Drug manufacturers looking to avoid Form 483s take note: the US Food and Drug Administration (FDA) has recently tweaked its compliance guide on pre-approval inspections, which according to one consultant will impact analytical procedures and data included in regulatory submissions.
A pre-approval inspection is performed by FDA to ensure that a manufacturing establishment named in a drug application is capable of manufacturing a drug, and that submitted data are accurate and complete.
The front of the updated compliance guide, which was first released in September but which will not fully take effect until 16 September 2022, explains the changes: “Revision: Program revised to add instructions for potential official action indicated (pOAI) reporting responsibilities and to align with the Center for Drug Evaluation and Research (CDER) and Office of Regulatory Affairs (ORA) agreement Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of Operations.”
The 46-page guide also explains on its last page how the updates include redefined collaborations and shared responsibilities between CDER and ORA for determining and conducting an inspection, as well as updates to field reporting requirements, including updated instructions for pOAI reporting responsibilities.
And although the 2022 deadline may seem far away, the guide says the initial implementation date is 16 September 2019 and consultant R.D. McDowall explained in Spectroscopy how what’s in the guide will likely be phased in over time and how “any analytical development work conducted that is part of a regulatory submission to the FDA” comes under this new version of the guide and, “Such work may be inspected against these more detailed requirements.”
The new guide also discusses its three objectives: 1: Readiness for Commercial Manufacturing (i.e., “Determine whether the establishment has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operation”); 2: Conformance to Application (i.e., “Verify that the formulation, manufacturing or processing methods; analytical (or examination) methods; and batch records are consistent with descriptions contained in the CMC section of the application”); and 3: Data Integrity Audit (i.e. “Audit and verify raw data at the facility that are associated with the product.”).
For the third objective, McDowall notes that the guide now shows some indicators of possible laboratory data integrity problems. And if data are unreliable, the new version of the guide suggests that an inspector can expand the coverage of the inspection to marketed products under Compliance Program 7356.002 for Drug Manufacturing Inspections, or that FDA can invoke the Application Integrity Policy.
“If either of these occur, the laboratory has begun the long and very uncomfortable descent into inspection hell,” McDowall writes.
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