Establishing An Effective Calibration Program

Calibration is defined as the comparison of the inspection, measuring, and test equipment against a traceable reference device to determine if accuracy and precision limits are met. Calibration is one of the fundamental requirements for good manufacturing practices and yet calibration programs are often neglected.

Several international standards, regulations, and guidance provide requirements for calibration. The requirements for calibrations are very similar and are designed to ensure the validity of monitoring and measuring results. The FDA regulations pertaining to pharmaceuticals, biologics, medical devices, and human tissues are shown below.

21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals

Sec. 211.68 Automatic, mechanical, and electronic equipment. 

(a) Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

Sec. 211.160 General requirements. 

(4) The calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met. Instruments, apparatus, gauges, and recording devices not meeting established specifications shall not be used.

Sec. 211.194 Laboratory records. 

(d) Complete records shall be maintained of the periodic calibration of laboratory instruments, apparatus, gauges, and recording devices.

21 CFR 606 Current Good Manufacturing Practice for Blood and Blood Components

Sec. 606.60 Equipment.

(b) Equipment that shall be observed, standardized, and calibrated.

Sec. 606.100 Standard operating procedures.

(b) Establishments must establish, maintain, and follow written standard operating procedures.

(15) Schedules and procedures for equipment maintenance and calibration.

Sec. 606.160 Records.

(5) Quality control records:

(i) Calibration and standardization of equipment.

21 CFR 820 Quality System Regulation

Sec. 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.

21 CFR 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products

Sec. 1271.200 Equipment. 

(c) Calibration of equipment. Where appropriate, you must routinely calibrate according to established procedures and schedules all automated, mechanical, electronic, or other equipment used for inspection, measuring, and testing.

(d) Inspections. You must routinely inspect equipment for cleanliness, sanitation, and calibration, and to ensure adherence to applicable equipment maintenance schedules.

(e) Records. You must document and maintain records of all equipment maintenance, cleaning, sanitizing, calibration, and other activities performed in accordance with this section. You must display records of recent maintenance, cleaning, sanitizing, calibration, and other activities on or near each piece of equipment or make the records readily available to the individuals responsible for performing these activities and to the personnel using the equipment. You must maintain records of the use of each piece of equipment, including the identification of each HCT/P manufactured with that equipment.

Records of the results of calibration and verification shall be maintained.

The organization shall document procedures for the validation of computer software used for the monitoring and measurement of requirements. Such software applications shall be validated prior to initial use and, as appropriate, after changes to such software or its application.

The specific approach and activities associated with software validation and revalidation shall be proportionate to the risk associated with the use of the software, including the effect on the ability of the product to conform to specifications.

Records of the results and conclusion of validation and necessary actions from the validation shall be maintained.

Inspectional Observations

During 2019 and 2020, issues related to calibration accounted for approximately 4.8% of FDA 483 Inspectional Observations.  Table 1 provides a summary of FDA 483 Inspectional Observations during 2019 and 2020.

Table 1: FDA 483 Inspectional Observations during 2019 and 2020.

While FDA 483 Inspectional Observations related to calibration only account for approximately 4.8% of observations, a poorly managed or neglected calibration program can have a far greater impact on product safety, including making improper release decisions leading to complaints, adverse events, field corrections, and recalls leading to further compliance risk. Additionally, the organization can experience increased financial losses due to scrap, rework, lost opportunities, remediation, and loss of public trust.

Calibration Determination

An effective calibration program must first identify which items must be calibrated. The following items must be calibrated: items used to make a release (quality) decision, items used to set critical process settings, items used to monitor critical process (environmental) conditions, and items used to make measurements supporting equipment product, process, design verification/validation/qualification activities.

Items used to make a release (quality) decision or used to approve materials, components, subassemblies, assemblies, and finished goods at incoming, in-process, or final inspection must be calibrated to ensure compliance with predetermined specifications. 

Items used to set critical process settings must be calibrated. Items that set critical process settings, such as temperature, pressure, time, etc., are examples of items typically used to control a process to ensure process outputs meet predetermined specifications.

Items used to monitor critical process (environmental) conditions must be calibrated. Items used to monitor critical process conditions such as pressure differential, temperature, and humidity are examples of items typically used to monitor critical process conditions to ensure process outputs meet predetermined specifications.

Items used to make measurements support equipment product, process, design verification/validation/qualification activities include those that are used to approve materials, components, subassemblies, assemblies, and finished goods, set critical process settings, and monitor critical process (environmental) conditions.

Reference Only Calibration Not Required

Instruments that are not used to get exact measurements but are used only to obtain status information do not require calibration. Table 2 provides some examples of when calibration may and may not be required.

Table 2: Calibration not required/calibration required examples.

Another simple test that I like to use to determine if calibration is required is to apply this simple test: If the item was covered (not visible), can the process be set up, monitored, and operated correctly? If the answer is no to any of these questions, the item must be calibrated; otherwise, calibration is not required.

Inspection, Measuring, And Test Equipment Labeling

All inspection, measuring, and test equipment should be appropriately labeled. All items that are calibrated should be clearly labeled with a unique identifier. Some organizations will identify the items with its serial number. However, I suggest assigning each item a unique coded sequential identifier.

For example: A-NNNN, where A is a character assigned to a department (e.g., P for production, L for lab, M for maintenance) and NNNN is a four-digit sequential number. This method allows for easy organization and prevents typing long serial numbers.

For items not requiring calibration, labels should be affixed identifying the items as ‘FOR REFERENCE ONLY’ or ‘CALIBRATION NOT REQUIRED’. Inspection, measuring, and test equipment that is not labeled or is improperly labeled can raise issues during regulatory inspections and certification audits.

If it is not possible to place the label directly on the inspection, measuring, and test equipment due to the size, configuration, or the operating environment (oil, grease, chemicals, water, etc.), the label can be placed on a case or plastic bag.

Conclusion

Calibration is one of the fundamental requirements for good manufacturing practices. An effective calibration program must first identify which items must be calibrated. All inspection, measuring, and test equipment should be appropriately labeled. A poorly managed or neglected calibration program can significantly impact product safety, including making improper release decisions, leading to complaints, adverse events, field corrections, and recalls leading to further compliance risk.

I cannot emphasize enough the importance of establishing documented procedures to manage the calibration program. The concepts presented in this article can and should be utilized based upon industry practice, guidance documents, and regulatory requirements.

About the Author

Mark Allen Durivage has worked as a practitioner, educator, consultant, and author. He is managing principal consultant at Quality Systems Compliance LLC, an ASQ Fellow, and SRE Fellow. Durivage primarily works with companies in the FDA-regulated industries (medical devices, human tissue, animal tissue, and pharmaceuticals) focusing on quality management system implementation, integration, updates, and training. Additionally, he assists companies by providing internal and external audit support as well as FDA 483 and warning letter response and remediation services. He earned a BAS in computer aided machining from Siena Heights University and an MS in quality management from Eastern Michigan University. He holds several certifications, including CRE, CQE, CQA, CSSBB, RAC (Global), and CTBS. He has written several books available through ASQ Quality Press, published articles in Quality Progress, and is a frequent contributor to Life Science Connect. You can reach him at mark.durivage@qscompliance.com with any questions or comments.