Over the past two decades, research organizations and pharmaceutical companies have invested billions of dollars into the development of new biopharmaceutical medicines. This research has resulted in a burgeoning biopharmaceutical industry, with ground-breaking advances in treatments for severe systemic illnesses such as cancer and hemophilia.

However, the focus of academic research has historically been centered on drug discovery and development rather than on operational issues relating to drug manufacture. In the past five to ten years there has been an increasing recognition that the biopharmaceutical supply chain presents a unique production challenge not addressed by any single cohesive body of research. Biotech manufacturing requires massive capital expenditures on potentially high-risk projects, exceptionally stringent levels of cleanliness, quality control mechanisms that track complex and incompletely understood biological processes, and complete transparency to regulatory agencies in multiple jurisdictions. The nascent industry is still developing standardized mechanisms for drug production, with new technologies such as continuous perfusion and purification having the potential to radically change the evolution of operations.

“The question is, How do you efficiently and cost-effectively mass produce large quantities of a high-quality product and get it into the supply chain?” — Professor Lee Schruben, University of California–Berkeley (1).

UC Berkeley’s new Stanley Hall, site of interdisciplinary bioscience research. ()

Six Sigma, Operational Excellence, and Lean groups have made significant progress in alleviating the challenges facing biotech manufacturing. Just as importantly, these groups have also helped outline features of the biotech industry that are notoriously difficult to model and address using existing toolsets. These include issues such as the need for very high supply reliability for life-saving medicines, large uncertainty in demand and in supply and production processes, and inherent process and quality analysis (QA) and quality control (QC) variability not seen in other industries. New technologies and methodologies are clearly needed to meet these challenges if the industry is to mature and meet low-cost, high-reliability goals.

In Fall 2007, the University of California at Berkeley formally recognized the need for research in biopharmaceutical operations and established a forum for operational issues in biopharmaceutical production.

Personalized Medicine and Fragmentation of the Supply Chain

A significant theme in the September 2007 Bioproduction Forum was the increasingly fragmented market for biopharmaceutical medicines compared with that of their pharmaceutical counterparts. Robert Booth, ex-CSO of Celera and chairman of Virobay, examined the movement toward targeted or even individualized therapies based on knowledge of the underlying biology of disease coupled to a corresponding diagnostic test.

The advent of industrial-scale proteomics and genomics analysis provides an ability to more accurately recognize and target disease, but individualized treatment regimes present a number of issues for operations. Traditional drug manufacturing paradigms are based on large-scale manufacture of a single homogeneous product, but this approach is not designed for small batch sizes of highly-customized product targeted at specific patient indications. Personalized medicine and more targeted medicines may lead to considerably more complex manufacturing problems than those addressed by current pharmaceutical production methods, with traditional “single-therapy” markets segmented into smaller heterogeneous market segments.

The first forum’s keynote address examined the theme of fragmentation from a supply chain perspective, with Thomas Panzer (vice president of global supply chain PS Biotech at Bayer Healthcare) discussing the production of Bayer’s Factor VIII product Kogenate. Although Kogenate is ostensibly a single protein compound, patient-specific demands and complex worldwide regulatory issues create a proliferation of product “flavors,” fragmenting the supply chain. Many different varieties of product provide huge challenges for supply-chain responsiveness, because each product variant must be tracked and managed uniquely. This issue has repercussions across the supply chain, requiring improvements in quality assurance, safety stock policies, investment in operational excellence, and a number of other initiatives.

Product Regulation and Process Improvement further complicate the biotechnology supply chain. Biotechnology is unique in that the entire production process is regulated, rather than just the final product as is the case in most other medical products. Although this improves the provable safety and efficacy of biologic products, it can create a culture that is highly risk-adverse to process change. With each and every process or technical improvement requiring some level of validation and relicensing in multiple markets, most biotech companies resist technological improvements — even when such improvements have significant financial incentive.

Most companies in the industry have a “build-and-maintain” philosophy, so each plant undergoes significant validation only once (with minor retrofitting throughout its lifetime). Bayer’s approach in embracing technological improvement creates a need to actively manage this regulated parameter throughout the supply chain. Regulatory changes compound challenges of different product variants as each filing in each different country creates segregated material that must be separately managed until global approval is obtained. This challenge is not addressed by existing materials requirements planning (MRP), enterprise resource planning (ERP), or systems planning and scheduling.

