It is safe to say the pharmaceutical and biotech market today bears little resemblance to the market of the last twenty years. The rapid advancement of emerging markets that drive down the standard cost of therapy has forced the industry to look for ways to catalyze business performance and manage risk while still maintaining shareholder value. Historically, we have been slow to embrace innovation. However, the FDA’s landmark guidance in 2004 — cGMPs for the 21st Century – A Risk Based Approach — challenged us to find better ways to develop our products, taking up the mantra of mechanistic understanding and a processcentric approach to quality assurance. This new philosophy has opened the door to proven improvement frameworks such as Lean Manufacturing, Six Sigma,* and Design for Manufacturing to gain a foothold in our product development lifecycles. While at first blush these approaches seem focused on catalyzing process performance, in reality, each has a tangible impact on process stability and predictability. This stabilization is due to several factors. Mechanistic understanding allows any process to be better controlled. Whether the process is transactional, requiring an individual to complete a task and behave as expected, or a manufacturing unit operation essential to product performance, these improvement philosophies leverage the basic principle of standardized work practices. This approach is often captured under the umbrella of “Operational Excellence.”
Standardized work practices strive to design process steps that encourage or enforce execution the same way every time. From a Lean Manufacturing perspective, standardized work practices allow an operation to optimize its process velocity. From a Six Sigma perspective, it eliminates another source of variability that can cloud the true variability of the process. While traditionally applied to the process, these approaches can be extended to the design of the facility, creating an environment that is conducive to greater process and operational predictability.
FACILITY DESIGN CONSIDERATIONS
Applying the principles of Lean Manufacturing to facility design is nothing new. The Lean facility design roadmap mirrors the approach to standard facility design. While all facilities consider the operations that will take place in the facility, Lean design takes these considerations to a new level. Lean facilities marry classical design component criteria (material, personnel, equipment, and finished product flow) with operational considerations such as information flow, performance, and value stream measurement. This distinction is the essence of the competitive advantage created by Lean facilities.
The result of Lean facility design is an operation which is better aligned with needs of the business in terms of flexibility to respond to market fluctuations, reduced indirect and direct labor requirements, and better information process flow. In this era of dwindling equity markets for capital expansion, industry has no choice but to find a way to do more with less and move toward multi-functional facilities, often having to handle products with widely varying biosafety levels, manufacturing steps and escalating levels of complexity. Each of these challenges by itself represents a significant problem for controlling operating variation, but when combined, they can present an almost untenable scenario. Given the reality of this new marketplace, it is essential to look at new ways to apply the proven principles of operational excellence to minimize the impact of process and procedural variation.
FACILITY DESIGN AND TRAINING
Classical facility design exercises revolve around analyzing the process streams for the operation and building the support and information corridors around them. Lean facility design takes this one step further and seeks to optimize the relationship process requirements and business performance by eliminating inefficiency throughout the value stream for each product or process. There are several areas within facility design and construction that can be leveraged in terms of promoting process predictability, where the facility becomes a part of the overall cGMP training strategy.
ENSURING PROPER FLOW
As part of any cGMP operation, the recommended procedures for its operation will be dictated by the area-specific procedures. The facility, however, can complement this component by reinforcing the overall process flow. This can be achieved through several techniques:
Dividing the facility into zones that correlate with their corresponding unit operation is a basic way to reinforce to an auditor and to an operator the proper flow. These colors can also correspond to the ISO rating in each area, further reinforcing when a process moves from one level of environmental rating to another. While there is no formal rule for color selection, it is advantageous to move to lighter shades as you move to higher levels of cleanliness. For example, a compounding area that may have a rating of ISO 8 would have a darker color such as blue, while an aseptic filling operation with an ISO classification of 5 or 6 would be white. Corridors can also be used to visually indicate leaving one area of unit operation and entering the next, even if there is no change in area classification.
Similarly, utilizing color in a consistent pattern to identify ingress and egress through an area is a simple way to reinforce proper procedure. An example of using color as part of the facility design is shown in Figures 1 and 2.
In addition to color, proper practice can be reinforced by physically sizing material “pass-through” points differently than personnel access points. If material is introduced to an area on a cart or on a pallet, the dimensions of the access point should be sized appropriately, and if possible, in such a way that material cannot be easily introduced via personnel access points. This can be further complemented with color to designate material and equipment access points and clean or dirty access points.
Reinforcement of proper procedure should be able to be achieved without actually having to enter a controlled area. This allows supervisors and quality personnel to routinely ensure that individuals behave as intended when operating in a designated area. The use of viewing corridors is a simple but effective tool to reinforce to all personnel the principles of best practice. When identifying possible locations for viewing corridors, it is important to ensure that placement does not unnecessarily challenge the area’s HVAC system in terms of maintaining temperature control. An example of a viewing corridor is shown in Figure 3.
Establishing an effective training program is a fundamental component to an operation’s cGMP argument. In addition to the conventional program that reinforces knowledge and understanding of area- and process-specific procedures, we can complement this understanding in the basic design of the facility. The use of basic Lean principles will group operations in the most efficient manner to meet the needs of the business. Once this optimized relationship is established, the use of color can be a simple, effective tool to reinforce proper operational flow and to indicate critical area changes that require area-specific procedures. When combined with area-specific access sizing and strategically placed viewing corridors, the facility itself now becomes a key component to demonstrating and reinforcing compliance with your own operating and quality systems.
*Six Sigma is a trademark of the Motorola Corporation
Bikash Chatterjee is the president of Pharmatech Associates, Inc. He has been involved in the bio-pharmaceutical, pharmaceutical, medical device and diagnostics industry for over 20 years. His expertise includes site selection, project management, design, and validation of facilities for both U.S. and European regulatory requirements.