Pre-Approval Inspection: The Three Objectives FDA Arrives With

A pre-approval inspection (PAI) is FDA's on-site check that the facility named in an NDA, ANDA or BLA can actually make the product you described, and that the data in the application is real.

It is not a general GMP inspection that happens to fall near an approval. It is an inspection of your application, conducted at your site, and its outcome gates the approval.

The three objectives

FDA's compliance program states them, and knowing them tells you how the visit will go.

1. Readiness for commercial manufacturing. Can this site make this product at commercial scale, under a quality system that works? Equipment, qualification, personnel, procedures.

2. Conformance to the application. Does what happens on the floor match what you filed? The investigator will pull the batch records for the exhibit batches and compare them line by line to the description in the application.

3. Data integrity audit. Is the data supporting the application complete and accurate? This is the objective sponsors underestimate, and it is the one that sinks applications.

Why the third objective is the dangerous one

The first two are about capability, and you generally know where you stand. The third is about whether the record can be trusted, and a finding there is not fixable with a corrective action plan.

What investigators look at:

• Audit trails on chromatography and other lab systems. Were they enabled? Can they be disabled? Who has the rights to?
• Deleted, reprocessed or reintegrated results, and whether the original is retrievable.
• Trial injections and unreported runs.
• Whether the ALCOA attributes hold for the data in the application: attributable, legible, contemporaneous, original, accurate.

A Form 483 citing data integrity at a PAI raises a question about everything else in the file, because the file is made of data.

When it happens

FDA has moved to a risk-based decision about whether an inspection is needed at all, and its revised compliance program is explicit about using alternatives to an on-site visit where the risk profile allows: records requests under section 704(a)(4), reliance on a recent inspection, or a mutual recognition partner's report.

The practical consequence is that you cannot assume a PAI, and you cannot assume its absence. Plan for one.

Preparing

• Reconcile the application against the floor first. Somebody should read the filed description and walk it against current procedure, looking for the places they have drifted apart. That drift is objective two.
• Run your own data integrity audit before FDA runs theirs, on the systems that generated the application data.
• Have the exhibit batch records assembled, with the deviations and investigations attached, not filed separately.
• Name a readiness team and subject matter experts in advance. An investigator asking a question and waiting twenty minutes for someone who knows the answer is its own finding.