How to Respond to an FDA 483 Observations?

 

GMP deficiencies are sometimes found during FDA inspections. It is important to respond to this deficiency report, otherwise a Warning Letter may be issued. 

As the FDA inspector wraps up the inspection, he will share with you a summary of his observations. In the event that the inspector found issues, he will discuss and provide a draft of FDA Form 483 Inspectional Observations. The inspector will ask if you agree to correct the issues and record your responses. 

But how should one respond?

The example of a manufacturer who had no validation of his manufacturing process is a good illustration of how not to respond to FDA "findings".

Besides the lack of process validation, the FDA also criticised the lack of qualification protocols and reports as well as the lack of acceptance criteria showing that the manufacturing process was in "state of control". Furthermore, the holding time of the bulk was not validated.

As a remedy, the company said it would hire a third party to assist with validation. This was not enough for the FDA.

The authority demand for such finding:

• A detailed overview of the validation programme with the appropriate written instructions
• A detailed programme for development validation, maintenance, control and monitoring of each manufacturing process
• The process performance qualification (PPQ) programme
• The continuing monitoring programme for intra-batch and inter-batch variability
• A timeline for the implementation of PPQ for each marketed product PPQ protocol(s)
• A programme for equipment and facility qualification and written instructions for these activities

Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs.

For bulk holding times, the FDA requested a description of how time limits are set for these. In addition, a retrospective evaluation of manufacturing activities is required with the aim of identifying possible effects on the stability and quality of the medicinal products.

In respond to FDA 483 inspection observations following steps are to be taken:

• Establish a Timeline for Response Activities
• Identify Root Cause
• Issuing CAPAs
• Establish a Timeline for Addressing 483s
• Draft Initial Response Letter
• Consistent Follow Up
• Get Ready for Re-inspection

In response to "findings", the FDA would like to see detailed documents on how these "findings" are remedied. Furthermore, it is often necessary to look back to see whether the defects have had an impact on the products manufactured to date.

Related:

• FDA Inspection Checklist
• Trends of FDA Warning Letter
• FDA Inspection Database
  
• Preparation for Pre-Approval Inspection