An emerging challenge for biotech companies is understanding the bigger picture: How should manufacturing facilities be configured to link together process technologies? Should plants be highly flexible or focus on process standardization? How would a disruptive new technology affect current supply chains, and how could it be implemented? Meeting the challenge requires a complete and detailed understanding of supply chains. Much current focus in process development is on improving operations, with limited consideration to how improvements affect “big picture” variables. Evaluating a portfolio of overlapping incremental improvements requires detailed understanding of a plant, biological variability’s effects, the impact of testing and quality control, and other issues. Berkeley’s Bioprocess Forum series addressed them in four meetings held in November and December of 2007.

Focus on Operational Issues

Supply chain issues and technology management are crucially important not just for reducing cost, but also increasing revenue, ensure reliability, and building and maintaining a robust supply network. Building flexible plants that make reliable, consistent product to meet demand on-time is a vital cost-reducing goal that eliminates the need for the huge capital investments in new manufacturing facilities. Operational inefficiencies and the traditional “license-and-leave” philosophy for building plants can cause capacity limitations at very real cost to manufacturers (e.g., limited capacity cost $200 million in potential Enbrel revenue). Neglected inventory management strategies have also led companies to accumulate large stocks of product that expire before release.

Chris Horan, vice president of global supply chain planning and logistics for Genentech, tackled these issues in our Bioproduction Forum’s second keynote address last fall. He noted that titer increases over the next five years will require retrofitting existing recovery trains and that biosimilars could take advantage of recent technology advances to produce material cheaper than legacy plants can. So it becomes essential to incorporate new technological innovations into manufacturing processes and be aware of the tradeoffs between flexible capacity and large-scale single-product manufacturing facilities.

Supply Chain Operations

Improvements in expression and recovery technologies could dramatically reduce production costs of biopharmaceutical products by orders of magnitude more than their pharmaceutical counterparts. With increasing competition and a wider world market incapable of affording drugs, such performance improvements are greatly needed. However, all changes presents considerable difficulties for supply chain networks. Retrofitting processes into current plant operations can require extensive requalification and revalidation.

At one forum, Scott Wheelwright (president and CEO of Strategic Manufacturing Worldwide) examined cost drivers and emerging patterns in expression technology. He described considerable need for new plants that are highly flexible and built quickly to maximize lifetime revenue for new products. They can decrease cost of goods sold and improve output reliability, making it possible to modify production to meet uncertain demand or new launch products.

Brian Maiorella, former vice president of biopharmaceutical process development at Chiron, confirmed that we must look beyond technology innovations to supply chain infrastructure. He argued that current manufacturing strategy for clinical trials relies too heavily on “tricks” unique to each product. It limits the number of products that can be tested in parallel, stifling the ability to quickly develop new products and transfer process technologies into commercial operations. Standardized technology platforms allow production of several parallel candidates at high quality.

New Technology with Regulations

An added complication for operations is the need to relicense a product in each region where it is sold after a new process implementation. Bob Kozak, senior director in global regulatory affairs at Bayer Healthcare, outlined the need to carefully manage a strategy for implementing new technologies within a supply chain. He argued that continuous improvements can be implemented in existing facilities while ensuring continued product safety and efficacy. It’s achieved through a plan shared among process development and engineering, regulatory affairs, and supply-chain planners to ensure that process changeover includes continuing high service levels.

A significant tradeoff lies in deciding whether process settings should be standardized across markets. Although companies may desire a single process description for all markets, in reality each regulatory agency has a different focus on testing and quality requirements. Manufacturers can either produce material conforming to every regulatory standard or segregate material in the supply chain for use only in certain countries. With maturing plants and products, these issues become increasingly significant.

Facing Our Challenges

The greatest emerging consensus from the Bioproduction Forum series is that current issues in biopharmaceutical operation cross traditional functional areas. A single group or approach cannot effectively address these issues with the required detail while maintaining a broader perspective. Guidance is required to overcome barriers between different research areas and disciplines, and a common language and toolset needs to be developed to facilitate continuous process improvements. Our Bioproduction Forums are a modest first step toward understanding the issues; a common biopharmaceutical operations research agenda is clearly needed to address them from an industry-wide perspective.