ABSTRACT
This article details a risk-based methodology designed to assign environmental classifications to the different operations in biopharmaceutical facilities manufacturing non-sterile (low bioburden) drug substance. Generally, environmental conditions for active pharmaceutical ingredient manufacture are established based on previous experiences or expectations or on extrapolated interpretations of current good manufacturing practices guidelines. Improvements in equipment design and operation, especially the use of closed systems, allow certain process steps to take place in controlled environment areas rather than in classified clean rooms. However, the design of facilities has not developed to reflect these technological advancements. The result is that facility designs are more complex with multiple environmental classifications, resulting in far higher capital and operational costs than necessary given the current technology and understanding. The authors propose a formal risk assessment-based methodology that is applicable in the early design phase of new facilities and facilitates the fast selection of the environmental conditions required for the different process steps. The risk assessment describes the risk to product quality or patient safety from environmental contamination, and this is expressed in terms of impact, probability, and detectability. The assessment considers growth potential in terms of time, nutrients, and temperature; bioburden limit; level of closure of the system; and the ability of the process to detect contamination to assign an environmental classification. Because closure is a key factor in the methodology, the authors propose a practical definition of closed systems, building on existing International Society for Pharmaceutical Engineering guidance. A fundamental of the assessment is that closed system operations only require controlled not classified environments, and any increase in classification does nothing further to protect the product. Results of the assessment are discussed in relation to a variety of process steps in different operating scenarios, to demonstrate how the assessment is applied. The methodology strongly supports the implementation of closed systems and demonstrates the limited need for classified areas. With fewer classified rooms, companies can reduce the complexity of facility layout and save costs without compromising patient safety or product quality.