Planning and Scheduling: On 26 September 2007, professor Rob Leachman discussed ongoing research at UC Berkeley on biotech planning and scheduling in the presence of regulatory constraints. His research agenda aims to develop tools and approaches that enable biopharmaceutical supply chains to optimally react to changes in regulatory approvals or technological changes. An initial working prototype, the “Planning Engine,” is currently being tested at Bayer’s Berkeley site. The goal is to help planners understand the complex interactions between different regulations in various facilities and optimally react to changes in product demand and supply.

Leachman’s talk also outlined a number of open research issues in the field relating to very long QA/QC cycle times — typically an order of magnitude larger than the processing time. These long cycle times and high variability in product release pose a significant challenge for most planning and scheduling systems.

A BIOPRODUCTION FORUM



The Bioproduction Forum builds on UC Berkeley’s rich history in biotechnology and other high-technology initiatives such as the Center for Competitive Semiconductor Manufacturing. UC Berkeley’s involvement in the semiconductor industry in the 1980s and 90s was instrumental in establishing a set of common benchmarks and models, wh
ich are now used by more than 80% of semiconductor manufacturers worldwide. An initial workshop conducted in April 2006 with key biotech industry representatives outlined the need for further research in the following areas:

Interdisciplinary Collaboration: The Forum differentiates itself from other workshops and seminars in two important respects. First, the audience is composed of researchers from incredibly diverse backgrounds — including bioengineering, biophysics, industrial engineering, economics, and biochemistry — as well as industry representatives bringing a wealth of practical experience. The goal is to bring together industry and academia to discuss current topics in the field: The breadth of experience encourages innovative and nontraditional approaches to problem solving.



Interactive Inquiry: The forum follows a nontraditional format with speakers discussing open issues in an interactive lunchtime seminar. Rather than discussing “success stories” in the industry, speakers are encouraged to discuss challenges and problems they face. Extensive audience participation makes each lunchtime session more of a collaboration than a presentation. The vision is to come to a broad consensus on what issues face the field, rather than having a number of diverse perspectives from individual experts.



The forum’s diversity and format are a reflection of the structure and sponsors of the forum. This foundation is made of an interdisciplinary group based in UC Berkeley’s industrial engineering and operations research (IEOR) department working with the Center for Information Technology Research in the Interest of Society (#CITRIS). The long-term vision is to establish a center of excellence that would provide common toolsets and technology research to benefit the entire industry.



Invitation to Get Involved



The Bioproduction Group at the University of California, Berkeley, has implemented a weekly seminar series that brings together the issues confronting our industry. Beginning this month, BioProcess International will bring to you a synopsis of key questions and answers that are addressed in this forum. We hope this will lead to further discussion within the industry on these important topics. We welcome your suggestions for additional questions and examples of how you have solved them. Send your comments to .



— Scott Wheelwright, president, Strategic Manufacturing Worldwide, and member of BioProcess International Editorial Advisory Board.

Lean Manufacturing and Supply Chain Responsiveness: Jorge Vilalta and Fadel Hamed from Genentech examined the potential impact of Lean manufacturing on biotech operations. A number of challenges to implementing Lean ideas in the biotech industry are becoming apparent. Examples of such challenges include lengthy manufacturing process lead times, dedicated (inflexible) facilities, a complex development process, and strict regulatory requirements. Their talk examined the current trend of building larger single-product facilities, that allow efficiencies of scale but prevent the successful implementation of Lean philosophy: “the elimination of anything not absolutely required to deliver quality product or service, on time, to customers” (2).

Although large-scale single-product plants have successfully been justified on a cost-per-gram basis, Vilalta and Hamed argued that such plants make process standardization across sites difficult and prevent the implementation of “just-in-time” manufacturing philosophies. Larger production runs also create large inventory buffers between stages, lowering overall supply chain responsiveness and creating the risk of a supply-driven, rather than demand-driven, supply chain. Vilalta and Hamed’s challenge to academia was to propose metrics by which the value of flexibility in manufacturing can be evaluated, as well as to produce models that could measure and test effective and efficient manufacturing capabilities.

The Bioproduction Forum’s inaugural month shows promise to deliver both a research agenda in the field and to educate students and industry in biopharmaceutical operations. Attendance to the forum is open to industry professionals and academics. More information is available at http://biog.berkeley.edu.

REFERENCES

1.) Schruben, Lee 2003.Industrial Engineering and Operations Research Department, University of California at Berkeley College of Engineering Lab Notes.

2.) Vilalta, J, and F. Hamed. 2007.Challenges and Opportunities for Lean Manufacturing in Biotechnology Presented at the Berkeley BioProduction Forum, University of California at Berkeley, Berkeley.