As we review FDA 483 letters we quickly see no slow down due to Covid-19! 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? View Text of § 111.35 Under this subpart D, what records must you make and keep? Title 21 Chapter I Part 111 (3) Documentation of any calibration, each time the calibration is performed, for instruments…calibrated; (ii) Provide the date of calibration; (iii) Identify the reference standard…recertification of accuracy; (iv) Identify the calibration method used, including appropriate limits § 111.117 What quality control operations are required for equipment, instruments, and controls? View Text of § 111.117 What quality control operations are required for equipment, instruments, and controls? Title 21 Chapter I Part 111 Periodically reviewing all records for calibration of instruments and controls; (c) Periodically…Periodically reviewing all records for calibrations, inspections, and checks of automated § 120.11 Verification and validation. Title 21 Chapter I Part 120 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 View Text of § 1.1101 What documents are incorporated by reference in this subpart Title 21 Chapter I Part 1 requirements for the competence of testing and calibration laboratories, Third edition, November § 106.100 Records. View Text of § 106.100 Records. Title 21 Chapter I Part 106 accuracy check, the standard used, the calibration method used, the results found, any actions…the instrument is found to be out of calibration, and the initials or name of the individual…individual 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
Background In the event of a violation of the Federal Food, Drug, and Cosmetic Act, depending on its nature, FDA may give individuals and firms an opportunity to take voluntary and prompt action to correct the violation before FDA initiates an enforcement action. Untitled letters are used for violations that may not meet the threshold of regulatory significance for a warning letter and request correction of the violations. Unlike a warning letter, an untitled letter does not include a statement that warns the individual or firm that failure to promptly correct the violation may result in enforcement action. FDA generally is under no legal obligation to warn individuals or firms about violations before taking enforcement action. Source :https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/issuance-untitled-letters Matters described in FDA warning letters may have been subject to subsequent interaction between FDA and the letter recipient that may have changed the regulatory status of issues discussed in the letter. Source: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters Observations are listed on a Form 483 in order of significance by the investigator. The format of any single observation begins with a statement based in a citation of law, regulation or Act and is followed by a statement of specific conditions observed during the inspection. For a description of the citations and the data in the attached spreadsheets, please see A Short Description of Citations. You really don't want to receive this letter from the FDA. As of December 11, 2020 the FDA has issued 595 483 letters. Calibration and measurement are specifically called out in many letters. What are the common issues for those receiving an FDA 483 letter that mention calibration? Stay On Schedule Keep Calibration Records Have Written Procedures Here are some snippets from FDA 483 letters issued in 2020: you should also provide evidence that you have reviewed other validations for the presence of all required testing, calibration of all equipment used for each study for the range of use, number of samples used as required and adequacy of sampling plans. Stay On Schedule The press sensors (b)(4) were not calibrated prior to executing the performance qualification. The IM 08 sensors have not been calibrated since the unit was initially placed in service prior to 2009 and were overdue for calibration per your Injection Molding Machine Calibration Schedule. You failed to calibrate instruments and controls you use in manufacturing or testing a component or dietary supplement, as required by 21 CFR 111.27(b). Specifically, our investigator observed your (b)(4) model scale contained a calibration sticker stating the last calibration date was July 23, 2012, that expired on July 23, 2013, and you could not provide evidence this scale has been recalibrated since this date. Keep Calibration Records 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. In addition, you did not provide records that document calibration of (b)(4) used to measure (b)(4) in your acidified products. Your response states you have contacted a calibration company and included an invoice from this company but documentation was not provided to show your equipment was calibrated. Have Written Procedures Your firm has not established a procedure to provide specific directions and limits for accuracy and precision for the calibration of the flow meters. Specifically, your firm has not adequately validated, reviewed, or approved the manufacturer change for the calibration heater test fixtures. 