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
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.