Covid did not slow down FDA 483 letters!

As we review FDA 483 letters we quickly see no slow down due to Covid-19!

FDA 483 letetrs_summary_alliance calibration

Let's start with a review of CFR Title 21.

§ 58.63 Maintenance and calibration of equipment.

(a) Equipment shall be adequately inspected, cleaned, and maintained. Equipment used for the generation, measurement, or assessment of data shall be adequately tested, calibrated and/or standardized.

(b) The written standard operating procedures required under § 58.81(b)(11) shall set forth in sufficient detail the methods, materials, and schedules to be used in the routine inspection, cleaning, maintenance, testing, calibration, and/or standardization of equipment, and shall specify, when appropriate, remedial action to be taken in the event of failure or malfunction of equipment. The written standard operating procedures shall designate the person responsible for the performance of each operation.

(c) Written records shall be maintained of all inspection, maintenance, testing, calibrating and/or standardizing operations. These records, containing the date of the operation, shall describe whether the maintenance operations were routine and followed the written standard operating procedures. Written records shall be kept of nonroutine repairs performed on equipment as a result of failure and malfunction. Such records shall document the nature of the defect, how and when the defect was discovered, and any remedial action taken in response to the defect.

[43 FR 60013, Dec. 22, 1978, as amended at 52 FR 33780, Sept. 4, 1987; 67 FR 9585, Mar. 4, 2002]


§ 820.72 Inspection, measuring, and 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.

(1) Calibration standards. Calibration standards used for inspection, measuring, and test equipment shall be traceable to national or international standards. If national or international standards are not practical or available, the manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall establish and maintain an in-house standard.

(2) Calibration records. The equipment identification, calibration dates, the individual performing each calibration, and the next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the equipment.

§ 111.35 Under this subpart D, what records must you make and keep?

(3) Documentation of any calibration, each time the calibration is performed, for instrumentscalibrated; (ii) Provide the date of calibration; (iii) Identify the reference standardrecertification of accuracy; (iv) Identify the calibration method used, including appropriate limits

 § 111.117 What quality control operations are required for equipment, instruments, and controls?

Periodically reviewing all records for calibration of instruments and controls; (c) PeriodicallyPeriodically reviewing all records for calibrations, inspections, and checks of automated

§ 120.11 Verification and validation.

unidentified critical control points; (ii) The calibration of process monitoring instruments; (iii)120.25. (2) Records that document the calibration of process monitoring instruments, in


§ 1.1101 What documents are incorporated by reference in this subpart

requirements for the competence of testing and calibration laboratories, Third edition, November


§ 106.100 Records.

accuracy check, the standard used, the calibration method used, the results found, any actionsthe instrument is found to be out of calibration, and the initials or name of the individualindividual performing the test. If calibration of an instrument shows that a specification


As you can see, calibration is mentioned more than a few times in CFR Title 21.


Let's start with some immediate must haves.

Use an ISO 17025 accredited calibration laboratory. 


21 CFR 113.100(c)(3) The identity of the reference device, equipment, and procedures used for the accuracy test and to adjust the temperature-indicating device or, if an outside facility is used to conduct the accuracy test for the temperature-indicating device, a guarantee, certificate of accuracy, certificate of calibration, or other document from the facility that includes a statement or other documentation regarding the traceability of the accuracy to a National Institute of Standards and Technology (NIST) or other national metrology institute standard;


How do you know if your calibrations include traceability?

All ISO 17025 accredited calibrations must include traceability through NIST or another NMI( National Metrology Institute) to the SI unit. There should be a statement of traceability on the calibration certificate issued. If you do not see this statement in is a red flag. You need to ask your calibration provider why it is not there.

You might want to read What is traceable to NIST standards?


With that background in place, what can we discover about 483 letters than mention calibration?


Below are actual citations from 483 letters.

" Your response acknowledges that the use of ancillary equipment is not documented in your batch records. However, you failed to include systemic corrections to your batch records and documentation systems to ensure traceability of each piece of equipment used during manufacturing, including but not limited to, their use, cleaning, sanitization, calibration, and maintenance."

"Failure to maintain records concurrently with the performance of each step required in Subpart D and Subpart C of 21 CFR 1271. The records must identify the person performing the work and the dates of the various entries, and must be as detailed as necessary to provide a complete history of the work performed and to relate the records to the particular HCT/P involved [21 CFR 1271.270(a)]. For example, you have not maintained complete records that include, but are not limited to, the following:  

a.    Facility cleaning and sanitation [21 CFR 1271.190(d)];
b.    Environmental control and monitoring activities [21 CFR 1271.195(d)];
c.    Equipment maintenance, cleaning, sanitizing, and calibration [21 CFR 1271.200(e)];"

"Additionally, you did not provide recent calibration information for your equipment, including the scales used to weigh active drug ingredients in the manufacture of your drug products. "

"The records and information you submitted demonstrate that you lack an adequate quality unit (QU). For example, your firm failed to provide adequate written procedures for QU responsibilities such as batch record review, supplier qualification, equipment qualification and calibration, process validation, cleaning validation, and annual product review."

"You did not establish and implement written procedures for the method and frequency of calibrating verification instruments as required by 21 CFR 117.165(b)(1). Your firm utilizes a (b)(4) Thermometer to monitor the temperature of incoming refrigerated/frozen ingredients. You did not establish a written calibration procedure to verify the accuracy of your thermometer. Further, during our inspection you stated that your firm has not been performing calibration or verification activities for your (b)(4) thermometer."

"The validation records lack calibration reports, a record of the personnel that performed the individual task, the date, and an adequate description of the manufacturing process that would be supported by the validation activities"


What are the lessons learned from reviewing FDA 483 letters?

Some common themes were present in a review of Form 483's issued regarding calibration.

  • Not applying Calibration Traceability
  • Lack of calibration reports
  • Lack of a defined calibration process
  • Lack of documentation

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Phil Wiseman

Phil Wiseman

Phil Wiseman is Chief Marketing Officer at Alliance Calibration. He earned a B.S. in Chemical Physics from Centre College. Phil is an ASQ Certified Quality Auditor and ASQ Certified Manager of Quality/Organizational Excellence.

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