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Feature Articles : Feb 15, 2011 (Vol. 31, No. 4)

Single-Use Implementation a Group Effort

Potent Relationships with Suppliers Essential for Successful Utilization of Disposable Systems
  • Gail Dutton

Single-use biomanufacturing systems promise to reduce the risk of cross-contamination, provide low-cost scaleup, and allow multiple products to be manufactured at a single site with minimal validation issues. While all of this is true, they are not necessarily plug-n-play. Instead, deploying a single-use system in a bioproduction process requires operator training and some forethought, according to presenters at IQPC’s “Disposable Solutions for Biomanufacturing” conference held earlier this month.

Merck Serono is testing several single-use bioreactors at a production site in Martillac, France. “The site has performed 13 fed-batch runs with mammalian cells using four different technologies of single-use bioreactors,” explained Aurore Poles-Lahille, assistant scientist for new technologies and manufacturing support. Others are being tested now for cell seeding and clinical material applications.

The benefit, Poles-Lahille said, is that disposable bioreactors decrease the lead time between runs from fifty hours to about one hour. “This is especially important for seeding applications, where bioreactors are only used for a few days,” she explained. They also decrease the consumption of energy, water, steam, and cleaning agents.

“Deploying single-use bioreactors is not really difficult. The challenge is managing different disposable elements simultaneously—culture media, feed and bioreactor bags, in addition to aseptic connectors and disposable probes,” she said. “One needs to connect these elements to properly grow the cells, so if you do not have a welder, a sealer, or have not been well-trained, contamination or bag disruptions can easily occur.”

Beyond extensive on-site training, Poles-Lahille recommended that users analyze the bioreactors and the strategies to manage the connections between the media and feed bags, filters, and cell inoculums. “Extra sterile tubing to weld tubing from bags to tubing on the bioreactor may be necessary, as well as the preparation of extra sterile tubing that is compatible with long-term pumping for pH regulation.”

Applications

Single-use systems offer a low-cost route to early-stage development. “For small-scale and early-stage products, disposable systems are easier, faster, and cheaper, because you don’t have large capital expenditures and you can change out all the equipment and use the same process platform for other products without the risk of cross-contamination,” noted Tony Hitchcock, head of manufacturing technologies at RecipharmCobra Biologics.

“This is especially critical for novel therapeutics such as viral gene-therapy vectors and other products destined for first-in-man studies.”

“Because disposable bioreactors range in size from 10 mL to 2,000 L, they can be used for process development, seeding stainless steel bioreactors in a GMP facility, or to perform a scaleup of a process,” Poles-Lahille added. “They are attractive for optimizing lead time between production runs and to minimize the use of utilities.”

They also can be automated to some degree. According to Bruce Rawlings, senior marketing manager of Allegro single-use systems at Pall, the approaches to automating single-use processing solutions are similar to those of stainless steel systems, but the technologies are mainly plastic.

“Automation becomes an issue at larger scale. Pinch and control valves for one-inch flexible tubing are not yet available or are prohibitively expensive to consider as a single-use approach. Also, some sensor technologies are either limited in range of measurement or relatively expensive compared to other single-use components, so are not appropriate for all applications.”

“But, in general, if the scale fits for the available technologies, there are not too many issues with automating the basic features of fluid-management systems in upstream and downstream processing.”

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.

Bag Holders Go Vertical

SciLog  introduced the WeighStation this month for upstream and downstream development as well as pilot and small-scale manufacturing applications. The device is a compact, mobile vertical bag holder with integrated load cells that also displays the weight of its contents.

According to Kyle Ritchie, bioprocess systems product manager, “I’m not aware of any product like it on the market.” Although there are other bag holders, he said this system is unique because it integrates load cells into the bag holder. “Otherwise, you would have to lay it flat on a floor scale.” In contrast, this system features a top-mounted hanging bag support and display for easy, ergonomic use, he explained. The WeighStation operates as a stand-alone component or can be integrated into SciLog processing platforms for dispensing and buffer preparation and purification, including normal and tangential flow filtration.

The WeighStation can hold bags up to 30 liters in size and weights up to 35 kilograms. Ritchie said the scale is accurate to 0.01 kilograms. With a built-in communications system, the WeighStation can send bag-weight information to other SciLog platforms. The device has a compact footprint that measures 29x29 inches and a height of 70 inches. It rests on four lockable, rotating casters, for easy transfer of bioreactor contents, according to Ritchie.

Also, SciLog has developed disposable conductivity sensors that are presterilized, precalibrated, and prevalidated to store calibration and production information in either a barcode or a memory chip on the sensor. These patented systems may be used with in-line systems, closed fluid circuits, bioprocessing systems, or systems that require an aseptic environment.