Risks and Limitations
Single-use systems do have their limits, of course. Poles-Lahille said these relate to processes performed under pressure or to high-temperature transfers. “Plastics do not conduct heat or cold as well as stainless steel,” she noted. “Another limitation may be continuous processes with Fibracell or microcarriers inside the bioreactor bag. Right now, only a few solutions are available.”
“Other limitations may be linked to the mechanical agitation system, the level of maintenance, and the availability of spare parts.”
Implementing disposable manufacturing is not as straightforward as many first thought. “People thought they were very simple…that they could buy the parts, put a system together, and start using it successfully,” Hitchcock recalled. “But, you have to do a full design study to make single-use systems safe.”
He recommends performing a hazard and operability (HAZOP) study to determine if single-use systems are appropriate for the intended process. Some operations or processes may be unsuitable because of the nature of the hazard or incompatibility of the process, Hitchcock emphasized, specifically noting some chemical inactivation procedures.
“HAZOP studies can be used to assess and develop potential single-use systems with regard to both the system design and intended operational procedures, including an assessment of potential failure modes and procedures for decontamination and waste disposal.”
One big difference Hitchcock pointed out is that stainless steel systems traditionally are designed offsite by mechanical engineers to meet robust parameters for years of flawless performance. Single-use systems, in contrast, are assembled each time a process is performed.
Also, stainless steel systems can demonstrate integrity before going online, but single-use systems are very difficult to integrity test, so users must rely on the quality of the systems provided by the suppliers and assume that the system was assembled correctly at the point of use. Therefore, much greater emphasis should be placed on system design and assembly procedures, and upon assessing and auditing potential vendors.
“The most likely causes of failures are poor quality connections or wrong connections that would lead to breaches or process failure,” Hitchcock said. Therefore, he emphasized the importance of learning to build stronger systems. A key aspect of that involves eliminating unnecessary connections, because each valve or splice in the tubing represents a potential failure point. “Assess different options and design out the potential for failure,” he stressed. In doing this, a risk assessment of the engineering process is critical.
Another improvement strategy is to involve operators early on. “In single-use systems, the actual operator needs to be involved much, much earlier in their design.”
“Operators need to know how to open, assemble, and maintain disposable systems so the components remain intact and sterility is maintained,” insisted Heike Frankl, director of validation services Europe for Sartorius Stedim Biotech.
“There are no regulations dedicated solely to single-use systems, but there are some very big differences between single-use and stainless steel systems.” With stainless steel systems, biomanufacturers would expect to flush and clean the systems before use to ensure sterility. Single-use systems, however, are ready immediately. Therefore, “companies are completely dependent on suppliers regarding sterility and intactness of single-use devices.”
The other main differences, she said, involve mechanical stability, extractables and leachables, and the relationship between the supplier and the biopharma company. “Plastics and rubber are not so resistant and inert as glass or steel, therefore extractables and leachables must be addressed,” Frankl said. She recommended that suppliers provide comprehensive extractable/leachable data to customers based upon specific analysis methods using water and ethanol solutions. “Additional tests may be initiated by the biopharma companies using their actual processes, equipment, and fluids.”
“We are still in a period where the extractable/leachable data is heterogenous,” Frankl observed. There are numerous different materials that may be used to manufacture disposable biomanufacturing systems. Reporting data from these materials and from the companies developing and manufacturing them is not yet uniform. “Some is good, some is poor. Companies that don’t provide appropriate data won’t be considered for the pharmaceutical market,” stressed Frankl.
Supplier Partnership Needed
“Because the entire downstream process and entire fermentation operation can be performed in a single-use system, companies are very dependent on suppliers,” Frankl said.
“I have observed that the development of single-use equipment is market-driven like never before. Users are very creative regarding what they want, and the combinations of components. Therefore, they must work very closely with their partner.” For example, Frankl recommends that suppliers share change notifications, compliance qualifications, and other information with their customers. They also should provide operator training and validation services, she added.