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Insights on single-use systems implementation and exploitation in biopharmaceutical manufacturing and processing, based on a QbD approach.
During the past three decades, single-use technology (SUT) has evolved many fold. From its origins with filter housings and bioprocess containers to today, disposable process applications practically cover the entire spectrum of biopharmaceutical manufacturing, from cell banking to fill/finish (1, 2). It's of interest to consider a commonly used industry definition for single-use systems (SUS) as defined by the Bio-Process Systems Alliance: "Single-use systems consist of fluid path components to replace reusable stainless steel components. The most typical systems are made up of bag chambers, connectors, tubing and filter capsules. For more complex unit operations such as cross flow filtration or cell culture, the single-use systems will include other functional components such as agitation systems, and single-use sensors" (3).
This is a basic definition, and in practice, should be modified to take into account other simple systems, including bottles, syringes, pipettes, and culture flasks such as rollers, T-flasks, and erlenmeyers. Nevertheless, it remains a straightforward reminder of what SUS are.
The application of this technology for the manufacture of biopharmaceuticals represents a major technology innovation in the 21st century and can bring a number of advantages, such as:
It's important to examine the shift in process paradigm surrounding SUS. Traditional multi-use biotech processes use fixed stainless-steel upstream and downstream systems of various sizes in fixed facilities that can take three to four years to build and start (1, 5). The change of process paradigm with SUS means that their inherent flexibility and impact on plant design, exploited together with a just-in-time production and supply-chain approach, as part of a manufacturing strategy will likely render some classical production philosophies obsolete (5, 6). It's not surprising that industry surveys are projecting that the trend towards adoption of SUT will continue, with rapid growth in this market (7).
While SUS are innovative, they cannot always provide an acceptable manufacturing strategy at a full industrial scale. For example, for monoclonal antibodies (mAbs), single-use bioreactors (SUBs) of 2000 L are available and "off the shelf" and fully integrated plants at a similar scale such as the KUbio (GE Healthcare) integrated concept are offered by one large supplier (8, 9). Nevertheless, a number of hurdles still stand in the way of larger scale SUS, such as component design and/or the risk of failure where the single-use bag lacks structural integrity or suffers easily from fissures or pinholes created during deployment. For these reasons, it seems likely that stainless-steel systems will remain as the large-scale production tool (10–16000 L).
When Vivalis started to use disposables, like many companies engaging SUT for the first time, we saw it as a means for improving efficiency and quality of our research and biomanufacturing operations as part of a customer-driven focus. Subsequent experience drew out the nonconventional nature of SUS and three significant points were noted.
First, although it was thought that SUS would be qualified in the same manner as classical and reusable stainless-steel systems (referred here as multiple-use systems [MUS]), actual experience proved this assumption to be wrong. Second, key benefits such as rapidity of deployment and turnaround quickly became apparent such that the tendency was to think more along the lines of, "How many of these things can we deploy and how quickly"—a philosophy observed in many circumstances.
The third point was an appreciation of the tremendous innovation represented by SUT, which has significantly changed the way biopharmaceutical processing is now performed as shown in many different circumstances from applications in gene and cell-based therapies to CMO operations. For a cell-therapy application, for example, specific cell populations can be selected using SUS (10). The installation of SUBs in an existing facility significantly improved operational turnaround times during the execution of engineering runs and clinical lot productions, saving the time required for the SIP, SIP-decontamination, and CIP cycles. In addition, time-consuming preparation work was reduced since the SUB could be set up in a couple of hours. The total time economy shaves several working days from the overall schedule. While some quality attributes will vary if different products are used between campaigns, the example illustrates the savings that can be realized. The beneficial environmental impact of this last point for SUS compared with conventional technology has also been recognized (11).
Beyond the advantages of SUT, as with any technology, there are some pitfalls. The implementation of SUS and their physical nature can bring forward complex issues such as the following:
The topic of extractables and leachables is a frequently aired but often poorly discussed topic with many end-users having questions as to how to effectively address the subject. In practice, it depends on many issues such as product type, contact time and position in the product lifecycle. There is available guidance (see Refs. 12–15). The other points mentioned above illustrate the somewhat unconventional "out-of-the-box" nature of SUS compared with classical technology; these points are easily addressed as part of a structured implementation process based on current principles and practices and will be discussed in the following sections.
A manufacturing strategy can be defined as a structured approach to the definition of the capability of a manufacturing system, specifying how it is organized and how it will operate, to meet objectives, which are consistent with the business objectives.
The development of a sound manufacturing strategy for the implementation of SUS in a biopharmaceutical context should be based on a quality-by-design (QbD) approach but what does this mean for the industry, and how can one relate to it?
In short, a QbD approach, which is based on the principles of International Conference on Harmonization (ICH) Q8, embraces the complementary concepts of quality risk management and pharmaceutical quality system management as detailed in ICH Q9 and Q10, process validation and verification and stakeholder management. These approaches have become part of the 21st century manufacturing paradigm, laying the foundation for quality-driven processes (16–24).