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. It is unclear if procedure (b)(4) is a new procedure developed as a result of this observation; however, this procedure has not been provided for review nor have any records of PQ (or calibration) results been provided for review. It is also unclear how your firm determined a calibration window of (b)(4) was acceptable to ensure acceptable performance of your (b)(4). your firm has not established and maintained procedures for all steps you perform, including but not limited to, performance of communicable disease testing, documentation of test kit lot numbers, equipment used during testing, incubation times, steps in reporting results to clients, and calibration/maintenance of testing equipment. The FDA regulates $1 trillion worth of products a year. It ensures the safety of all food except for meat, poultry and some egg products; ensures the safety and effectiveness of all drugs, biological products (including blood, vaccines and tissues for transplantation), medical devices, and animal drugs and feed; and makes sure that cosmetics and medical and consumer products that emit radiation do no harm. Source: FDA.gov Whose Job Is it To Be Responsible For Calibrations Due? This may come as a surprise, but it is NOT the responsibility of your calibration company. Many companies, including Alliance Calibration do send out a notice when items are coming due for calibration. However, it is the end user of calibrations responsibility to ensure their gages are calibrated. Click here for more details. Alliance Calibration provides online 24/7 access to calibration data to help you in the event of an audit. In addition, we inform you when measurement & test equipment is due for calibration. You may want to read 3 Big Mistakes When Changing Calibration Intervals.
You really don't want to receive this letter from the FDA. As of August 1, 2017, 248 FDA 483 letters have been issued and Calibration and measurement are specifically called out in 13 letters. What are the common issues for those receiving an FDA 483 letter that mentions calibration? Lack Of Adequate Documentation Inadequate Procedures Addressing Calibration Past Due Calibration Lack Of Or Improper Training Here are some snippets from FDA 483 letters issued in 2017: INSPECTIONS AND COMPLIANCE Read your calibration report: Your firm failed to investigate and identify any actions needed to evaluate the impact of the (b)(4), ID # C5003 after a calibration service provider reported it “failed as found”. This flow meter was used in routine device acceptance activities to calibrate the (b)(4) adjustments of your Criticare patient monitors. Stay on Schedule: Your firm failed to routinely calibrate, inspect, or check according to a written program designed to assure proper performance and to maintain written records of calibration checks and inspection of automatic, mechanical, or electronic equipment, including computers, used in the manufacture, processing, packing, and holding of a drug product (21 CFR 211.68(a)). Understand the measurement device: Specifically, you were not calibrating your pH meter according to the directions stated in the user manual. On 01/12/2017, you demonstrated how to calibrate the pH meter by placing the pH meter in a (b)(4) buffer solution first and a (b)(4) buffer solution second, which were both at room temperature. You stated there is no particular order for which buffer solution to use first; you just grab and use whatever is closest. You did not have the owner’s manual for your pH meter at the start of the inspection. If it is not in writing it didn't happen: You failed to establish and follow written procedures for fulfilling the requirements for equipment and utensils, including written procedures for calibrating instruments and controls that you use in manufacturing your dietary supplement, as required by 21 CFR 111.25(a). Additionally, you failed to calibrate instruments and controls you use in manufacturing or testing a component or dietary supplement, as required by 21 CFR 111.27(b). Specifically, you have not established and followed written procedures for calibrating instruments used in manufacturing your dietary supplements, and you have never calibrated the weighing scale (b)(4) used to weigh components. Once you have established the required written procedures, you must make and keep records of calibrating instruments and controls that you use in manufacturing or testing a component or dietary supplement, as required by 21 CFR 111.35. Your firm failed to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, electronic equipment, or other types of equipment, including computers, used in the manufacture, processing, packing, and holding of a drug product (21 CFR 211.68(a)). The BIG Picture... 13 mentions of calibration in Inspection Citations in 2017. Learn from the mistakes of others. Avoid these issues. Click the image below to download the Calibration Audit Check List. Visit our International Standards used in Calibration page for more on standards used in calibration.