FDA Warning Letters: Structure and the "Lessons Learnt" Effect

The Warning Letters are official deficiency letters from the FDA, which are sent to the companies concerned as a consequence of an unsuccessful inspection by the investigators of the agency. Before a Warning Letter is issued, the agency requests the company to comment on the deficiencies listed in Form 483 that were found during the inspection. If the FDA judges this response to be unacceptable, a Warning Letter will be issued.

FDA Warning Letter Structure

The GMP Warning Letters are usually formalised. They provide a structural framework through some standard formulations and are based on the following scheme:

1. Introduction:

• Indication of the inspected production site and the date of the inspection
• Indication of general violations against GMP requirements according to 21 CFR Parts 210 and 211.
• Confirmation with reference to the Food, Drug, and Cosmetic Act that the products manufactured at this site are not in compliance with GMP ("adulterated").
• Confirmation with brief justification that the company's response to the deficiency report (Form 483) sent out shortly after the inspection was reviewed and found to be inadequate.

2. Description of the GMP violations observed:

• General description of the deficiency, including the paragraph from 21 CFR 211 (usually highlighted in bold). "Your firm failed to..."
• Detailed description with information on the area, product batches, personnel present, documents and, in some cases, the sequence of a non-GMP-compliant procedure, etc.

3. Short description of the company's response to Form 483 regarding the GMP violation in question - "Your response stated that...".

4. Justification of the FDA why the response is considered "inadequate" - "Your response is inadequate...".

5. Request for additional documents - "In response to this letter, provide ...".

The detailed description of the inspection procedure (point 2) usually provides a lot of information about the approach of the inspectors, their questions and the answers or reactions of the interviewed employees of the company (sometimes the descriptions of individual situations even offer a certain entertainment value). The list of evidence requested by the authorities (point 5.) ideally complements this information. With this information, the FDA practically defines a catalog consisting of documents that the inspectors had expected during their visit to the site. This is almost always the same documentation for the individual areas.

Example: GMP violation of §211.100 Written procedures; deviations. (Subpart F-Production and Process Controls):

General description of the GMP deficiency

"Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess."

Request for documents ("In response to this letter, provide ...")

• A summary of the Process Validation Program. The program should include information on process performance qualification and continuous monitoring of intra-batch and inter-batch variations that demonstrate that the manufacturing process is under control throughout the life cycle of the product.
• Deadlines for process performance qualification for each drug on the market.
• Process Performance Qualification Protocols
• SOPs for the qualification of production buildings, rooms and equipment.

As part of the preparation for an FDA inspection, such a systematic analysis of FDA Warning Letters provides a useful "lessons learnt" effect, particularly with regard to the documents that must be made available upon request by the inspectors.

Note: In the next issue of the GMP Journal, you will find a detailed article on the systematics of FDA Warning Letters, including the most frequent GMP violations in the last few months. Please also see the latest issues of the GMP Journal.