In February of 1985, Ed Bjurstrom’s article, “Biotechnology,” was published in Chemical Engineering magazine. It was an early survey of the unit operations, from a process engineering viewpoint, that comprised the typical bioprocess manufacturing trains of the time. A look back at this article today is highly informative; it serves as a base point from which the trajectory of the industry emanates at the time of Eli Lilly’s Humulin, and in the years before the approval of Epogen and Protropin. Fermentation processes are discussed in great detail, but the term “cell culture” is noticeably absent. Bioreaction systems contain “potential product worth perhaps tens of thousands of dollars” and chromatography column diameters are measured in centimeters, not meters. There is no mention of virus clearance using TFF or any other means. And as one would expect, the article in no way anticipates single-use systems and related technologies like in-line dilution buffer manufacturing.
A read of Bjurstrom’s article in today’s context provides a single, clear illustration of the degree to which the Biotech Industry has changed and continues to change. But these changes extend far beyond the process technologies that were the focus of the article.
The growing availability of health care around the globe, and improving living standards required to pay for that health care, are driving increases in product demand. Legal and geopolitical changes are creating new drivers to manufacture in different regions, countries, and continents. Consumers are less and less tolerant of product quality failures, and regulators are more willing to take action against the non-compliant. Communities are more sensitive about the use of local resources, such as water. And of course, investors are just as interested in conserving capital and maximizing their returns as they have ever been.
MARKET PRESSURES
The pressures from myriad market forces in the environment of the Biotech Industry have made designing, building, qualifying and operating biopharmaceutical manufacturing facilities a pursuit dramatically different in the twenty-first century from that of Bjurstrom’s article. But biopharmaceutical industry scientists and engineers are a resilient, creative lot, and they have risen to the challenge to conceive numerous valuable enabling technologies that can be exploited to address these market pressures. Of all these developments, none shows greater promise than the single use systems currently being implemented by industry visionaries. Single use technologies promise to improve flexibility, reduce energy and water consumption, cut capital investment, minimize Cost of Goods Sold, and increase the capacity per square foot of a biopharmaceutical manufacturing facility.
These improvements will be critical for the industry to continue to grow. Facilities will need to achieve high product quality in the shortest possible time following the decision to build. Flexibility to allow for multiproduct manufacturing, application of continuous improvement in operations, and rapid campaign changeover will be necessary for organizations to respond to the increasing pace of change. Minimization of environmental footprint will be important to drive down costs.
With increasing in-vivo insights into product requirements and improving in-vitro analytical protein characterization methods, the critical path for the development of new products will continue to shift toward the process development and manufacturing phases of the product life cycle, resulting in changes to the focus of equipment and facility design. That is, higher process outputs and better characterized products and processes will need facilities that take advantage of these advances. This requirement represents the primary challenge for the future of manufacturing in the Biotechnology Industry.
TECHNOLOGY AS AN ENABLER
The bioprocess technologies that have emerged in recent years, and the technologies that continue to emerge, will be the enablers for the development of facilities that are capable of achieving these cost and flexibility requirements. But the influence of these technologies will span far greater than the design and construction of a new building; the influence will spread through the life cycles of an organization’s product portfolio, from capacity planning through product maturity.
Starting with capacity planning, the agile, flexible facility of the future will have a dramatic impact by reducing and organization’s dependence on accurate forecasting. It is extremely challenging to estimate, even with-in an order of magnitude, the capacity requirements for a new product. Between variations in dosage, market penetration, ever-changing competition, and uncertain process performance, the required size of a facility can vary by several orders of magnitude. Although progress is being made, particularly in process performance, determining the size and nature of a manufacturing facility remains a huge challenge.
Moving along the product life cycle, it is apparent that the new technologies available to the industry will have a significant impact on late-stage clinical manufacturing. Most biopharmaceutical organizations place a high value on the capability to manufacture Phase III material using the same process and facility that will be used for commercial production. There are significant cost and schedule opportunities to be taken by manufacturing launch material from the same facility that made the clinical material, and regulatory risk is significantly reduced when Phase III material comes from the commercial facility. After Phase III material is manufactured, redeployment of the facility to manufacture other products while maintaining the ability to make new products is another opportunity as the waiting time between Phase III material production and the next step can be significant.
The production of material to support product launch, generally a considerable amount of material depending on market projections, is demanding. After the launch material is produced, turning over a facility to manufacture other products is a significant challenge. Addressing this issue is a key concern for many organizations as they conceive their upcoming factories, and application of the latest bioprocess technologies will support this level of flexibility.
Many of the issues discussed above extend through the life cycle of the product into maturity. But the length of a product’s life cycle is another critical factor driving the need for flexibility in biotech facilities. Some products are quickly replaced due to competition, while the life cycles of other products may extend for long periods. Some products need to be relocated for tax or logistical reasons. Demand may suddenly increase in response to the discovery of new indications. These ever-changing requirements are leading manufacturers to solutions employing single-use manufacturing platforms, flexible multiproduct manufacturing units, improved cell culture technologies, and more efficient product purification operations.
2012 INTERPHEX BIOLOGICS TECHNOLOGIES TOUR DETAILS
The Biologics Technologies Tour at INTERPHEX 2012 will survey many of the same unit operations described in detail by Bjurstrom in 1985. However, due to the rapid pace of change and development in each of these manufacturing process steps over the past 25 years, many of these unit operations are barely recognizable; they are now designed for single-use and application in multiproduct facilities. Product storage containers are no longer expensive, fixed stainless steel vessels; they are now plastic bags in light-weight portable assemblies. Many of the problems of integrity of bag seams and leaching of polymeric components into product have been resolved, and now this bag technology is being applied to the manufacture of common biotech solutions such as media and buffer.
Key unit operations such as bioreactors are now conducted in similar plastic bags, complete with agitation and feed ports. Disposable instruments, such as pH, conductivity, and dissolved oxygen sensors, are now readily available and integral to the disposable bioreactor.
In downstream processing, microfiltration and ultrafiltration elements have been disposable for many years. Today, complete MF and UF rigs are available in single use assemblies, and manufacturers have recently introduced disposable depth filtration systems as well.
In addition, the Biologics Technologies Tour will survey the latest advances in the most challenging single use applications: solution manufacturing through in-line dilution and chromatographic separation. As these technologies become mature and are accepted by the industry and its regulators, one can see the shape of the biotechnology facility of the future come into clearer focus.
The organizations that are on the leading edge of these advances will be the focus of the Biologics Technologies Tour at INTERPHEX 2012. The tour will provide attendees the opportunity to learn specifics on how these technologies are changing the face of biologics manufacturing today. Led by noted industry experts, the tour will make stops at selected vendor exhibits and provide an ideal opportunity to obtain information on the latest advances in these technologies and exchange information with commonly-interested attendees. This event has been designed to include the organizations currently making the greatest advances in the enabling technologies that will drive the paradigms for the biotech facility of the future. These organizations include EMD Millipore, Sartorius Stedim, Xcellerex, GE Healthcare, GEA Process, Abec, Inc., Thermo Fisher/Hyclone and Pall Life Sciences.
Read the full article in the INTERPHEX 2012 Pharmaceutical Processing supplement.
