By James Netterwald, Ph. D.
It is no secret the FDA provides oversight for the biopharmaceutical industry. Oftentimes, this oversight comes in the form of documentation review. In fact, the FDA encourages drug manufacturers to maintain documentation outlining all changes in their processes including the approval and deployment of new technologies that will be used in those processes.
It’s also no surprise that single-use or disposable manufacturing technology has become more prevalent in the biopharmaceutical industry. However, “there is no definitive set of standards today for single-use components or systems used in the biotechnology industry,” explains John Boehm, bioprocessing business unit manager for Colder Products and vice chair of the BioProcess Systems Alliance (BPSA). Such standards would dictate the way in which single-use equipment is validated prior to its use in the manufacturing of biopharmaceuticals. And although validation processes differ between single-use equipment and stainless-steel equipment, there is still a need for some set of standards. Single-use industry groups are currently trying to guide discussions with the FDA to implement such standards. One of those groups is the BPSA.
Developing Single-Use Standards
The BPSA was formed in 2005 as an industry-led, corporate member trade association dedicated to encouraging and accelerating the adoption of single-use manufacturing technologies used in the production of biopharmaceuticals and vaccines. The BPSA facilitates education, sharing of best practices, development of consensus guides, and business-to-business networking opportunities among its member company employees. The organization has 35 member companies including manufacturers of single-use technologies, service and consulting companies, and drug manufacturers.
“One of the first tasks that the BPSA put together was a single-use test matrix that analyzed the test methods of the different components [e.g. fittings, connectors, and tubing] that were used in a single-use system and how each of the different companies was performing those tests,” says Bill Hartzel, business development engineer for Arkema, Inc., a chemical manufacturer in Philadelphia and a member of the BPSA board. The main goal of this initial work was not to ensure each of the companies performed the same test, but to educate the user on how to interpret the results.
As engineers familiar with stainless-steel systems move into single-use, BPSA members require education on these new technologies. This includes gaining an understanding of the capabilities and properties of plastic processing equipment, understanding studies on the effects of extractables and leachables on the performance of single-use equipment, and understanding current methods for disposal of single-use systems. The BPSA has developed online resources and is actively participating in conferences aimed at providing education and furthering the acceptance of single-use technologies. The BPSA also has published best practices guidelines on single-use equipment. And, although the BPSA is not a standards producing agency, the best practices guidelines it has published are a valuable resource for manufacturers, technical agencies, and other trade organizations involved with single-use manufacturing. “These publications are industry-authored consensus guides that will be referenced by regulatory agencies [such as the FDA] responsible for standards development,” says Boehm.
BPSA representatives also are active in organizations like American Society of Mechanical Engineering BioProcess Equipment (ASME/BPE) that create standards associated with stainless-steel processing equipment. They will likely participate in developing future standards associated with single-use equipment. “The BPSA will continue to assist in providing the needed expertise in plastics and plastics processing to ensure the biopharmaceutical industry is able to continue to bring much-needed therapies to market in an expeditious, cost-effective, and safe manner,” says Boehm.
“New technology runs into an obstacle in this risk-averse culture. So even though you can show all the technical and economic advantages of employing a single-use system, the risk of change makes it more difficult to move forward with the new technology,” says Hartzel. “BPSA is trying to show what processes are needed to get people accustomed to plastic systems and change from stainless steel.”
Challenges To Implementing More Standards And Validating Systems
Paul Priebe, director of fluid management technologies for Sartorius Stedim Biotech North America, agrees. “There still exists a bit of fear and lack of established practices for qualification and validation of single-use systems, but that is much less of an issue than it was even just a few years ago.” He adds that the experience base is still less than the experience base for multiuse equipment, but there are multiple organizations that are aiding to bridge this gap in experience, including the aforementioned BPSA and the Parenteral Drug Association (PDA). The latter has a task force that is writing a technical report to assist end users to implement single-use. “This training is an important activity that will likely save our industry a lot of effort in the coming years,” says Priebe.
The fact that more users have experience with stainless-steel systems is also a challenge to the validation of single-use equipment. “One of the concerns companies have when thinking about going to single-use is that fixed-systems have an extensive amount of historical data on the processes needed to prove validation,” says Hartzel. “One of the big changes with the single-use system is that the end user is basically outsourcing a lot of the validation process to the supplier.” And, this is an important point because, as more companies are retooling their facilities with single-use equipment, there is greater involvement by vendors of that equipment.
Gernot Thomas John, director of marketing and innovation for PreSens Precision Sensing, adds, “I think the validation process affects any company which is involved in the process right from the start of the development of their product.” This is a relevant point, as PreSens is a supplier of single-use sensors for single-use bioreactors or single-use fermenters. The company supplies sensors for the measurement of oxygen, pH, and carbon dioxide in the reactors and also assists customers in the validation process performed by providing data on their sensors. John adds that the validation process starts with the careful choice of bioreactor materials to ensure all surfaces that will come in contact with the drug product are nontoxic to humans. Validation is necessary for many applications of single-use equipment (e.g. single-use bioreactors), but it is not necessary to validate the cleaning process for this equipment, which is an advantage for end users of this disposable biomanufacturing equipment.
Requirements For Validating Single-Use Equipment
Biopharmaceutical companies often wrestle with the decision of whether to implement single-use systems in their manufacturing processes, to maintain their traditional stainless-steel processes and equipment, or to combine the two technologies. Additionally, these companies need to justify their investment in the new technology and identify the ultimate return on their investment. To do this, many biopharma companies work with consultants or develop their own financial models to justify the decision to convert to single-use or to combine technologies. These models calculate the reduction in manufacturing costs and capital expenditures associated with new methods. They may also capture the operational benefit of minimizing contamination risk and potential loss of production batches achieved by converting to single-use manufacturing.
“We work with a number of major companies that have made significant investment in stainless-steel equipment within their existing facilities. They are not ready to make a complete conversion to new technology,” says Boehm. “However, they want to take advantage of the flexibility of single-use by introducing a modular manufacturing process. In this scenario, where they traditionally have stainless piping between stainless components, they are replacing that piping with single-use tubing. Using these single-use transfer lines enables them to quickly connect and disconnect process lines between manufacturing steps, thus gaining process flexibility without time-consuming system teardown and revalidation typically associated with changing over to different batches or products.”
According to Boehm, unlike companies with a large investment in stainless equipment, a small biotech company that has no previous investment in stainless steel is likely to go straight to single-use because the up-front capital requirement is much lower. Additionally, the time to get a new facility built and validated tends to be at least a year less than a facility built with traditional stainless-steel equipment. The turnaround time and the return on investment can also be much faster for companies that go with single-use.
In summary, single-use technology continues to meet obstacles for full acceptance by the industry. This includes challenges to validation of the equipment and to the establishment of standards for its use. Industry groups such as the BPSA are diligently working to meet these challenges and bring greater acceptance of single-use technology in the biopharmaceutical, pharmaceutical, and biotechnology industries.