Under the twin shadows of a struggling world economy and a growing mistrust of the global supply chain, is it possible to drive productivity and efficiency without sacrificing quality and safety? Over the last decade we have seen the industry embrace the basic tenets of Six Sigma1 and Lean Manufacturing, spurred in no small part by the 2004 FDA guidance which describes a Risk Based Approach to cGMPs and the ICH 8, 9 and 10 guidances.
While big Pharma and Biotech have made tremendous progress in eliminating variation and waste on the shop floor through mature programs such as Right-the-First-Time, Six Sigma and Lean, it is not surprising that they should look further upstream at new product development for additional advantage. This article examines the value of applying operational excellence models to the development phase of a product’s lifecycle.
Drug Development Today
Applying operational excellence methodologies in the development environment is fundamentally very different from manufacturing. The challenges facing drug companies in bringing their products to market quicker with a high probability of success has never been greater. And as the complexity of drugs and their associated process steps and test methods escalate, so do the consequences of poor choices in the product development process. Product development is a highly cross-functional exercise which makes communication, coordination and decision-making very complicated. Unlike manufacturing, which is largely a recurring process, product development is in many ways a singular event, unique unto itself.
The latest proposed FDA drug development process (Figure 1), summarizes the key activities and phases in the development of a drug. As mentioned, the drug development process is stranded in a morass of interdependent tasks. Despite their interdependence, these considerations rarely move beyond assessing their impact on project timing. As a result, the inefficiencies typically encountered by Pharma as CMC, supply chain, clinical and technology transfer issues that creep into the product development program are never addressed until too late.
Six Sigma Product Development Models
Six Sigma models concentrate on eliminating potential sources of variation in processes. On the shop floor, Six Sigma follows what is known as the DMAIC roadmap (Define Measure, Analyze, Improve and Control). Moving Six Sigma into the product development phase would employ a version of DMAIC tailored according to the type of development structure being used and the product being developed. When Six Sigma moves to the product development phase of a product’s lifecycle it is termed Design for Six Sigma (DFSS). Three different versions of DFSS have been developed: DMADV (Define, Measure, Analyze, Design and Verify), IDOV (Identify, Design, Optimize and Verify), and DCOV (Design, Characterize, Optimize and Verify). The DMADV model has been very successfully deployed in the medical device industry, while DCOV, with its characterization phase is more suitable to in the drug development process. The three models and their definitions are shown in Figure 2.
In conventional product development the formulation and pre-clinical phase and Phase 1 activities center on product performance, first through animal models then in a clinical setting. Typically, Phase 2 is where process development and manufacturability studies begin in earnest. By this point there is little opportunity for aligning formulation, test and capability requirements with commercial requirements.
By contrast, in the DFSS models the intent is to align the product design activities with manufacturability considerations from the outset. By considering process capability as a design requirement it is possible to characterize and identify the key factors which drive the process stability and product performance. In this way, downstream program considerations—such as critical component supplier capability—and key CMC demonstration milestones—such as extractable/leachables testing or specification validity—can easily be integrated into the milestones for the development process. In essence these requirements form the foundation for a QbD approach as advocated by ICH Q8.
Lean Manufacturing and Product Development
Lean Manufacturing, as applied to the manufacturing shop floor, focuses on maximizing value within the value stream of a process. In 1996, James Womack and Daniel Jones published Lean Thinking, outlining the five principles that they believe embody a lean organization: (1) value (2) identifying the value stream (3) flow (4) pull and (5) perfection. A Lean organization achieves efficiency by identifying and improving the flow of value to the customer.
Toyota and Honda contend that they are and always will be a manufacturing company. However, this argument may distract from the true basis for their success, which is really knowledge management. Having built their organizations as learning organizations, both Toyota and Honda recognized that to become leaders and remain competitive, they needed to monitor three key aspects of their business constantly. First, they must harness the power of innovation to develop products that meet market need. Here is where Six Sigma tools and similar structured brainstorming frameworks ensure that knowledge is efficiently evaluated and interpreted to minimize the risk in development decision-making. Secondly, cost needs to be managed so that the final commercial product will generate a large profit. This means that commercial considerations become a primary attribute of the product development process. The third and final component is time. In our industry, the rapidly changing marketplace has nearly inverted the importance of these three factors, with new product development primarily driving new business growth.
Creating a knowledge management framework which applies across the continuum of product development is the hallmark of highly successful Lean organizations. As with all optimization initiatives there are several schools of thought on how to implement Lean in the product development environment. These five major schools of thought are summarized in Table 1.
