbD initiatives, accelerated production start-ups, and improved supply security.

The prerequisite is closed, preconfigured, single-use unit operations. These units serve as process platforms while supporting bioprocess and user safety. By maintaining flexibility and allowing different configurations, process complexity is significantly reduced, which is often considered a key success factor by the end user.

Several suppliers have already launched their first configurable disposable solutions or systems (CDS). These solutions address the different volume needs, within the development cycle to production-capacity needs for buffer or media preparation, from 50 to 1000 L. The integration of monitoring and control features for pH, pump-speed, and fluid-level control is an additional milestone in the development and implementation of process-relevant, single-use equipment. The integrated controls allow end users to perform other tasks during, for example, buffer-preparation operations.

Whether a production facility is a retrofit or green field, the process and workflows must always be defined to assist in developing the facility layout. Logistics for material handling, segregation of critical steps, space requirements for work-in-progress and storage, plus provision of the utilities required for process and cleaning needs at every critical process step, must be fully specified.

Finally, support spaces required and their interactions with the process path must be clearly defined (5). Employing single-use equipment generally requires more space to accommodate movement and handling. For this reason, horizontally-positioned production operations located on one floor, with sufficient space for material and personnel transfer, are the best layout for disposable-production facilities. Although this may require more floor space than production facilities which are installed vertically, this arrangement is recommended for bag-based transport and storage of raw materials, semi-finished, and finished products.

Vertically arranged equipment (common in many current biopharmaceutical-production facilities) tends to be more cost-effective, due to the compact-building design possible and the resulting low ground-area footprint. However, in the conventional arrangement, where both medium and buffer preparation take place on the floor above the process suites, a vertically-designed, disposable production facility is at a disadvantage because transporting medium and buffer bags must be done over one floor or the fluid transport must be accomplished between different floors and, thus, involve piping. In the latter case, the potential advantages associated of storage and transporting media and buffers in disposable bags would be negated.