As Prescribed


On October 17, 2022, the US Food and Drug Administration (FDA) implemented revisions to two of its compliance policy guides (CPGs). CPGs are intended to advise FDA staff as to the agency's strategy when assessing and enforcing industry compliance. They typically establish FDA policy and interpretation where there is a need for clarification or to address other issues not covered by existing FDA laws, regulations, or guidance.

The revised CPGs—CPG 7346.832, which covers preapproval inspections (PAIs) and CPG 7356.002, which covers routine good manufacturing practice (GMP) drug inspections—were updated to address facility inspections through use of alternative tools, added sections covering nitrosamine risk assessments, and incorporated International Council for Harmonization (ICH) guidelines.

CPG 7346.832 – Preapproval Inspections

FDA has revised this CPG to fortify the agency’s risk-based approach to facility inspections. In determining whether to conduct a PAI, FDA uses four criteria: (1) an establishment’s readiness for commercial manufacturing; (2) whether the establishment has conformed to the application; (3) whether there are data integrity issues; and (4) the establishment’s commitment to quality in pharmaceutical manufacturing. To satisfy criterion two (2), establishments must now, in addition to existing requirements, verify that they have implemented a risk management system that ensures proper controls for hazardous impurities such as nitrosamines.

This CPG was also updated to expand the FDA’s toolbox for regulatory oversight, including requesting existing inspection reports from trusted foreign regulatory partners through mutual recognition agreements (MRAs) and other confidentiality agreements and conducting remote regulatory assessments (RRAs). Before inspecting a facility, FDA will use the information a company provides in its marketing application, in conjunction with any information FDA already has about the facility, to determine whether a PAI is necessary or if an RRA will suffice.

Additionally, this revised CPG also incorporates the ICH Q10 guidelines on pharmaceutical quality systems and the ICH Q12 guidelines on post-approval changes, which together, will “enhance industry’s ability to manage CMC changes effectively with less need for extensive regulatory oversight before implementation.”

CPG 7356.002 - Drug Manufacturing Inspections

This CPG revision is meant to “ensure that establishments consistently manufacture drug products of acceptable quality and minimize consumers’ exposure to adulterated drug products.” FDA has revised this CPG to explain how FDA may use MRAs and RRAs as part of the regulatory oversight program to support regulatory decisions, inform inspection planning, and verify certain information submitted to the agency.

As with the CPG on PAIs, this CPG now incorporates elements of the ICH Q10 guidelines on pharmaceutical quality systems, the ICH Q12 guidelines on post-approval changes, and additionally, on the ICH Q9 guidelines on quality risk management. It also adds a new section on evaluating an establishment’s quality risk management program to control nitrosamine impurities.

Key Takeaway

Throughout the COVID-19 pandemic, FDA relied on virtual facility inspections in lieu of onsite inspections. These two revised CPGs further show the agency’s commitment to establishing alternative tools to onsite inspections and importantly, reinforcing risk management among pharmaceutical establishments.