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.
It is, therefore, important for single-use vendors to supply a scaling-basis system supported by various single-use sensor
technologies and appropriate qualification documentation. The benefits of single-use unit operations include less human intervention
and fewer possible set-up failures. The process step is assembled and ready-to-use coming as soon as it comes out of the package.
The assembly is fitted into the supporting hardware systems, which is simpler than disassembling a process step, cleaning
the components, assemblying the components, and sterilizing the system before moving to point-of-use (POU).
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.