The pharmaceutical market today can be considered a true global marketplace. While the U.S. remains the largest market in the world, the emerging markets are growing rapidly and narrowing the gap, with China to become the second largest pharmaceutical market by 2015. In this global expansion, companies are building facilities with the intent of supplying drug therapies to multiple markets that are governed by different regulatory authorities. With harmonization of regulations in the United States, Europe, and Japan progressing over the past 20 years, harmonization process efforts have only begun to take hold in the last five years in the emerging markets. For some markets harmonization may not be truly achievable yet and the convergence of regulations may be a more practical reality. These moving parts greatly complicate the challenges of establishing manufacturing operations capable of supporting multiple markets.
Recently, I was involved in the design of a large scale biotech facility in China as part of a large U.S.-Sino endeavor. The phased business plan for this organization included an initial design objective to create a facility at small volume capable of meeting the Chinese SFDA regulatory standards. Because the next markets envisioned for this operation were Europe, then the U.S., our design objective was to establish a Basis of Design (BOD) that would satisfy all three regulatory requirements.
The challenge is that the underlying philosophy behind these regulations varies. The USFDA relies heavily on room pressurization as the foundation for ensuring a GMP environment, while the EMA relies upon an escalating cascade for room cleanliness. These two requirements are not discontinuous but, if they are not considered at the outset, the ability to retrofit an area can be very difficult and costly. The new SFDA guideline is called GMP10 and very closely reflects the same design philosophy as the WHO and EMA, however, the enforcement of this new guideline is being implemented based upon the SFDA’s interpretation of public risk. Consequently, interpretation of the new guidelines can vary from product to product and by regional office. Complicating matters is the historical legacy of the SFDA’s guidelines prior to the issuance of the GMP10. Many of these regulatory design criteria were born from infractions and transgressions encountered by regional offices and hence do not have a solid foundation in scientific theory from a design and control perspective.
Establishing a multi-market basis of design (BOD)
For multi-market facilities there are several activities within the establishment of the BOD critical to managing business and program risk:
1. Volume and Product Mix Programming
2. Process User Requirement Specification
3. Risk Management Plan Development
Volume and product mix programming
Most facility development programs begin with a programming exercise. Multi-product, multi-market plans often carry with them the compliance differences that correspond to the proposed market. For example, designing a receiving area for satisfying the PIC/S or Japanese Ministry of Health requirements of labeling control is potentially very different from trying to satisfy the security and control requirements of the USFDA. Similarly, as the product mix increases in complexity, so potentially does the space and facility classification requirements. Having a clear understanding of these differences will maximize the usefulness of the facility and reduce the risk of non-compliance during a pre-approval inspection.
Process user requirements specification (Process URS)
The Process User Requirements Specification captures the environmental, operational, flow, and utility requirements for each unit operation of a process. This summary, developed room by room, is the foundation for satisfying the disparate requirements of different regulatory philosophies. For example, a Class 1,000 (ISO 6, EMA Grade B) area which houses a Class 100 (ISO 5, EMA Grade A) BSC may only concern itself with air changes and particulate counts to satisfy the USFDA requirements. For EMA, classifying the area as Grade B involves additional requirements, such as a dedicated gowning and de-gowning area, and dedicated material pass-through area. In addition, the adjacent areas must complete the cascade as the product moves toward the Grade A processing environment. If the facility is intended to build product for the SFDA or Japanese Ministry of Health, an air shower may be required as well. Framing the Process URS at the BOD level allows the tradeoffs necessary to manage project risk.
Risk management plan
To navigate potentially contradictory requirements requires a clear scientific and compliance rationale. The Risk Management plan should address operational and process related risks to the product at each unit operation. As an example, in the purification operation of a mammalian cell culture operation, it is customary to separate the pre-viral and post-viral operations procedurally and physically, and to escalate the room classification from Grade C to Grade B. Where the separation should be implemented is not specified. Some facilities may place the separation after the first viral inactivation step, which only results in a 1-2 log reduction. Others will place the separation after the final diafiltration step because this is where the true final log reduction is achieved. Linking the basis for the separation with a comprehensive risk management plan will allow design differences to bridge differing regulatory guidance.
The final element to keep in mind when designing facilities for multiple markets is that regulatory compliance requirements continue to evolve. What is considered marginally acceptable today may be unacceptable in the next iteration of guidance. Wherever possible, adopting a design solution based on sound scientific and quality principles will ultimately be the best hedge against evolving standards and is the best way to meet the demands of multiple regulatory authorities in a pre-approval inspection.
Bikash Chatterjee has been involved in the biopharmaceutical, pharmaceutical, medical device, and diagnostics industry for over 30 years. His expertise includes site selection, project management, design, and validation of facilities for U.S. and European regulatory requirements.
This article appeared in the March 2013 issue of Controlled Environments.