Manufacturing Perspectives: Lessons for Biomanufacturing from Small-Molecule Manufacturing

As biopharmaceutical product-development intensifies, what knowledge can be applied from small-molecule manufacturing? Lou Schmukler, senior vice-president of the Specialty/ Biotechnology Operating Unit at Pfizer, shares his perspective on process understanding and control, operational excellence principles, and cultural and organizational transformation.

The biotechnology industry has come a long way in a relatively short time. Over a period of just three decades, the industry has gone from consisting of only start-up companies to businesses that in aggregate will exceed $125 billion in global revenues this year. There are more than 30 biotechnology products with annual sales of $1 billion or greater. Biotechnology is the fastest-growing sector of the bio/pharmaceutical industry with growth highest in vaccines and emerging markets. Biotechnology companies' pipelines are replete with more than 5600 candidates that are currently in clinical trials and are designed to treat a plethora of different diseases. Forecasts project that by 2014, seven of the world's top 10 pharmaceutical products will come from biotechnology companies, according to data from Evaluate Pharma. This impressive performance reflects tremendous technological advancement and innovation across the biotechnology value chain. Biotechnology has brought extraordinary and novel therapies to treat cancers, diabetes, pneumococcal disease, rheumatoid arthritis, hemophilia, bone growth, and anemia, for example.

Illustration: Melissa McEvoy; Images Don Farrall/Photodisc.

This period of strong drug development ushered in significant progress and improvement in bioprocessing. With the development of recombinant DNA technology in the 1970s and the creation of monoclonal antibodies, organizations began tackling the challenge of effectively and efficiently producing new biotechnology products. A transformation has long been underway, which has moved biomanufacturing from art to science and has challenged the notion that once characterized biomanufacturing as "the process is the product." In the mid-1980s, achieving yields in quantities of milligrams per liter in monoclonal antibodies was an accomplishment. Today, by incorporating bioprocessing-intensification strategies of the past 15 years, biomanufacturing organizations now routinely can produce yields in quantities of multigrams per liter with an increased emphasis on economics, quality, process robustness, and reliability.

The progress in biomanufacturing has been truly remarkable, and we can expect continued progress in upstream and downstream process optimization, new analytical technologies, application of single-use and modular technologies, multiproduct facilities, higher expression-system productivity, and new delivery systems. Growth in emerging markets and the resulting need to address access and affordability issues will challenge current biomanufacturing-supply strategies. In addition, the emergent biosimilar market will require special capabilities from today's biomanufacturing organizations. In short, the continued dynamics of the business and regulatory environment will further drive change.

Lessons from small-molecule manufacturing

The biotechnology industry has learned many good lessons as biomanufacturing has matured during the past 30 years, but there are still important lessons to be learned. Biomanufacturing would be well served to take some guidance from its older, traditional small-molecule cousin. With more than 100 years of history to its credit, traditional small-molecule pharmaceutical manufacturing has undergone its own transformational journey. Challenges in capacity, cost, quality, and compliance have required new technological and organizational solutions. Today's small-molecule supply chains would be unrecognizable to those working in the industry 50 years ago.

Of the many valuable small-molecule learnings, three are of particular interest and warrant closer examination by biomanufacturing organizations. These lessons include the small-molecule perspectives on achieving process understanding and control, embedding operational excellence principles, and driving organizational and cultural transformation.

Process understanding and control. Variability is the primary enemy of manufacturing, so strategies to understand and minimize its effect are crucial for any manufacturing unit. Small molecule-manufacturing has achieved significant progress in this area. Total quality tools, statistical methodologies, and quality risk management are regularly applied to identify, minimize, and eliminate process variability and improve product quality. Process analytical technology (PAT) is particularly important in this regard

PAT has been applied in small-molecule manufacturing for decades. In some cases, energetic PAT scientists wanted to measure everything possible and later determine what data was meaningful. This approach was often costly and burdensome to operating sites and negatively affected their enthusiasm for PAT applications. Over time, PAT advocates and operational managers aligned around identifying parameters that contribute to process understanding and ultimately to a control strategy that reduces process variability. This focus on improved process performance is consistent with lean-manufacturing principals (e.g., fewer results out of specification, increased yields, and reduced cycle times).

Highly capable processes can take advantage of real-time-release with associated benefits in reduced testing and inventory. Biomanufacturing processes can benefit from this small-molecule experience. The first goal of PAT should be process understanding, and much of this knowledge can be gained at laboratory and pilot scale. Biomanufacturing systems are typically more complex than small molecules, and analytical techniques are more specialized, thereby making it even more important to identify the critical parameters and understand their relationship to quality and productivity outputs before implementing production at commercial scale.

Another important small-molecule lesson, aligning with process understanding and control, has been the use of standardized platforms throughout development and commercialization. This approach avoids having to re-engineer the hardware part of an application for each process although method capability and calibration will be process-specific. Applying a standardized platform strategy for technology and operations in biomanufacturing will transform the current business model by increasing speed-to-market, facility flexibility and manufacturing capacity and by lowering cost structures and capital investments.

