How To Prepare A Facility For The Biopharmaceutical Revolution
Drug discovery is an inherently inefficient process. It takes thousands of failed compounds before one can get approved as safe and efficacious, and this effort does not come at a low cost. Because of this, the industry is constantly looking for ways to bring safe, compliant, and profitable drugs to market faster and cheaper.
Flexible factories and single-use technology are obviously growing in popularity. On their own, each can enable low-cost biomanufacturing without sacrificing quality. In a recent article on Pharmaceutical Online, Merck’s Jeff Johnson stated if a company could achieve titers above 10 grams per liter in a single-use facility, there would no longer be a need to build stainless steel bioreactor facilities. This change is one he believes would alter the future of the pharmaceutical manufacturing industry.
At Patheon’s mammalian cGMP production in Brisbane, Australia, single-use technology, in combination with internal patented technology, is being used to clarify cell densities at 200 million cells per milliliter and produce titers up to 20 grams per liter. With titers this high, the future Johnson suggested is becoming more possible and the Patheon facility exemplifies the facility needed to survive the future of pharma. But how did they do it?
Flexible Operation Without The High Cost
|Manja Bouman, President and CEO of Patheon Biologics and Patheon Biosolutions|
In order to conduct the design, Manja Bouman, president and CEO of Patheon Biologics and Patheon Biosolutions, says an international team of experts spanning across the globe was formed. “The team was based largely in Australia, but to complete the conceptual design, the project required expert biotechnology and GMP facilities specialists from Germany, The Netherlands, New Zealand, and the United States,” says Bouman. “There was an in-house team based at our biomanufacturing facility in Groningen, The Netherlands, who drove much of the equipment design and facility layout. In addition, a dedicated engineering design company was commissioned to manage the conceptual and detailed design stages. External experts were also involved to complete an independent review of the design of the facility, especially with respect to the plant meeting quality and GMP standards of all territories globally.”
The facility, which was recognized by ISPE as the 2014 Facility of the Year for Process Innovation, offers unique design aspects, such as pre-sterilized and disposable cell culture equipment from cell bank to production bioreactor. This allows flexible operation without the need to install high-cost utilities, such as clean-in-place and steam-in-place, which at one time were thought to be essential for large-scale cell culture products. For the upstream process, a patented technology similar to perfusion technology is utilized; however, it operates at higher densities and titers while retaining the product inside the bioreactor during perfusion. For the downstream process, an additional internal technology eliminates the need for harvesting and recovery steps. “The primary drivers for the design were quality and safety of the biopharmaceutical products manufactured within the facility,” says Bouman. “These products, therapeutic proteins and monoclonal antibodies, are parenterals, which demand the highest quality standards as well as flexibility of biomanufacturing operations.” She adds that environmental sustainability of biomanufacturing, biological containment, and utilities usage were also important considerations.
When it came to selecting and purchasing equipment for the facility, Bouman says special attention was given to partnering with innovative equipment suppliers who could support Patheon’s vision to build a facility for the future. Another key requirement was selecting equipment that would enable technology transfer of bioprocesses between the facilities in Brisbane and Groningen, where they could be replicated and scaled up.
Preparation Through Evaluation
For the construction and validation phases of the facility, a number of criteria were used to evaluate the project quality, project capital expenditure, and timeliness of the project completion. This criteria was based on scores developed by the American Construction Industry Institute, or Project Definition Rating Index (PDRI). “The PDRI scores for each stage of the project gave an indication of the risk level associated with progressing to the next stage of the project. This particular project assessed the project at several stages and came up with a PDRI scores based on safety, reliability, operability, cGMP compliance, maintainability, sustainability, Australian building standards, and project spend. The project would only progress to the next stage if it met the required pre-determined PDRI score at each stage of the construction and validation projects,” she explains. Despite this potential for delay, Bouman says the project was completed on-time, within budget, and has been licensed by The Therapeutic Goods Administration (TGA) for GMP manufacturing.
For the manufacturing phase of the facility, operational excellence criteria, such as Right First Time was applied throughout operation, is used to evaluate the success of batch manufacturing, product testing, and facility operation.
Planning Requires The Right People With The Right Focus
A good plan means nothing without the right people. While design was a focus at the Brisbane facility, Bouman says having a highly qualified staff was and is imperative. “More than 10% of our staff has PhDs, which is a high academic level for a manufacturing site, but we feel this high academic standard is essential to developing innovative biomanufacturing processes,” she explains. “More generally, we looked for engaged, enthusiastic, and flexible people suited to a start-up environment, and we found many suitable people in Australia and abroad who have come together to make a great team.” She adds that key staff has training on operational excellence programs that include the principles and techniques of Lean Six Sigma
In addition to this, Bouman says Patheon applies other process improvement techniques during operation and evaluation. “Risk assessment methods, such as FMEA (failure mode effects analysis), are used extensively to improve quality, efficiency, and compliance of the operation,” she explains. “The application of GMP quality systems, such as change control and deviation investigation, help improve processes like effective corrective and preventative measures.”
In a recent statement about the ISPE Facility of the Year winners, Nancy Berg ISPE president and CEO, said, “The facilities honored by the 2014 ISPE FOYA Category Winners embody the ideals of the Facility of the Year Awards program, incorporating custom-developed equipment solutions and novel uses of new and existing technologies to create world-class facilities that are well positioned to meet and exceed contemporary standards for flexibility, sustainability and product demand.” Overall, the Brisbane facility is a testament to the direction of the industry, and it’s recognition by ISPE in process innovation proves Patheon’s biomanufacturing strategy is preparation for the pipeline of the future.