FDA revises Guidance Document on Pre-Approval Inspections

In 2002, the FDA announced its new initiative called Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century. In accordance with this initiative, the Compliance Program Guidance Manual on Pre-Approval Inspections was issued, including scientific, risk-based approaches that incorporate inspection of the level of the firm's process and product understanding, an evaluation of the firm's manufacturing readiness, and verification of authenticity of submitted data. The Guidance Manual is addressed to FDA staff but gives industry a good source of information of the process of a pre-approval inspection.

The U.S. Food and Drug Administration has now revised this Compliance Program Guidance Manual on Pre-Approval Inspections. The Guidance document has been completely reworked and will be implemented on 5 December 2010. The date for completion is 5 November 2012.

The objectives are:

  • Readiness for Commercial Manufacturing with its areas investigations, raw material handling, cross-contamination, SOPs and scale-up and process validation
  • Conformance to Application
  • Data Integrity Audit

With the new approach, FDA won't necessarily need to cover all of the objectives (as was done in the past). This will depend upon a risk-based decision.

Here are some other major changes:

  • The establishment inspection report (EIR), FDA-483, and coversheet need to be forwarded to CDER/DMPQ/New and Generic Drug Manufacturing Team (NGDMT) within 30 business days.
  • For an inspection that might result in an OAI status ("official action indicated"), whether or not the inspection is associated with a pre-approval inspection, the Pre-Approval Program Manager (PAM) of the respective District Office must enter a "Potential OAI Alert" into EES as soon as possible. This includes any cGMP surveillance inspection!
  • Definition of the two types of pre-approval inspections performed: Priority and Discretionary. With the new document, FDA is taking a more risk-based approach., defining nine criteria which require a Priority Pre-Approval Inspection if any of those criteria are met (the criteria are defined under section 2.2.1 of the document with the respective Program Management Instructions under 2.3 of the document).
  • CDER has initiated a "Knowledge Transfer Program" to enhance the risk-based focus of drug pre-approval inspections. Specifically, CDER staff will alert the inspection team to manufacturing and laboratory issues found during the pre-market application review.
  • Part 3 "Inspectional" is now describing in detail inspection scheduling and preparation, composition of the inspection team and the inspection strategy based on the objectives named above.

Very interesting is section 3.4 with respect to inspection coverage and techniques, defining in detail what to look for and how to proceed to determine and verify for example

  • whether the establishment(s) has a quality system that is designed to achieve sufficient control over the facility and commercial manufacturing operations.
  • that the formulation, manufacturing or processing methods, and analytical (or examination) methods are consistent with descriptions contained in the CMC section of the application for the biobatch (and other pivotal clinical batches, when applicable), the proposed commercial scale batch, and the API(s).
  • integrity of raw data and all relevant data

In this context, also other drug products may be reviewed to evaluate the firm's capabilities and procedures.

After the inspection is conducted, investigators communicate findings primarily through establishment inspection reports (EIRs). Telephone calls, emails, or EES (Establishment Evaluation System) are often used for timely update of CDER on problematic findings. When the inspection reveals a potentially violative cGMP finding, or data integrity issues, the district should enter a "Potential OAI Alert" into EES as soon as possible. Any reportable inspection observations will be issued via an FDA-483. In the new document, examples of types of findings are listed which should appear on the FDA-483.

Attachment A of the document gives a comprehensive overview of the responsibilities of the on-site inspection team and the CDER CMC Review and Assessment.

Attachment B describes pre-approval sampling and gives examples.

The Compliance Program Guidance Manual on Pre-Approval Inspections can be found here.

At the ECA Education Course on GMP- and FDA-Compliance in Pharmaceutical Development and IMP Manufacturing (23 - 24 September 2010 in Vienna, Austria), a former FDA Investigator and Compliance Officer will give a presentation on the FDA Pre-Approval Inspection (PAI):

  • Involvement of the R&D Department
  • What the FDA will look for
  • What happens at FDA during and after the PAI
  • Responding to FDA after the PAI

Wolfgang Schmitt
On behalf of the European Compliance Academy (ECA)

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