Operational excellence principles. It took a long time for traditional small-molecule pharmaceutical companies to realize that operational excellence techniques and philosophies, long valued in other industries, also had tremendous potential in their businesses. It was postulated that small-molecule pharmaceutical manufacturing was different; therefore, what was applied in the automotive industry or small-component, high-volume manufacturing had no place in a highly regulated, complex manufacturing environment. The key to realizing the potential has been in developing process understanding and subsequently using this new knowledge to significantly increase process robustness and deliver manufacturing and supply-chain efficiencies. Techniques, such as Six Sigma and PAT, have allowed the industry to understand the relationships between critical process parameters and critical quality attributes like never before so that new control philosophies could be developed. Lean manufacturing tools, such as standard work, Single Minute Exchange of Die (SMED), Total Productive Maintenance (TPM), and 5S (Sort, Set, Shine, Standardize, and Sustain) have removed variability in the way unit operations are performed. Lean supply-chain thinking, pull systems, and Kanbans (scheduling systems that tell the user what to produce, when to produce it, and how much to produce) have facilitated strategic management of inventory. The result has been increased supply reliability, improved assurance of quality, and lower costs. All of these lessons can be similarly deployed in large-molecule manufacturing and related supply chains to achieve operational excellence.

Apart from the direct benefits of quality, cost, and supply reliability there also are indirect benefits. Adoption of operational excellence principles has given small-molecule pharmaceutical manufacturing a new language and facilitated benchmarking with other industries. For example, small-molecule pharmaceutical companies can now compare inventory turns, overall equipment effectiveness, and defect rates with other advanced manufacturing industries and use the same techniques that produced world-class performance. Also, the adoption of lean and Six Sigma tools is completely synergistic with the modern management and organizational philosophy of arming engaged and empowered work teams with vital skills to improve their work.

Innovation is crucial for advanced manufacturing. In the past, there has been a perception that the rigor of Six Sigma and the standardization of lean manufacturing could be an impediment to innovative thinking. In fact, the opposite is true. The process understanding provided by Six Sigma provides a platform for innovation and standardization, solidifies the benefits derived, and prevents the natural fallback from optimum performance. Standardization of the innovation process itself is key to embedding innovation as a behavior in an organization. As a relatively young industry, innovation is paramount to advancing biotechnology at a much quicker rate than that experienced in small-molecule development and manufacturing.

Organizational and cultural transformation. Small-molecule pharmaceutical manufacturing organizations have been faced with the need for vast transformational change since the late 1980s. There have been various drivers for transformation, including but not limited to, loss of patent exclusivity, poor R&D productivity, increased regulatory requirements, and industry consolidation. To navigate this highly competitive landscape, organizations have had to rethink management philosophies, organizational design, and the internal environment in which they operate.

There are now myriad successful case studies that manufacturing organizations can use. Many of these success stories have common themes. They usually start with the end in mind: an agile, flexible commercially aligned manufacturing organization focused on and attaining aspirational performance goals across all key areas of the operation, not just cost. Overly ambitious targets force new thinking and ways of working whereas older operational paradigms give way to new models. A manufacturing organization often needs to build new capabilities while at the same time rationalize its operations. This dual approach is not easy, but it is paramount to establishing competitive advantage.

As companies in the small-molecule space embarked on these transformational programs, they quickly discovered that to achieve far-reaching transformation, two elements were pivotal: leadership behaviors and workforce engagement. Desired leadership behaviors included lean thinking, empowerment, ability to manage change, and a customer orientation. Workforce engagement meant people in the organization had to be fully involved at every step in the process. To compete by working smarter requires that people understand and care about the business. To facilitate this orientation, people need to feel that their voice matters, and they need to be included. Inevitably, the transformational programs that have been successful in the small-molecule arena have involved functional and cross-functional focus groups at all levels across all business organizations that were engaged in idea generation and solution delivery. Transparency in communication has been a key ingredient of these efforts.

These industry transformations have often led to the concept of delayering organizations, which involves streamlining the traditional hierarchy to avoid inadvertent distortion of the objective that can result from too many filters. A culture of high ownership with open information-sharing is a proven model. Experience and confidence gained from such initiatives in organizations where the culture, which includes mindsets and behaviors, has been embraced by employees at all levels, have created an environment of sustained innovation and high performance.

Looking ahead

The French academic Paul Valery said, "The trouble with our times is that the future is not what it used to be." Every manager would like to know what the future holds to take the risk out of business planning. That degree of knowledge of the future, however, does not exist. Biomanufacturing organizations, however, have the benefit of what has been learned from traditional small-molecule pharmaceutical manufacturing organizations, both the successes and failures. Today, biomanufacturing finds itself in a time of great change; it is at an inflection point. The trends discussed in this article require decisive leadership on the part of biomanufacturing management. Biomanufacturing strategy needs to proactively address the large issues, such as loss of patent exclusivity, emerging technologies, localized manufacturing, and the impact of low-volume personalized medicines. The three small-molecules perspectives presented in this article (i.e., process understanding and control, operational excellence principles, and organization and cultural transformation), along with others, can certainly be helpful in charting a new course. Organizations need to be receptive to change and avoid the "not invented here" or "we've always done it this way" mentality.

Lou Schmukler is senior vice-president of the Specialty/Biotechnology Operating Unit at Pfizer.