It has been three years since the concepts of Quality by Design (QbD), risk management and process control were first introduced by FDA to impose scientific rigor on our current quality paradigm. Surprisingly, in taking stock of our progress, we find ourselves grappling with the same issues that have historically plagued our industry.
Product quality and reliability remain at the forefront of our business and commitment to excellence, while our ability to deliver consistently against these objectives remains our greatest concern. Unquestionably, progress has been made. Conferences have devoted hundreds of man hours to sharing the lessons learned regarding PAT and QbD. Big Pharma, in particular, has embraced the concepts of process stability and predictability. Some of this movement can be attributed to an industry-wide interest in Lean Manufacturing and Six Sigma. Often lumped into the general category of Operational Excellence (OE), the tools and philosophies of OE have laid the groundwork for transforming organizational culture. The renewed desire to demonstrate corporate performance to shareholders has catalyzed companies to seek better ways to run their operations. While the motivation may have been cost reduction and operating efficiency, a tangible by-product has been process stabilization.
Other positive trends are evident. Increased use of risk assessment early in the product design phase has helped identify and eliminate potential sources of variation downstream. The rising incidence of risk-based validation as the baseline approach to qualification is evidence of the benefits that can be enjoyed by organizations willing to follow the ICH guidance. These trends point to an industry beginning to embrace the principles of QbD and process understanding.
At odds with this optimistic assessment is a recent report “The Quality Function: Structures, Staffing and Execution,” by Best Practices, LLC. The study states that the best-in-class examples in our industry maintain an operations to quality resource ratio of between 1:4 – 1:7. Historically, branded pharma has operated in the range of 1:2, biotech at 1:3 and generic manufacturers at 1:1.2. If the study’s ratios reflect the best we have to offer, then one could conclude we are moving in the wrong direction! How do we explain the shift?
The truth may lie in the commitment to these initiatives, that is, both industry’s commitment to change and FDA’s commitment to changing its philosophy on quality and compliance. There is significant confusion regarding how to transform organizational structures and functional job responsibilities into a conceptual framework that can leverage the benefits of QbD. Couple this with the Agency’s passive, almost apologetic approach to driving QbD, and you must question whether there is a sufficient impetus to be successful. The impact of FDA’s recent move to train 150 specialists, dubbed “Pharmaceutical Inspectorates,” has yet to be felt. So one could speculate that in the absence of pressure we are falling back on our old habits.
So, what will it take to move us forward? The global interest in outsourcing manufacturing, research and clinical trials management will certainly raise the quality exposure for industry. Despite China’s quality travails, Big Pharma and Biotech are investing heavily there. The question remains, can we really hit our quality objectives through inspection and testing? The body of evidence seems to say no. While Big Pharma and Biotech seem to be exploring the promise of QbD, mid-tier, emerging and generic firms have been slow to respond to the challenge.
Generic drug companies contemplating initiatives such as PAT cannot use the Big Pharma model. Simply, they do not have the magnitude of financial and human resources or the time required to implement these initatives. Emerging pharma and biotech firms preparing their programs for Phase 1 and Phase 2 clinical trials struggle with the lack of a roadmap for establishing quality systems that are FDAcompliant and practical, given their business models.
If we are to be successful in realizing the full benefit of initiatives such as QbD and PAT, then industry and the Agency must move towards a cohesive message and methodology. QbD initiatives veiled within the old framework of inspection and testing will ultimately undermine any attempts to realize the benefits of increased process understanding. Designing a QbD solution that is both pragmatic from a compliance standpoint and flexible from a business perspective will keep the pressure on industry to truly embrace the principles of QbD.