The need to develop a final formulation process for a parenteral product sensitive to stainless-steel gave Patheon the opportunity to evaluate the potential of single-use technology in fill- finish operations.
After watching biopharmaceutical companies adopt single-use systems for the manufacture of large-molecule active pharmaceutical ingredients for several years, Tony Pidgeon, senior manager of global science and technology with Patheon, recognized the potential of the technology for sterile fill–finish operations but needed the right opportunity to put his ideas to the test. That opportunity came along approximately eight years ago when Patheon was contracted to manufacture clinical trial material for Phase II and beyond. Small batches were initially formulated, and it was discovered that high levels of drug product-related impurities appeared over the shelf life of the product. Investigations showed that the product was both sensitive to oxygen and stainless steel. A project was thus initiated to minimize exposure to oxygen and eliminate stainless steel from the equipment train, which was accomplished largely through the adoption of single-use systems.
Taking it in stages
“Before we decided to go with single-use systems, a number of other alternatives were suggested, including glass-lined stainless steel equipment, and even reinforced, rigid polypropylene–all of course designed to mimic the original equipment components,” notes Pidgeon. “However, as a contract manufacturer, we need to differentiate ourselves from the competition, and the idea of moving to a single-use system was recognized as a way to do that,” he adds.
The first step was to break the existing system down into five stages—the compound vessel, the holding vessel, the manifold/recirculation system, the filling pumps/needles, and the connections and miscellaneous items—all of which were stainless steel. Such an approach made it easier to tackle the different issues associated with replacing these different components with single-use alternatives, according to Pidgeon.
Designing a compounding vessel
The compounding vessel was used to mix the API with salts and water. It was critical that exposure to oxygen be avoided during mixing. There were no off-the-shelf units in which nitrogen sparging was possible, so Patheon, in collaboration with a supplier of single-use carboys and vessels, designed a 200-liter system (bag) that also had a material addition port, four nitrogen sparging lines, lines for water injection, recirculation return, and recirculation outfeed, and a vent filter. “Even though we went through several iterations, the changes could be made very rapidly, which provides greater flexibility to system designers,” Pidgeon observes. “In the end,” he adds, “we had a system that was applicable for the production of both development quantities and commercial scale manufacture if needed.”
For the holding vessel (Stage 2), which did not have any special requirements, an off-the-shelf single-use bag was selected. The same was true for the filters, which were also standard components.
Clever use of existing equipment
In Stage 3, Patheon tackled the manifold and recirculation system. Here again, there were no off-the-shelf options, and Pidgeon collaborated with the filter supplier to design a complete system. The first “prototype” consisted of T pieces connected with tubing, which was ultimately replaced with a single-piece manifold comprised of a molded rigid plastic with platinum-cured silicone tubing. “While the first basic system worked effectively, the use of the molded part significantly reduced the perceived risk of leakage by eliminating a large number of the plastic/tubing connections,” Pidgeon explains.
The original recirculating system also included a stainless-steel reservoir that was used to even out the flow of liquid from the recirculation pump to the manifold by taking up volume as needed. There was no similar single-use component available at the time, but a scientist at Patheon suggested the use of an empty capsule filter, which worked very well. “The solution involved the clever use of existing technology, and because it was a common single-use component, [it] was easy to incorporate into the new system,” says Pidgeon.
As previously described, the same capsule filters were used while the stainless-steel tubing was replaced with platinum-cured silicone tubing. All stainless-steel connectors were also replaced with single-use connectors.
Ceramic pumps for overall hybrid approach
The use of peristaltic pumps was not an option on the filling line used for this product. Thus, the stainless-steel rotary piston pumps used in the original system were replaced with permanent, ceramic pumps. “While there are other single-use pump options today, at the time of this project, such a wide range of choices did not exist. The use of a hybrid system with the ceramic pumps was a very practical solution,” comments Pidgeon.
Benefits beyond prevention of product degradation
The goals of the project to eliminate stainless steel from the manufacturing train and reduce oxygen levels to less than 0.5 parts per million were achieved with the new system. There were several other benefits as well that Pidgeon indicates are quite noteworthy. First, the amount of cleaning that was required was dramatically reduced. “The only parts of the system that required cleaning and cleaning validation were the ceramic pumps, which were accomplished fairly quickly. The savings in time and cost was really tremendous, though, due to the fact that the cleaning methods development and validation and the actual cleaning and cleaning validation steps were all eliminated for the rest of the system. As a result, we also achieved our goal of creating a differentiating advantage for our customers,” he concludes.