If anyone knows the direction that biopharma facilities are headed, it is Peter Watler. Watler, chief technical officer for Hyde Engineering + Consulting, has two decades of process development and GMP manufacturing experience in the biotechnology industry. His specific areas of expertise include process validation, fermentation, centrifugation, filtration, chromatography, process modeling, capacity planning, economic/COGs analysis, facility validation and manufacturing operations.
Watler and his firm have been involved in many of the more progressive drug facilities to be built in recent years, and we get his feedback on key issues today:
- extractables/leachables and the quality of single-use systems
- what future hybrid (stainless and single-use) facilities will look like
- modular construction
- shrinking design-to-production timelines
- what continuous manufacturing means for drug facilities
PhM: When you think of today’s groundbreaking facilities, what do you think of? Where are the real innovations happening?
P.W.: The most innovating facilities being designed and constructed are smaller, less complex and easier to operate biopharmaceutical and vaccine facilities. These are designed with a vastly different mindset and strategy than the large, complex, stainless steel facilities which dominated the past decade. Most innovative facilities feature bioreactors in the 500 to 2000 L range. This reduction in scale is crucial as it opens the door for a change in design philosophy. First, facilities can take advantage of innovative single-use systems (SUS) such as bioreactors, storage and mixing tanks which are widely available at this scale. With SUS, there is less need for steam and CIP, and at this smaller scale process streams are more easily managed. Then, as a result, complex transfer piping, panels and valve configurations are not needed and this simplifies the design and reduces costs.
Also, biologic processing equipment is now designed for much more closed processing, this enables design innovations in facility layout and classification. Since the processing equipment protects the product from the environment, environmental controls are less critical for product safety. Groundbreaking facilities are moving towards controlled non-classified operation with architectural finishes and HVAC designed to GRADE D.
And finally, with the smaller equipment and less complex HVAC systems, facilities can be designed with simpler, more open, multi-function processing suites. This de-segregation of process rooms means fewer airlocks and a smaller facility footprint. These innovations reduce capital and operating costs.
So the real innovations we are seeing are with smaller, more closed single-use processing equipment, smaller, more open facility layouts, and much less sanitary piping and valves.
PhM: Please share a few thoughts on modular construction—in the coming decades, to what degree will all new facilities be modular? Is there any reason manufacturers will opt for large, traditional, customized sites?
P.W.: Smaller facility footprints, construction in diverse geographical locations, and short timelines will drive new facilities to modular construction. However, module construction and transport costs are higher, and some firms will prefer a stick-build approach. So it is unlikely that all new facilities will be modular. Modular construction is particularly well suited to geographic locations where qualified cleanroom and sanitary piping construction is difficult to come by. Some manufacturers with market exclusivity, high dose products and large markets may require large, traditional facilities. But, in the last few years, industry has clearly moved away from construction of such facilities, in fact several have be decommissioned.
As facility layouts become simpler and more standardized, module costs will lower. We are likely to then see construction of smaller, closed processing type facilities in both developed and developing countries. As Dr. Isaias Raw of Brazil's Instituto Butantan recently noted, developing countries no longer want to be “Coca-Cola bottlers”—simply filling imported drug substance. They are moving toward self-sufficiency for the therapeutics and vaccines unique to their regions, and small, low-cost, modular facilities featuring single use systems are well suited to meeting this need.
PhM: Disposable equipment is obviously transforming facilities, but you’re not sold on the “fully disposable plant.” Why not?
P.W.: It depends on the facility scale, intended use of the facility and the technology required. Engineers must be careful not to ‘shoehorn’ a disposable system into a facility just for the sake of building a fully disposable plant. Disposable systems have transformed facilities by reducing facility complexity, cost and timeline. They offer fantastic advantages when appropriately implemented. However, there remain technical and scale issues which limit the suitability of implementing disposable equipment. For example, disposable sensor and instrumentation technology, which is more complex and costly to develop, is just now emerging.
As a result, thay have not advanced to the point of more simple components such as bags and connectors. Many conventional sensors have been adapted to disposable systems, but this means cleaning, sterilizing and reusing the sensor, which violates the disposable concept. A variety of disposable pH, conductivity, pressure, and UV sensors are coming to market, but it will be years before they become commoditized and the price declines to a fraction of a conventional sensor. A 200 L disposable tank can be changed over in 5 minutes—which outcompetes cleaning a conventional tank. However changing over a 2,000 L tank requires more time effort and skill to ensure it is properly seated and connected. Such scales require large diameter tubing, connectors and valves, which challenge the limits of disposable offerings. In short, at larger scales, the availability, and operational advantages of disposable equipment diminishes while the cost increases.