The US regulatory environment for chemistry, manufacturing, and control (CMC) issues is changing rapidly, driven largely by FDA's new Pharmaceutical Quality for the Twenty-First Century initiative. Under this system, changes to API processes will be assessed on the basis of risk with regards to concepts of quality-by-design (e.g., design space, critical process parameters, process analytical technology [PAT]) that are used to develop robust API manufacturing processes. Accordingly, it is understood that a future FDA guidance addressing both API documentation for original new drug applications and postapproval changes might be appropriate under the new system. For some period of time, however, there will be many legacy products on the market for which more traditional development principles were followed. For such products, the present discussion would be applicable in terms of defining potential areas for regulatory clarification and relief.
The PhRMA BACPAC II Working Group identified the following important concepts, which industry hopes FDA will consider during the development of the new BACPAC II guidance:
PhRMA believes that this decision tree represents an approach that will provide clarification and regulatory relief for industry while respecting the concept that the later in the process that a change occurs, the more significant the potential for adverse impact. Nonetheless, it is also reasonable to believe that the proposals contained herein representing late-stage regulatory relief can be achieved without compromising quality or public safety, particularly because all changes will require data to demonstrate that there is no adverse effect.
The PhRMA Working Group recommendations focus on the determination of the filing category. It is fully recognized that ultimately BACPAC II, as in BACPAC I, also will contain guidance for supporting data to be included in the regulatory submissions. Although the latter is not discussed in detail in this article, the group requests that FDA also consider the nature and potential influence of the change in determining its recommendations for supporting data.
In general, PhRMA believes that, other than in cases of changes with high potential risk (e.g., prior-approval changes), drug product data should not be required in support of the regulatory filing for API changes. Acceptance of this point lies in the concept that all relevant API (or any post–final intermediate) quality standards be identified and included in pre- and postchange quality comparisons. As we discuss, such relevant quality standards may extend beyond regulatory specifications and must be carefully assessed on a case-by-case basis.