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.
PhM: If hybrid (conventional/single-use) designs are the future, how will manufacturers best decide what mix of equipment to employ? Will there be some standardization to hybrid designs?
P.W.: A hybrid design integrates the best in class disposable systems with the best conventional (stainless steel) systems. The first question to ask is, is the single-use system designed from the ground up, or is it simply a modification of a conventional system? If it is simply a modification, did the work around result in follow-on issues which must be addressed?
The rectangular disposable bag in bin is a good example of a ground up design. It is not a mere modification of a round stainless steel tank. Rather, it is rectangular, stackable, fits easily against a wall, has an open top and side panels for access—quite different from a conventional tank, and it works. On the other hand, buffer preparation tanks have been more challenging—there are no baffles so mixing is not as rapid, solids can settle in corners and crevices, it’s a challenge to insert sensors into the tank, etc. The competition stainless steel mixing tank is of proven design, and with an optimized CIP cycle can be changed over in 15 minutes. At larger scales, this conventional tank may be the best option, operationally and cost wise.
To sort through the mix of single use and conventional equipment, we’ve employed FMEA and PHA risk analysis tools to identify the best solution, without pre-judging or being married to any one system.
As facility design evolves and disposable systems become further incorporated, there will likely be some similarity but perhaps not standardization of hybrid facility designs. With the simplified cleaning that disposables offer, water and steam systems will be designed to be smaller and simpler. Long piping loops with numerous drops will not be required. Water generation systems will be smaller, more compact and easier to operate. Today self-contained purified water systems that look akin to a home refrigerator are available. WFI systems are moving in the same direction. This means hybrid facilities won’t need a large central utility plant, but rather a few small self-contained systems that can be maintained by the vendor. These systems are so simple that there will be less of a need to purchase and transport purified water, WFI or buffers from outside suppliers.
PhM: You advocate a risk-based selection of single-use systems. In the next 10-20 years, will most current major risks (e.g., extractables/leachables) be overcome?
P.W.: It is now common to have a risk management program to evaluate and mitigate potential facility and equipment system risks. For disposable systems, a tool such as FMEA can delineate how the disposable system will be used, identify failure modes, evaluate design limitations and provide a clear rationale for selection. It can also be used to evaluate the materials of construction for types and levels of leachables and extractables and the associated toxicity.
There have been cases of vial and stopper leachates affecting product quality and patient safety, and the FDA has issued 483s for inadequate evaluations on materials of construction. Because of the relative newness and the large number of elastomeric materials, it is incumbent on the end user to evaluate leachables and extractables and leverage the studies of suppliers. Fortunately, most studies have found levels to be within acceptable toxicological limits, and within the next decade as substantial experience base and body of knowledge will have been acquired to diminish these risks.
Other failure risks include improper operator assembly, shipping damage, componenet failure and leaks from poor installation. Vendors have responded by beefing up protective packaging, factory integrity testing, designing installation aids and simplifying component assembly. Based on this progress, it is reasonable to expect that within the next decade, disposable components will present no greater risks than conventional systems.
PhM: Will design-to-production timelines for facilities continue to shrink, or do you think there’s a limit as to how quickly sites can get up and running?
P.W.: A decade ago 4-6 years was a common facility design-to-production timeline. Facilities were large, and every facility was uniquely designed. A few years ago we took a GMP facility from design-to-commissioning in just 12 months. It was a smaller (1200 L) facility, with an open ballroom concept, common corridor and few airlocks. For such facilities the timelines will continue to shrink, likely to just 6 months. This will be accomplished by using modular, pre-configured facilities and commercially available off-the-shelf (COTS) equipment, which will vastly reduce the design and construction phases. These facilities will have a simple ‘ballroom’ layout and a smaller footprint, requiring just a few cleanroom modules. Most areas will operate in a controlled, non-classified environment so HVAC and air locks will be less complex.
They will employ non-customized, off the shelf process and utility systems, and feature disposable systems, thus eliminating long equipment lead times. A risk-based ASTM E 2500 type commissioning and qualification program will shorten the time to GMP operation. Test protocols will be pre-written and standardized by system experts. Much of the testing will be pre-executed at qualified vendor sites, with some critical functions verified at the installed site. The timeline will eventually be defined by the shipping and assembly times. In fact, we're now working with vendors, clients, and not-for-profit organizations to develop these concepts into what we call a "Modern Modular Manufacturing" approach.
PhM: What have we missed? Are there trends shaping tomorrow’s facilities that are still mostly under the radar?
P.W.: Personalized medicines are now requiring vastly different facility designs. Many designs are simply borrowed from hospitals and labs, but designs will evolve to meet the unique GMP production needs for individuals.
Initiatives driven by GAVI, Gates Foundation and the WHO will lead to compact, modular vaccine facilities being built in Africa and South America. This will enable countries to control their vaccine supply and tailor it to the unique infectious disease profile of their region.
In a similar fashion, biosimilars will drive construction of smaller, flexible, multiproduct facilities in a variety of geographic locations including Asia, South America and Eastern Europe.
A move towards continuous processing (interestingly stimulated by the FDA’s 2011 paper “Advancing Regulatory Science at FDA”) will transform the design and operation of manufacturing facilities. For example, a simple 45 cm diameter chromatography column operating continuously could replace a complex and costly 200 cm column operating once per batch. This will drive a need for enhanced unit operation science and superb automation, but it will result in reduced facility footprint, complexity and cost.