The drug development process is difficult at best, but “lean” methodologies borrowed from other industries can make a difference.

Rama Shankar, MS 
Xavier Frapaise, MD
Betsy Brown, MS

TAP Pharmaceutical Products Inc., Lake Forest, Ill., is, as are all drug manufacturers, under tremendous pressure to introduce new products as early as possible. Thanks

click the image to enlarge  Lean drug development uses a variety of tools and techniques, including point of use storage (POUS) and value stream mapping (VSM). (Source: National Institute of Standards and Technology)

to genomics in particular, discovery is recovering, but development is still lagging and can become the bottleneck. Only a limited number of compounds achieve approval and successful commercialization. Many discussions and meetings within TAP center on R&D productivity, the challenge of decreasing time and cost associated with product development, maintaining or improving quality levels, and increasing R&D output and the number of approved compounds.

The following are some statistics about the drug development and approval process:
• Cycle time from experimental drug to medicine chest can take anywhere from seven to 12 years.
• Only five in 40,000 compounds screened in animal testing make it to human testing.
• Of the five tested in humans only one is approved.
• The development cost is close to $1.2 billion.

Why Use "Lean" in R&D?
TAP R&D embraced and implemented a "lean" methodology that originated in improving manufacturing and called it lean drug development. While it is true that the lean methodology was created and developed for manufacturing industries, it's proven beneficial in several industries. And while TAP R&D doesn't manufacture items in the traditional sense, there are relevant examples of tasks within R&D that meet that definition. For example, the deliverable products in clinical operations are all protocols, reports, and summaries. Likewise, in regulatory affairs, investigational new drug submissions, new drug applications, and annual reports would constitute deliverable products. Another example in the design phase would be forecasts and budgets. Nearly all functional areas have similar types of examples that comprise "products" that TAP R&D "manufactures."

Lean drug development is a term that the organization adapted from a philosophy known as "lean" that incorporates a collection of tools and techniques into business

An Example of Using Lean to Reach a Goal Work Process Documentation Process {Policies, Procedures and Guidelines (PPG) System} Business  To ensure FDA compliance with drug development documentation. Case (Why) TAP’s quality management structure has evolved to support the core needs of our industry. We are now moving to adopt a more efficient process, one that is in line with global QMS standards. Solutions • Establish standardized definitions for policies & standard operating procedures hierarchy • Redefine PPG review committee membership & review process • Establish standardized PPG impact analysis process • Establish key drug development categories for PPG documentation process Result See graph below   click to enlarge  TAP has used lean drug development principles in a number of areas, including documentation processes. Using lean tools, they were able to reduce documentation processing times by 68%. (Source: TAP Pharmaceutical Products Inc.)

processes to optimize the various factors contributing to effective drug development. The overall concept of analyzing a process to eliminate waste and improve overall manufacturing dates back to Henry Ford in the 1920s, but Toyota brought the term to life. Toyota gave the concept structure through actual practice, emphasizing practicality over theoretical analysis. Terms such as "The House of Lean" and "Lean Manufacturing" became the lingo the company used in improving its output, terms that other organizations adopted as well. So how does House of Lean apply to the drug development process? Quite simply, it examines the entire organization's processes and procedures, looking for better ways to optimize time, human resources, and assets while improving the quality level of our products and services to our customers.

Basically, the lean process ensures that R&D delivers high-quality products to our customers faster than our competition. The neat part of the lean model is that quality is built into the process—it is one of the building blocks within the House of Lean. The quality goal cannot be achieved independently of the primary goal or goals of cycle time reduction and cost reduction, since "errors and defects" are considered "waste" in a lean process.

A quality performance management (QPM) department was established within the R&D area at TAP two years ago to support and manage lean drug development projects across R&D. The QPM department was made up of managers who resided in each functional area and worked on improvement projects within and across functional area boundaries. This structure was key to enabling lean drug development methodology to be implemented within R&D.

R&D's QPM team studied the building blocks in the traditional House of Lean model and altered areas to make them relevant to TAP R&D's business—drug development. Overall, the lean drug development process is two-tiered, meaning that it has a macro and micro level, much like the study of economics. At the macro level, a cross-functional team can study the "house" from above, examining the overall drug development process from top to bottom. From this perspective, it is easier to identify processes and procedures that work smoothly, while simultaneously locating obstacles and bottlenecks in the drug development process. At the micro level, all bottlenecks and inefficiencies are analyzed carefully. Each bottleneck process is broken down into a set of activities to differentiate between activities that are "value added" or "work," and those that are "non-value added" or "waste."

The other key to lean drug development is the creation of value from the customer's perspective. Employees know who their internal and external customers are. The voice of the customer is critical to business success; their requirements are also identified in the applicable GxP regulations. Once the elements of the process that actually add value are understood, the challenge becomes how to align the work so that value is created and the process flows smoothly.

