As we head into the New Year, it’s time to take stock of the shifts taking place in the pharmaceutical industry. After scrambling to catch up with FDA guidance and adopt a more scientifically rigorous approach to product development, our industry is slowly but surely turning to process understanding rather than product testing as the primary quality driver.
In 2007, the industry began to recognize the potential benefits of embracing a Quality by Design (QbD) philosophy in drug development. One key indicator of this is the ever-increasing number of suppliers offering software systems designed to facilitate data management within a QbD structure. Another has been the proliferation of case studies presented at technical conferences around the world by large pharma and biotech organizations that describe the application of operational excellence, QbD and process analytical technologies (PAT) programs.
What I’ve found to be most revealing about these case study presentations is the realization that there is no one-size-fits-all solution. Successful multinational companies now fashion their own versions of these initiatives, piecing together key elements from proven operational excellence philosophies such as Six Sigma and Lean Manufacturing to create something that fits their organizational culture and energy.
Several trends have emerged that emphasize the degree to which industry is beginning to embrace this new way of thinking:
- Large Pharma is synchronizing strategic and tactical goal-making as part of their business strategy for success
It’s fundamental to any business to make sure that its resources target the right programs at the right time, with a clear understanding of the metrics for success. To this end, more companies have borrowed the Balanced Scorecard concept as a basis for developing strategic and tactical goals. This approach ensures that the relationship between individual, department and corporate goals are clearly defined. Whether the organization is a start-up under pressure to meet its business milestones or a large multinational struggling with cultural and organizational differences, the ability to focus a team upon the business’s most important goals is a major step toward improving corporate performance and efficiency.
- Large Pharma is driving Lean Six Sigma principles further upstream in the drug development process
In recent years, the industry has struggled to embrace the basic principles of Lean Manufacturing and Six Sigma. Although it initially eschewed these approaches as the latest “system” for improvement, Large Pharma has demonstrated that it can implement them successfully without reinventing the wheel. Today, more firms seek to leverage the same benefits earlier and avoid many of the downstream problems associated with scale-up and commercialization. The success of this initiative may yet have the most profound impact upon the industry and its ability to compete in the world marketplace. The medical device industry has employed these principles within the structure of 21 CFR 820 for many years, integrating commercial criteria early in the design and development process. Those companies that do it well find they can lay the foundation for an effective Product Lifecycle Management (PLM) program, which enables product longevity and earning power. On the other hand, pharma and biotech have largely left R&D largely alone as an incubator for creativity.
- Large Pharma is leveraging risk-based opportunities as presented in the latest ICH and cGMP guidance
FDA’s latest guidances advocate the use of scientific inquiry in developing quality initiatives that will ensure ongoing product quality. The application of risk assessment within the product development lifecycle presents an opportunity to optimize the time, resources and cost for developing a drug product. This approach represents a shift from the traditional mindset, where blanket inspection and testing are a surrogate for process understanding, to one driven by control and monitoring. Today, many companies would consider it unthinkable to proceed with process or method development without a Failure Modes and Effects Analysis (FMEA) in place. The shift in how tools such as FMEA are applied has made a significant impact on both program management and process quality, and has demanded a definitive understanding of such processes. Subjective and ad hoc information is quickly dismissed when assumptions cannot be corroborated with data. Ironically, this requirement is one of the basic tenets of ICH Q8 and Q9, which much of the industry has struggled with implementing.
I predict several other trends will have an even greater impact in embedding this shift in focus:
For years, pharmaceutical companies have relied upon Contract Research Organizations (CROs) to address capacity shortages in manufacturing or to help compress development timelines. Often considered an extra pair of hands, CROs have emerged as much more. Routinely tapped to assist with pre-clinical work, CROs are now capable of providing more than just resources. Intellectual property, novel delivery platforms and access to distribution networks have rapidly become key components in a firm’s decision to outsource to a CRO. Although manufacturing responsibility due to capacity or capital constraints has traditionally been the driver for seeking a contract organization, more upstream responsibility is being outsourced in an effort to leverage unique expertise and/or compress timelines. Complex formulation challenges or performance-driven reformulation responsibilities are now being outsourced to specialized CROs due, in part, to the emergence of skilled, low-cost CROs in Asia. It is easy to imagine the increased complexity in prescribing a QbD approach to any CRO, particularly one that resides in a different culture and time zone. If the advantages then are to be efficiently extracted, a clearly defined roadmap that integrates risk-based assessments and objective metrics for control is required. Ideally, a CRO can quickly morph from a hired contractor to a strategic partner, given the impact of its work on program timelines and milestones.
Another significant accelerator for change will be increased interest in benchmarking activities. Historically, our industry has not worried about comparative metrics. However, with increased pressure to perform, there is significant interest in gauging progress against other best-in-class performers within the industry. Previously this sort of benchmarking has been achieved through the compilation and analysis of survey data. Today, however, there are benchmark databases available, which are constructed from actual performance data from industry organizations. This data is scrubbed to ensure anonymity but represents the true — not perceived — level of performance achieved by best-in-class organizations. What does this mean for our industry with regard to maintaining a renewed focus on scientific understanding? First, Cost of Poor Quality (COPQ) data can now be used to gauge improvement in our quality systems. Key manufacturing metrics such as Overall Equipment Effectiveness (OEE), a metric which measures the percentage of time equipment is utilized to make quality products, and Cycle Erosion, which measures our ability to manage minor stops that cannibalize cycle time, can be used to chart progress towards great productivity. When coupled with QbD activities, the two types of metrics allow management to effectively and efficiently steer product development while encouraging process stability. If combined with risk-based methods, added benefits of reduced cost, resources and time can be realized as part of the marriage of these two benchmarking methodologies.
Drug Pedigree Legislation
Perhaps the least obvious but potentially most significant driver for change to consider is FDA’s decision not to delay the drug pedigree legislation requirement. A growing number of firms are purchasing API from overseas suppliers. India, China, Croatia and Korea all are major suppliers of API to European and U.S. pharma companies. With this emergence has come a heightened concern about ensuring product integrity. While not an explicit component of the ICH and cGMP guidelines, the ability to effectively implement anti-tampering technology — such as RFID — requires an in-depth understanding of the process train, sources of variability, and risks to product integrity. The same tools to characterize the process as specified in ICH Q8 and Q9 will need to be applied to the drug pedigree process. This merger of regulatory, technical and business sensibilities will elevate the urgency in adopting these new principles.
So let’s keep in mind that the rules that determine what is acceptable from a product development perspective are changing. Effectively integrated strategic and tactical goal-setting is becoming more prevalent. Coupled with the emergence of low-cost, highly skilled CROs overseas, the strategic exposure to a misstep will continue to escalate, prompting us to establish a more methodical roadmap to ensure business and technical risks are addressed. This synergy between business, technical and regulatory drivers will, for the first time, force us to embrace the new data-driven roadmap demanded by the new regulatory guidance.