The US Food and Drug Administration has issued a Guidance for Industry entitled BACPAC I: Intermediates in Drug Substance Synthesis (1) but has yet to issue a companion document that would cover postapproval changes from the final intermediate to the active
pharmaceutical ingredient (API). Because of the significant value in a guidance that will provide clarification as well as
regulatory relief for late-stage API postapproval changes, the Pharmaceutical Research and Manufacturers of America's (PhRMA's)
API Technical Group assembled a working group to compile industry recommendations for consideration by FDA in the development
of BACPAC II, as it had done for BACPAC I (2).
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:
- A decision-tree approach would allow for an easy-to-follow pathway to decision-making in determining a filing category based
on a logical assessment of risk.
- Changes can be categorized as site changes, specification changes, and process changes.
- A quality evaluation pre- and postchange is required for an adequate assessment of risk.
- For any change in which a comparable or higher level of quality cannot be ensured, a prior approval supplement (PAS) is required.
- The effect of changes in analytical methods can be adequately assessed using current scientific principles, including validation.
- Risk assessment should be considered in determining filing categories. The proposals made herein identify but limit those
changes that are considered to have a significant potential to adversely affect quality, thus requiring a PAS.
- The "last true solution" (LTS) should be used as an additional point in the assessment of potential risk to API quality.
To show how these concepts can be applied, the PhRMA Working Group has developed a proposed BACPAC II decision tree and has
worked with a specifications and BACPAC Working Group operating under the direction of the Product Quality Research Institute
(PQRI). The PQRI group also has developed a BACPAC II proposal that is fundamentally aligned with this position paper.
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.