Lean Development Methodology
The main focus of TAP R&D was to identify company-specific areas to address. In order to do this, TAP took a bottom-up approach by soliciting suggestions and ideas from R&D staff in identifying areas to address as candidates for undergoing lean. Based on the feedback received, six key areas were identified for the application of the lean drug development methodology. While narrowing down the selection, the project was selected based on the following considerations:
•Reduction in cycle time;
•Focus on problems;
•Focus on cost savings;
•Focus on process simplification.

An off-site meeting was held where speakers from different industries presented us with insight into how lean works. R&D leadership started the meeting with a presentation on the future of R&D and challenges to business success. We followed the lean drug development methodology by creating a value stream map for the work process. Members thought about, and shared information on, the cycle time for each step in the activity and the true value-added time (work time) to arrive at a total cycle time and work time for the process. For most work processes that we looked at, the value-added time (work time) was about 20% of the cycle time, indicating that the process had room for improvement.

Meeting participants then walked through the process. Each person who worked in an area described what they did in order to accomplish a certain step, and also identified where they thought the waste existed. The work process was then analyzed to identify the different types of waste encountered, and the team shared information on what worked well and what was problematic. With a great deal of waste within the work process identified, the team generated improvement ideas in conjunction with the principles of the House of Lean. Common themes were combined together and documented as action items. The improvement actions were then translated by the team to potential reduction in cycle time and realization of other benefits, such as cost reduction and improvement in customer satisfaction (see table below).

Implementation Challenges
Taichi Ohno, the pioneer of Lean at Toyota, said: "An organization is like the human body, designed to be self protective. There are antibodies inside the body. When a

Eight Different Types of Waste as They Relate to R&D: Over Production Producing more product than the customer needs for that moment.  Excess Inventory  More products or process requirements on hand than the customer needs. Waiting Idle time created when data, information, people, or product is waiting for various reasons Transportation Physical movement of people, product, equipment, and files in the organization that does not add value Motion Any movement by a person that does not add value to the product or service.  Over Processing Effort or work activities that add no value to the product or service from the customers’ viewpoint. Defects/Errors Work that contains errors, rework, mistakes, or lacks established necessary requirements. Waste of People’s Talents Not allowing people to utilize their intellect/creativity/job experience/skill sets to their maximum potential.

foreign substance enters the body, such as an infection, the antibodies not only get more active, they multiply." What this means is that the culture of an organization almost always wins if there is a clash between strategy and culture. Through implementing lean drug development, TAP gained some valuable insights.
1. Leadership has to manage the transition to lean drug development so that personnel support it. Change agents need to convert the majority of personnel sitting on the fence so they will support the transformation. Most employees like to wait a bit before embracing change. Some commonly heard comments are: "This is another flavor of the year! What's in it for me? Will this go away if I ignore it long enough? Let me see how long this is really going to last!" These uncertainties were addressed by the senior management committee (SMC).
2. Understand the core business process. At the start of lean drug development, there were many misconceptions at all levels about what the core business process is. By bringing in a cross-functional group of people, a "boundaryless" organization culture was fostered to share information across functional areas on what really happens in the process. Once members of the group had the same information, it was easier to arrive at a common solution.
3. Communication cannot be over emphasized. TAP communicated early and often, with SMC members articulating the need for change by making a business case for the projects selected to undergo lean drug development transformation.
4. Manage responsibilities so no one person gets overburdened. Because different projects are undergoing lean drug development, there are some people who are involved in multiple project teams. By knowing who is involved in which lean drug development project, SMC members and team leaders were able to assign activities to ensure those individuals were not overworked.
5. The shift to the lean drug development paradigm needs to be actively managed. This was done through providing training to all R&D personnel and including lean drug development performance as a part of an individual's performance. SMC and team leaders also removed confusion by defining priorities, improvement responsibilities, and project boundaries.

As a consequence of embracing the lean drug development methodology, TAP Pharmaceuticals now has the capability to improve work processes by breaking them down to the activity level and to monitor progress through action items and measurable targets. This framework is now integrated into the formal business review mechanism, whereby information from the working teams is reported by the SMC through monthly meetings, "State of TAP" meetings, and quarterly management reviews. The transformation of lean drug development into a strategic planning dimension has also been brought about through the reporting of metrics from key work processes into the performance "dashboard."

The lean drug development tools are not only easy to understand and use but have proven to be very beneficial to TAP. In a highly competitive industry with a rapidly changing marketplace, TAP utilized the lean drug development methodology to make improvements to its key processes and continues to be a standard bearer for lean manufacturing in the pharmaceutical R&D industry.

Shankar is quality performance manager and Brown is director of quality performance management at TAP Pharmaceuticals Products Inc., Lake Forest, Ill. Frapaise, former vice president for research & development at TAP, is now the chief medical officer at Ocera Therapeutics Inc., San Diego.