There really is not much rocket science involved when attempting to determine the odds of a device establishment being awarded a prized agency warning letter when the establishment is on the receiving end of sixteen Form 483 observations during an inspection. The question needing to be asked is no longer if, but when the warning letter will arrive. Dr. D is absolutely sure that no Chief Jailable Officer (CJO) wants to be sitting across from an investigator from the United States Food and Drug Administration (a.k.a. FDA) when numerous investigational observations are being discussed. Seriously, these types of inspection wrap-ups truly “inhale greatly” a.k.a. they suck. Usually, there is not a whole heck of a lot of prep work the CJO is going to be able to perform prior to one of these difficult closeout meetings. The best practice is to be contrite, agree to quickly remediate the nonconforming practices, and if offered, fall onto the proverbial sword. Dr. D is just kidding about the sword. When a challenging inspection finally comes to an end; and the FDA investigator speaks with “apodictic” (look-it-up), magisterial certainty that that serious Quality Management System (QMS) violations warrant immediate attention, the CJO better be listening attentively. Enjoy!
Warning Letter – 25 September 2017
The warning letter referenced in this week’s guidance had fifteen inspectional observations noted against the Quality System Regulation (Part 820) and one Form 483 observation noted against Part 803 (Medical Device Reporting). When an inspection ends with sixteen inspectional observations, there is no need to blow the dust off the old crystal ball to see that bad news is in the offending establishment’s future. Now granted, old Dr. D was not at the inspection, so any comments made toward the level of compliance, or lack of, would be conjecture on the part of the old doctor. That being said, Dr. D will focus on one of the observations that fall into the doctor’s basic blocking and tackling bucket (something the San Francisco 49ers have clearly forgotten how to do, sorry SF fans). Calibration (metrology) is clearly a basic requirement needed to support any functional QMS. Observation twelve, extracted from the warning letter, depicts concerns raised by the investigator over the availability of calibration records; and a procedure that fails to address all applicable quality, regulatory, and statutory requirements. Collectively, Dr. D likes to call this stuff “documented evidence of compliance!” “In God We Trust, all others bring data” (quote by Deming).
Warning Letter Excerpt
Observation Twelve (12) “Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a). Specifically:
- Your pH Meters, used for testing of your products, reportedly require (b)(4) calibration by an outside calibration laboratory; however, this requirement is not documented in your Calibration Program procedure (SOP #40.002) and there is no requirement to ensure this (b)(4) calibration is performed as required. For example, the last three (b)(4) calibrations for the pH Meter with Serial #(b)(4) show that the meter was calibrated on (b)(4), no record of any outside calibration was available for (b)(4), and it was only calibrated by the outside calibration laboratory 25 months later on (b)(4).
- The Calibration Program procedure fails to require that the standards used for inspection, measuring, and test equipment are traceable to National or International standards, as specified by 21 CFR 820.72(b)(1). For example, the Weighing Scale Calibration Logs do not demonstrate that the standards used (calibration weights) are traceable to a National or International standard. (b)(4) calibration is performed on (b)(4) scales used for weighing raw materials for manufacturing. Additionally, the Scale Calibration Logs do not include a tolerance range or the actual weight measurements obtained to clearly demonstrate that the scales met specifications.
We have reviewed your response dated July 5, 2017 but cannot fully assess the adequacy of your stated corrective actions because you did not provide a copy of your revised Calibration procedure, SOP40.002. Your response indicates this procedure was revised to include the (b)(4) calibration by an outside firm. The procedure, and your ability to follow the procedure, will be evaluated during a future inspection.”
21 CFR, Part 820.72 – Inspection, Measuring, & Test Equipment
(a) Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all inspection, measuring, and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for its intended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained. The procedures shall include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are maintained. These activities shall be documented.
(b) Calibration. Calibration procedures shall include specific directions and limits for accuracy and precision. When accuracy and precision limits are not met, there shall be provisions for remedial action to reestablish the limits and to evaluate whether there was any adverse effect on the device’s quality. These activities shall be documented.
Compliance for Dummies
It is Dr. D’s opinion: calibration is one of the easier QMS requirements to achieve compliance. Device establishments have two options: (a) equipment requiring calibration can be outsourced to a qualified metrology laboratory (ISO/IEC 17025:2005 accredited); or (b) equipment requiring calibration can be calibrated in-house. However, regardless of the choice, a well-written procedure addressing the entire calibration process is required including:
- Ensuring equipment selected is suitable for its intended use;
- Ensuring equipment is routinely calibrated, inspected, checked, and maintained;
- Ensuring calibration procedures (if deemed applicable) have established requirements for equipment accuracy and precision;
- Ensuring calibration standards are traceable to a national or international standard (can you say NIST?);
- Validating the use of in-house calibration standards and procedures, as appropriate; and
- Maintenance of impeccable calibration records (equipment identification, calibration dates, the individual performing each calibration, and the next calibration date).
The good news is that most qualified metrology laboratories provide the records and create on-line accounts so that their client base has access to calibration records. This type of access is a CJO’s best friend during an agency inspection, notified body audit, or any other type of regulatory assessment. In Dr. D’s backyard (the left coast of the United States) metrology services such as Simco Electronics, RS Calibration, and Precision Measurements, Inc. ensure that their customers are able to remain compliant with applicable quality, regulatory, and statutory requirements as they pertain to calibration. Sure, metrology support can be an expensive endeavor; however, partnering with a qualified metrology laboratory is money well spent (Dr. D’s humble opinion).
For this week’s guidance, the doctor will leave the readers with two takeaways. One – Dr. D hopes that none of the readers will ever have to deal with a warning letter that is comprised of sixteen inspectional observations. The number sixteen will equate to some serious sleep deprivation for the CJO and his or her team, tasked with navigating the treacherous regulatory waters surrounding the correction of sixteen inspectional observations. Two – by partnering with a qualified metrology service, device establishments can better position themselves in regard to complying with §820.72 requirements. Please keep in mind, a well-written procedure will be required; however, the doctor is quite sure a metrology lab will be a valued partner that can help with the scripting of the SOP. In closing, thank you again for joining Dr. D; and the doctor hopes you found value (and some humor) in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.
- Code of Federal Regulation. (2017, April). Title 21 Part 820: Quality system regulation.
Washington, D.C.: U.S. Government Printing Office.
- Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
- Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
- FDA’s enforcement page. (2017, September). FDA.gov Website. Retrieved November 6, 2017,