August 13, 2019

FDA Inspections and 483 Observations

Mark Dockter

Mark Dockter
Pharmaceutical Manufacturing Consultant/MD Pharma Consulting, LLC

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Title 21 of the United States Code of Federal Regulations, Part 211 (21CFR211) is entitled, “Good Manufacturing Practices.” These regulations are known as “GMPs” and are legal requirements for all manufacturers of drug products regulated by the FDA.  The FDA enforces the law through routine inspections of drug manufacturing facilities.

FDA inspections may be conducted without prior notification by the FDA.  Each inspection begins with inspectors identifying themselves and presenting their credentials along with a Form 482 notice of inspection.  If a drug manufacturer is out of compliance with GMPs, an FDA inspector will issue observations of non-compliance on form number 483.

During an FDA inspection, a company can request daily meetings with FDA inspectors to address daily observations. These meetings can provide the opportunity to avoid a 483 observation by addressing the specific observation while inspectors are present (if possible).  The daily meetings also serve as a way to avoid any surprises at the end of an inspection.

During the inspection, a company can also request to annotate any 483 observations made during the audit with their own comments. This can be very important in providing a complete understanding of each issue to personnel at the FDA district office who will review the 483 observations.  Annotations and responses to 483 observations should communicate recognition of the seriousness of each observation and the company's firm commitment to compliance.

After an FDA inspector formally presents a 483 to the company (at the end of the inspection), it is advisable to meet with subject matter experts and department management responsible for mediating each specific observation.  It is crucial to take the time to determine the root cause of each observation and then form a comprehensive plan (including a realistic time frame) for remediating each observation.  A comprehensive, well-reasoned response can prevent further action from the agency (e.g., the receipt of a warning letter).  The head of the facility or site head of quality should sign the response to the 483.

When each observation has been remediated, a comprehensive explanation must be sent to the FDA with evidence of compliance. For example, an observation may cite lack of a cleaning SOP for a certain piece of equipment. Along with the explanation of how the company is now in compliance, a company should send an effective SOP with records demonstrating that personnel have been trained and the equipment has been cleaned according to the new SOP (demonstrating that the company is now operating according the SOP).  Cleaning validation documents and analytical chemistry/microbiological test results from rinse samples must be sent demonstrating that the cleaning process produces effective and repeatable results.

When all 483 observations have been corrected to the FDA’s satisfaction, the FDA will provide the company with an Establishment Inspection Report (EIR).

IT'S ALL ABOUT THE DATA:

The FDA requires data from calibrated instruments and validated processes to ensure that the data is valid.  Objective, science-based data provides inspectors with an understanding of whether a facility is operating in a state of compliance with FDA requirements.  In one 483 observation an inspector wrote that the head of quality’s statements were “occasionally found to be inconsistent with observed information.” The inspector was compelled by the data, not the statements of the head of quality. In this particular case, the 483 was followed by a warning letter.  Warning letters, court ordered injections and consent decrees can all be avoided by presenting well-documented science-based compliance data in response to FDA Inspections and 483 Observations.

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