What are the key hurdles to overcome in adopting single-use processing?
Dr. Jenkins: Managing bag inventories can be challenging. A greater focus is needed throughout our supply chain. Sourcing and quality need to re-align to handle the change in manufacturing strategy. Auditing and partnership with our suppliers is a crucial function in ensuring quality and supply. Hence, supplier selection becomes significant in the overall single-use strategy. Vendors have satisfactorily addressed such issues as leakage, extractables, and leachables.
Matthews: The major hurdles are the investment cost in existing infrastructure, and the characterization of extractables and leachables. Also important are status quo (general fear of change) and supply chain security.
Manufacturers are concerned whether disposables are truly capable of replicating validated processes in disposable format. This relates to material of construction changes, and the ability to reproduce process control inside of the customer’s characterized and validated operating limits, especially pertaining to critical process parameters.
Munk: We believe the regulatory concerns to be the dominant hurdle industry-wide. The lack of experience by the regulators makes it difficult to address the most important risks, both real and perceived.
Furthermore, suppliers must realize that the end-users are actually outsourcing part of their quality system to them. Thus, the suppliers have to prepare for more audits, for which they must demonstrate GMP-compliant quality systems, including CAPA systems, change control, etc.
Additionally, how suppliers control their raw materials is of great concern, as changes in raw materials might lead to changes in extractables and leachables, which could affect process performance (for example cell growth) or the patient risk profile.
Dr. Runser: Routine use of today’s available disposable solutions still requires a lot of manual handling by well-trained operators, which limits single-use equipment in high-throughput facilities.
The risk of failure, caused either by material deficiency or by operator errors, is still higher compared to standard stainless steel systems. Therefore, the use of disposable systems in a large-scale facility is still preferred for process-supporting activities such as buffer and media storage, rather than for usage of product-containing solutions.
Dedicated disposable solutions still require a long lead time before first use in a GMP environment. In addition, dedicated bag configurations can show more deficiencies than off-the-shelf products. Novartis and its partners have worked to improve inspection and handling procedures to assure a smooth use of disposables in our large-scale manufacturing facility.
Dr. Schlatter: Second supplier concepts are one key challenge: the systems of different manufacturers need to become interchangeable. Regulatory acceptance and experience with the equipment are additional hurdles.
VonEsch: The biggest hurdle to overcome is legacy equipment, and the fact that drug and equipment manufacturers tend to push and develop what they know. Once vendors and manufacturers adopt these technologies and offer simpler implementations, they will grow.
There are five key components to adopting single-use equipment: educated drug companies, educated equipment vendors, educated disposable manufacturers, educated building design/engineer firms, and lastly regulatory oversight buy-in.
Today we have a mix of these components. But wider adoption of single-use will require that stakeholders understand the favorable applications in all aspects of drug manufacturing.
I would say that the smaller drug manufacturers are driving most of these efforts currently, companies that understand the costs, benefits, and flexibility of not just the systems but the manufacturing plants as a whole once these systems are in use.
Dr. Witcher: The reliability of single-use systems is of concern. The possibility of leaks and broken bags are perceived to be a problem. In addition, the ability to get special single-use items from vendors is also a concern.
How can vendors of disposable bioprocessing equipment improve their products or expand their applications?
Dr. Jenkins: They could do a better job providing sterile quick connects, and in linking upstream and downstream production in essentially a single, closed, disposable system with enough flexibility to support a variety of sizes and purification technologies. Complete flexible cGMP manufacturing in gray space would take this technology to the next level.
Supporting customers through the SUB learning curve is important. The adoption of single-use processes is about more than just ordering a system. Since adopting this technology involves a complete change in manufacturing strategy, a higher level of customer service is essential.
Even though the multisourcing of bags is a big issue from a business continuity perspective, parts availability, and having access to a top-tier service group, are vital.
Matthews: Competition is needed in all major unit operations to allow for second sourcing. Having suitable second sources of supply in GMP manufacturing is critical. There is still room for suppliers to innovate and obtain market share from the suppliers that feel they have a monopoly on their respective industry-leading equipment. This is particularly true with single-use bioreactors, chromatography skids, TFF skids, and fabricators of disposable sensors.
Munk: They should work even further together to ensure that different suppliers’ components may be easily assembled for the final manufacturing solution. This includes the connectors, but also that the components they use have similar properties, including extractables and leachables profiles.
Dr. Runser: In addition to the improvements I have already mentioned, disposable equipment is often based on proprietary standards that prevent interchangeability. However, commercial GMP manufacturing needs the availability of back-up solutions to assure its supply chain in case of issues. Therefore, the industry needs to define a set of basic standards to allow further adoption of disposables in commercial GMP environments.
Dr. Schlatter: The products can be improved by performing detailed studies on leachables and extractables, offering customization and compatibility with other vendors, and improving the accuracy of disposable sensors.
VonEsch: While drug manufacturers ultimately need to accept new technologies before implementing them, I feel it is up to the disposable equipment vendors to demonstrate that their products are viable and effective alternatives to stainless steel processing. The more involved and educated equipment and disposable manufacturers become, the better they will serve their clients’ current and future needs.
Dr. Witcher: The most important point is to assure the reliable supply of high-quality disposable components. Financial stability and the size of a disposable vendor is important in selecting a supplier of disposables.
Quality control and assuring that all components meet performance requirements is also very important. A broken bag or two goes a long way to making development people hesitant to use disposable systems. In addition, incorporation of new sensor technology for measuring critical outputs will help in the future.