Of these, the Toyota Product Development System (TPDS) is arguably the most mature of the Lean product development approaches. High-profile advocates such as Durward Sobek II, Allen C. Ward, and Michael Kennedy have touted the benefits of this approach through its success in the automotive and aeronautics industry. The question is can this be effectively applied to the pharmaceutical development model?
In my view, the challenge in pharma product development is translating downstream manufacturing considerations into terms that are relevant in the discovery (R&D) environment. This problem is compounded as organizations consolidate through acquisition, and have to integrate “stand alone or “shadow” development programs which may not be calibrated in terms of market opportunity nor aligned with current manufacturing capability. The advantage TPDS has over the other approaches is its emphasis on the role of knowledge in the product development environment. This is the same driver for performance in the R&D environment. If the required knowledge dissemination includes downstream considerations, it is possible to establish actionable milestones in the discovery and proof of concept phase of the drug development process that will positively impact the entire process and the bottom line.
The New Pharma Product Development Framework
Creating a knowledge-based organization will require establishing an organizational structure which promotes knowledge, resource and technical communication. As all organizations develop their infrastructure, there are several organizational models to consider. Matrix organizations utilize multidisciplinary teams to manage key steps within the product development program and commercial business. Functional organizations pull from departments which are aligned, based upon their role in the product development and business model, e.g., operations, quality, finance, etc. Mena manufacturing advocates have proposed a third model termed a Value Stream based structure. This approach creates a structure where there are semi-permanent teams that bring expertise across the value-stream for a specific product line.
Regardless of the approach embraced by an organization, to be successful will require a clear understanding of the overlap between critical elements of the discovery and development process. There is no silver bullet that will work for all organizations. However, existing Pharma companies with mature operational excellence programs could leverage a structure as shown in Figure 3.
This framework is based upon three critical new systems. First, the development, filing and commercial considerations must be captured as success metrics as part of an over arching project team. Termed an Operational Value Stream Team, this will be a multidisciplinary group, in lieu of a group based on function area responsibility, which is charged with establishing the upstream and downstream development success metrics. This team will be milestone-driven, much like phase gates in Six Sigma. Second, a Framework for Knowledge Management must be established to instill in the organization the challenges, mitigations and considerations required to quickly move a product throughout the development cycle and file with the FDA. Finally, the team must have an active Risk Mitigation element to its project management responsibilities. This is perhaps the largest opportunity for pharma to manage costs and time-to-market considerations in the development process. By installing clearly defined success metrics early in the process and evaluating performance against these metrics, programs which have a of low probability of success, based upon clinical, scale-up or market opportunity assessment criteria, can be terminated freeing up valuable resources to focus on the lower risk programs. This ensures that all risk, including clinical performance, is managed early to avoid costly downstream delays and disappointments.
The integration of operational excellence methodologies such as Six Sigma and Lean Manufacturing enjoys a long history of success outside the pharma industry. Established approaches for both DFSS and Lean Product Development exist and can reduce time-to-market and improve overall process robustness through the frontloading of the drug design process. For Pharma to leverage these productivity initiatives in product development, a radical transition in terms of product development is required. The framework we suggest builds upon existing paradigms in our industry and includes an operational Value Stream team, Knowledge Management and Risk Management process and milestones as the most suitable path forward. When tailored to an organization’s internal culture such a framework should allow the business to leverage the three basic tenets of a Lean product development organization: harnessing the innovation engine, integrating final commercial product cost as part of the initial product development system and—finally— realizing a shorter time to market.
1. Wheeler, Donald, Understanding Variation: The Key to Managing Chaos, ISBN 0-945320-35-3, SPC Press, Knoxville, TN.
2. Katherine Radeka, Tricia Sutton, “What is ‘lean’ about Product Development” PDMA Visions June 2007, Vol. XXXI, No. 2, Pages 11-15
3. M Kennedy, Product Development for the Lean Enterprise, ISBN 10:1-892538-18-0, Oklea Press, 2003.
4. R. Mascitelli, The Lean Product Development Guidebook, Northridge, CA.: Technology Perspectives, 2007
5. ICH Harmonized Tripartite Guideline, Pharmaceutical Development Q8, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, November 2005
6. ICH Harmonized Tripartite Guideline, Quality Risk Management Q9, International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, November 2005
7. James P. Womack and Daniel T. Jones, Lean Thinking, ISBN:0-7432-4927-5, Free Press, 1996
8. CDER Handbook, The New Drug Development Process http://www.fda.gov/cder/handbook/develop.htm *Six Sigma is a registered trademark of the Motorola Corporation