Implementing SUS using a QbD approach implies the application of a thorough science and risk-based approach and understanding not only for the process for which the SUS will be used, but also the SUT that will be deployed. Such an approach will allow the identification and management of critical sources of variability. Control strategies can be used to maintain a state of control and facilitate continual improvement applied throughout the SUS product lifecycle. These strategies support patient safety and product availability. The forthcoming PDA technical report on SUS has adopted this philosophy and the approach required will be discussed in further detail (25).
As previously mentioned, the nature of SUT and their physical nature can give rise to complex issues. A structured approach should be adopted for the implementation of SUS using "the QbD approach." Below are some of the practical issues involved.
Figure 1: Example of single-use system (SUS) implementation and process validation, including the application of FDA’s process validation model and product lifecycle. As product development moves through the clinical phases to marketing of licensed product, the complexity of the systems used and operations can increase. At the same time, process knowledge improves and is eventually maintained in a state of control where the risk is controlled with the help of specific tools applied according to a structured approach. (Adapted from FDA Process Validation guidance, Ref. 18.)
First and foremost, end-users should have an appreciation of how the complexity and risks involved change over the product lifecycle (see Figure 1). Below are a number of key points that should be addressed for a successful and structured approach to the implementation and exploitation of SUS as the product lifecycle progresses:
At all stages in the product lifecycle, an appropriate level of structure and documentation is essential.
The choice of SUS equipment and suppliers must not be allowed to become an ad-hoc process. This issue can be problematic for small–medium enterprises (SMEs) and large companies. Lack of control over this decisional process at an early stage can lead to the selection of multiple equipment redundancies and the use of multiple suppliers. Dealing with too many suppliers can significantly increase the resources, quality control, supplier qualification effort required and costs at a later stage of implementation (see Figure 2).
Figure 2: Application of SUS during pharmaceutical development: the importance of a structured approach in SUS utilization over the product lifecycle. Different types of SUS from various suppliers can be used over the product lifecycle, as illustrated by the different coloured SUS symbols. Careful stakeholder management is essential across company functional areas to avoid overruns of quality cost as product development advances to the marketing authorization. These costs may not have been apparent in the early stage of the product lifecycle.
Traditional validation app-roaches for SUS are not appliccable because these systems have a complex, integral, functional performance and cannot be sampled and tested like a consumable (26).
The complex nature of SUS and their end-use implies that the starting materials (e.g., resins, films, and so forth) should be treated as critical raw materials (27). Although the amount of resin needed for SUS is small compared to overall industry requirements for polymers, the propensity for uncontrolled change can pose a significant risk. Equally, the diverse nature and inherent variability of biotechnology based manufacturing processes, their design, equipment and facilities, the conditions of preparation, and addition of buffers and reagents and training of the operators are key considerations, which illustrate the importance of ensuring equipment compatibility for such processes (28).
As part of a quality audit process, an initial assessment called technical diligence extends beyond raw materials specification and evaluation to include the SUS supplier's manufacturing process, quality systems, sourcing strategy and the compatibility of the SUS with the end-user's process and facility (19, 29). This assessment provides a straightforward means of verifying SUS product quality and compatibility with the end-user's operating environment.
Vivalis has worked with SUT since 2006, and the company has gained experience in implementing and deploying SUS via a wide range of products. The experience includes:
The last two points are illustrated below.
A self-made assembly is a SUS designed, prepared, and controlled on the end-user's site. These are often process transfer manifolds, used for connecting equipment to allow fluid transfer. On-site preparation can lead to significant quality standard discrepancies compared with external sourcing. The lesson learned over several years was the importance of applying the same quality principles as those employed by an external supplier. Self-made assemblies must have specifications, appropriate documentation including batch process records, operator training and stability studies if appropriate, as well as be qualified (this includes sterility) and subject to change control process.
Assessing impact and compatibility at all levels
The example cited here is for an indirect impact situation. A rig for the sampling of condensates was used as part of the quality control process for the company's clean steam distribution system (sampling tubing, connectors and a bioprocess bag for sample collection). No previous validation or verification of the rig was carried out. During routine sampling, analysis of the condensates returned a non-conform test result, having very high levels of total organic carbon (TOC).Initial suspicion was directed at the clean steam distribution system and some unidentified contamination or some anomaly at the external testing organization. It was only after extensive investigation that the bioprocess bag was identified as the source of the high TOC results due to extractables and leachables in the bag. No prior evaluation of the compatibility of the SUS had been made. There is now a rigorous process in place for verification of SUS used for direct or indirect impact systems.
STEPHEN BROWN, PHD, is Chief Technical Officer at Vivalis, 6 rue Alain Bombard, 44800 Saint Herblain, France, Tel. +33.228.07.37.10, firstname.lastname@example.org
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