During this season of joyfully sending and receiving cards and letters to friends and family, let us not forget another kind of letter that can come to us, unexpectedly in the night, and keep on giving. Warning letters.
Every month FDA posts warning letters on their web site. These have a very long public lifetime: you can find letters in the database dating back to 1996. The letters are listed under Inspections, Compliance, Enforcement, and Criminal Investigations - not a section where I would want to see my company name. I frequently review newly-posted warning letters to see what kind of problems are prompting FDA to issue warning letters. That way, I can better help our clients avoid this type of pitfall when it's their turn to be inspected.
Hopefully you've never been issued a warning letter, so I'd like to walk you through what a typical one looks like. They start off innocently enough:
Dear [your CEO],
During an inspection of your firm located in [facility location], an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures [description of your product].
As applicable, they proceed to state the law under which your products are regulated and declare that your product is in fact a medical device. This finding alone may be a surprise to some companies.
The letter proceeds to say that your device is "adulterated" or "misbranded" or both. Then it describes in detail the evidence gathered to supports FDA's conclusions.
The letter will list violations, which typically include a citation of the regulation violated, followed by specific examples:
- Failure to establish and maintain adequate procedures for verifying the device design outputs meets the design input requirements, as required by 21 CFR 820.30(f).
- For example, the Device History File (DHF) for the [your study] for the [your product] did not include documentation that acceptance criteria were established for the study that was used in determining the dimensional characteristics of the product.
- Failure to establish and maintain adequate procedures for validating the device design to ensure that devices conform to defined user needs and intended uses to include risk analysis, where appropriate, as required by 21 CFR 820.30(g).
- For example, the design plan for the [your product] indicates that validation was completed on [date]; however, there was no documentation that the pre-determined user needs and intended uses were validated. A review of the risk analysis report and assessment stated that the hazard of [applicable hazard] would be mitigated by user training. There was no evidence of validation of the design for user needs and intended uses and no evidence that this risk was indeed mitigated.
- Failure to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test that the process is validated with a high degree of assurance and approved according to established procedure.
- For example, your firm failed to perform and document equipment cleaning validation for the production of [your product].
Some of the other issues I see written up repeatedly in warning letters include:
- Methods used in, or the facilities or controls used for manufacture, packing, storage, or installation are not in conformity with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (C.F.R.), Part 820.
- During an inspection your firm was unable to provide records to show qualification of the manufacturing processes for its intended use.
- Failure to establish and maintain adequate procedures for identifying valid statistical techniques required to establish, control, and verify the acceptability of process capability and product characteristics in production and process control systems, as required by 21 CFR 820.250.
- Failure to establish and maintain an adequate complaint handling system in which complaints are evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803, Medical Device Reporting, as required by 21 CFR 820.198(a)(3).
- Failure to establish and maintain adequate procedures for corrective and preventive action to ensure analysis of processes have occurred to identify existing and potential nonconforming product and to implement and record changes in methods and procedures needed to correct and prevent identified quality problems, as required by 21 CFR 820.100(a).
- Failure to establish and maintain adequate procedures for receiving, reviewing, and evaluating complaints, as required by 21 CFR 820.198.
Companies are required to respond in writing to warning letters within 15 working days. The response should describe the specific steps taken to correct the noted violations and explain how the company plans to prevent these or similar ones from occurring again. If your planned corrections will take some time to complete, a timeline for implementation should be included. You should also state the reason for the delay.
Fifteen days is never a lot of time for a busy IVD company to produce results like that. If you receive warning letter toward the end of the year, it can be the grinch that steals your entire company's holiday.
Fortunately, all of these potential violations are preventable issues with proper direction and planning during product development. Consider giving yourself and your staff a gift for next year and take care of your issues before you are inspected. There's nothing quite like the gift of having peace of mind to make the holiday season a happier time for everyone.