Lessons Learned from FDA Warning Letters

Many of AWPT’s customers are required to adhere to The FDA’s Code of Federal Regulations (CFR) for their calibration activities. As a helpful exercise, AWPT collaborator Walter Nowocin, Life Sciences Product Manager at IndySoft Corporation, collected information from several real but anonymized FDA warning letters to better understand what circumstances led to these letters. Below are four excerpts from those FDA warning letters, with identifiable information redacted, accompanied by comments on how the problems cited in these warning letters can be avoided. 

Understanding calibration best practices is crucial to the smooth operation any laboratory, and proper training is the most proactive way to anticipate and avoid similar problems. If any of these scenarios sound familiar, consider how you might be able to empower your staff with more comprehensive training, and avoid a warning letter in the future. 

Excerpt 1: Validation 820.75(a)   

“Your firm's protocol, [redacted], required that all report data sheets must be signed and dated by the individuals responsible for recording and verifying the data during test execution. The protocol also requires that the equipment used, and its calibration status, be recorded on the test forms. Your firm failed to document the execution of its protocol. The dates of testing, the individual conducting the visual inspection testing, the individual conducting the tensile testing, the equipment used, and the calibration status were not recorded.” 

In this case, the firm in question failed to follow their own protocol. Many FDA findings have to do with organization not adhering to their own processes and procedures. This specific example is related to 21 CFR 820.75(a), failure to ensure, when the results of a process cannot be fully verified by subsequent inspection and test, that the process shall be validated with a high degree of assurance and approved according to established procedures. 

Excerpt 2: “Calibration Not Needed” 820.72(a)         

“Your firm released to production processing instruments capable of calibration and labeled them as "Calibration Not Needed" without documenting a justification as to why these instruments used to manufacture media used in the production of identification and antibiotic susceptibility testing cards did not need to be calibrated. Calibration of an instrument at appropriate intervals ensures the instrument will continue to provide accurate measurements over time.” 

This firm failed to adequately establish procedures to ensure their equipment was routinely calibrated and inspected, as required by 21 CFR 820.72(a). This firm indicated that certain equipment did not require calibration, without providing a clear justification as to why it didn’t. It’s theoretically possible that the firm’s assertion was correct, but because calibration is so crucial to producing valid results, the claim that something needs no calibration would require a clear and well-documented justification. 

Excerpt 3: Out of Tolerance (OOTs) 820.72(b)   

“A review of the calibration certificate for the [redacted], dated May 16, 2012, indicated that the [redacted] meter was found to be out of tolerance and was used to [redacted] calibration of [redacted] on March 29, 2012. However, your firm's in-house calibration procedure does not include any instructions as to the steps to be taken when the [redacted] is found to be out of calibration.” 

Performing out-of-tolerance (OOT) investigations when calibration parameters are found to be out of specification is an essential calibration requirement. The part of the CFR that addresses this is 21 CFR 820.72(b) which specifies that laboratories must establish and maintain calibration procedures that include specific provisions for remedial actions to reestablish the limits and to evaluate whether there was any adverse effect on the device's quality, when accuracy and precision limits are not met. 

Excerpt 4: Calibration and Monitoring 820.72(a)  

“Your firm calibrated its incubators, [redacted] and [redacted], at a range of [redacted], per "Routine Calibration Inspection Procedure Check Sheet". However, your firm did not calibrate these incubators to include the biological indicator [redacted] respectively. Also, your firm did not monitor the incubation temperature utilized for bio-burden testing.” 

For the type of work they are doing, the FDA expects this company to monitor the incubation temperature while performing a bio-burden test, in addition to periodic calibration. The environment that any test is conducted in has an impact on the outcome, and specialized environments require specialized monitoring to ensure they can produce valid results. It is the laboratory’s responsibility to ensure that all inspection, measuring, and test equipment, is suitable for its intended purposes and is capable of producing valid results, and to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a).  

These are only a few examples, but they provide insight on how the CFR is applied in different scenarios and can serve as a thought exercise for examining the practices and procedures in your own facility. An effective audit can uncover such problems before they have an impact on your work, and a well-trained staff is more apt to recognize bad practices before they become routine. To help develop your staff’s calibration skills, consider the e-learning options offered by AWPT at a2lawpt.org/e-learning