Data Integrity: FDA 483s and Warning Letter Trends

Mack Powers | January 20, 2022

As the FDA continues to ramp up its data integrity enforcement efforts, companies in the pharma, biotech, and food manufacturing industries need to be aware of the warning letter trends for 2020 and 2021. In this post, we’ll take a look at the most common issues that have led to FDA 483 warning letters in recent years, and provide tips on how to avoid them. 

483 Forms

FDA initially issues 483 form observation reports (483 forms) as a non-punitive way for companies to improve their processes. Unfortunately, some companies do not give these enough consideration and ultimately experience negative consequences.

483 letters are typically issued when an inspection finds significant violations of cGMPs or other regulations. Common 483 letter issues are related to data integrity, manufacturing process deviations, and product quality problems.

The good news is that if the issues are addressed  in a timely manner, the company can often avoid more serious enforcement actions by the FDA. If the company takes action right away, then this letter will not escalate into a warning letter or worse (a recall). FDA 483 form letters are simply advisory notices about observations from inspections that need to be addressed. The goal is for companies to use them as opportunities for improvement, not as a reason for panic. Remember, the key is to be proactive!

FDA Warning Letters

A 483 warning letter is a formal notification from the Food and Drug Administration (FDA) that identifies serious regulatory violations. The letter is Issued by ORA Investigators and is considered an escalation from a 483 observation. The notification typically contains a list of observations made during an inspection and often provides the recommended corrective actions.

Data Integrity Violations:  Violation Triggers

  • Falsifying data
  • Manipulating test results
  • Changing record data or omitting data
  • Improperly creating or maintaining records
  • Failure to establish and follow proper procedures for handling, storing, and retrieving data.
  • Submitting false or misleading information to the FDA.
  • Improperly maintaining equipment or failing to follow standard operating procedures.
  • Misbranding drugs or food

FDA 483 Form:  Corrective Actions

If you receive a 483 form letter, it’s important to take action right away. Here are some steps that you can take:

  • Review the observations listed in the letter and determine which ones need to be addressed first
  • Create a plan of action for addressing the observations
  • Implement the plan of action
  • Submit documentation to show that the observations have been addressed
  • If you’re not sure how to address an observation, seek help from a qualified consultant or regulatory expert

Responding to a 483 Warning Letter

The first step in addressing Form 483 is to respond verbally to the findings at the end of the inspection. This can help identify and clarify any potential issues. Company executives and administrators need to clarify any misunderstandings and identify any issues that were found during the inspection.

Next, a written response should be sent within 15 days of receiving an FDA 483 warning letter. Even though it’s not required by law, this is a proactive step to potentially prevent further action from being taken by the FDA against a company or business owner.

In the response, your company should stress the importance of solving the issues as quickly and effectively as possible. Information on causes, corrective actions, and remedies already in place should be included in the response. If changes or resolutions can not be implemented immediately, then the document should provide a time frame for making changes with target dates if possible.

All issues should be corrected and documented prior to the re-inspection. The plan for correcting the issues should be as specific as possible.  In addition, great care should be taken in explaining how all global changes were addressed. Provide hard copies of any records showing corrections if possible. The FDA will follow up on promised corrections during the re-inspection, which will usually occur within the first year following the issuance of the letter. This is standard practice.

In addition, the company should prepare a list of all corrective actions taken in response to any unsanitary conditions or deviations from cGMPs that were found during the inspection.  The company should provide documentation supporting this information. The FDA will review your responses before making an assessment on further action against your company.

FDA Warning Letters and Inspection:  Observation Trends

The FDA has been very active in issuing warning letters over the past two years. In 2020, there were 81 warning letters issued.  In 2021, it is clear that the FDA will exceed that number. 

The following are some of the most common inspection observations that have led to warning letters:

1) On NOVEMBER 09, 2020, A warning letter was sent to Tarmac Products, Inc. for failing to keep complete laboratory records of test processes and test procedures as required by 21 CFR 211.194(a).

The FDA also accused the company of failing to maintain a stability testing program in place to assess drug products’ stability (21 CFR 211.166(a)), as well as of violating 21 CFR 211.160 (b), which calls for the establishment of scientifically rigorous laboratory controls to verify compliance with data identification, strength, quality, and purity standards.

2) On JANUARY 09, 2020, FDA sent a CAUTION letter to Huaian Zongheng Bio-Tech Co.Ltd,  stating that the firm had failed to establish sufficient written procedures for production and process control to guarantee that the drug products it manufactures meets (21 CFR 211.100(a)) requirements.

3) On AUGUST 17, 2021, a warning letter was sent to Adamson Analytical Laboratories, Inc. that stated that the firm did not use adequate security procedures to guarantee that only authorized personnel made changes to master production and control records or other documents (21 CFR 211.68(b)).

4) According to the warning letter dated SEPTEMBER 24, 2021, Chameleon Beverage Co. Inc. dba Chameleon Sanitizer Corporation was notified (21 CFR 211.67(b)), of failing to maintain or use adequate written procedures for cleaning and maintenance of equipment.

5) A NOVEMBER 8, 2021 warning letter addressed to Global Sanitizers LLC stated that the company had failed to fulfill (21 CFR 211.22) requirements, implying that it had no written procedures describing the responsibilities of the Quality Unit. The letter also stated the company lacked written batch records, processes, or other documentation to back up manufacturing operations carried out at the site.

The above examples show the common trend of FDA warning letters; namely, the FDA is focusing on specific areas of 21 CFR 211 cGMP standards during inspections. Companies should take note of these common inspection observations and adjust protocols accordingly.

The FDA’s warning letter trends are an important factor for companies to consider when planning their data compliance strategies. Understanding the regulator’s perspective is crucial in boosting compliance and avoiding enforcement activities that can result in costly fines, penalties, and seizures.

If you have received a warning letter from the FDA, please do not hesitate our expert team. We have extensive experience working within the Food, Pharmaceutical, and Biotech industries.  We can work with you through every element of these often complicated and complex procedures to ensure your compliance and business viability. 

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