The sterile injectable manufacturing site of a multi-national pharmaceutical company experienced a sudden and unexpected increase in units with visible crystals. Despite the drug being on the FDA drug shortage list, manufacturing was temporarily halted. Sufficient determination of the root cause of the crystallization with proposed countermeasures was required to restart manufacturing. The company brought skilled MetaExpert Scott in to lead the charge.
Sterile injectable crystallization is a niche technology that requires extensive expertise. MetaExpert Scott assembled a cross-functional Black Belt team which included operators, technicians, process engineers, and chemists. In close collaboration with his team of functional subject matter experts (SMEs), Scott developed and deployed a strategy to return the product to production and removal from the FDA drug shortage list. This was accomplished by:
- Investigating and responding to the manufacturing deviation
- Identifying the root cause(s) of crystallization
- Evaluating the feasibility of product reformulation
Under Scott’s leadership, the team of subject matter experts employed DMAIC (Define, Measure, Analyze, Improve, Control) and statistical tools to successfully identify the root causes and develop countermeasures to address each cause. In addition, Scott led the team in creating a detailed implementation plan, updating the GMP (Good Manufacturing Processes) documentation. Finally, the team validated that the formulation was super-saturated and inherently prone to crystallization over time. A long-term plan was created to reformulate the product.
MetaExpert Scott and his team of SMEs worked tirelessly to implement countermeasures to the root causes identified. As a result:
- Product manufacturing resumed, and the product was removed from the drug shortage list.
- After implementing countermeasures in the Improve phase, zero lots failed (out of 15 consecutive) in the Control phase for crystal defects.
- Enhanced inspection was first reduced, and then completely eliminated.
- Future costs of defective lots and the associated investigations were avoided.
The project focused on reducing variation in tablet hardness, a characteristic critical to dissolution time and the release of medicine. By identifying and mitigating the sources of variation in the tablet press dyes, variation in tablet hardness was reduced by 30% and all tablet harness deviations were eliminated.
Thanks to MetaExpert Scott’s unrelenting efforts and DMAIC expertise, a medically necessary drug was safely returned to the market. In addition, Scott enabled the pharmaceutical company to mitigate future risks and increased costs of crystallization.