| Title: Calibration | |||||
| Guidance Number: 85 | |||||
| Prepared by: | Date: | Supersedes: | |||
| Checked by: | Date: | Date Issued: | |||
| Approved by: | Date: | Review Date: | |||
Calibration
Introduction
This document provides guidance for the calibration of equipment, instruments, and standards used in production, storage, and testing that may affect the identity, strength, quality, or purity of Pharmaceutical drug products, active pharmaceutical ingredients (API) and medical devices.
1. Instrument Specifications include, and are not limited to, the following:
- Definition of required accuracy and precision;
- Expected Process Parameter values, including unit of measure;
- Expected Normal Operating Range (NOR) of the process parameter values;
- Acceptable tolerance;
- Instrument stability requirements; and
- Safety and environmental considerations.
2. An Instrument History File should be maintained for each instrument that includes, and is not limited to, the following information:
- Instrument identification;
- Instrument manufacturer, model, and serial number, if available;
- Instrument type (e.g., thermometer, pressure gauge);
- Instrument classification (e.g., critical, non-critical, major, minor);
- Reference to calibration procedure(s) for the instrument;
- Instrument location;
- Type and accuracy requirements of standard(s) to be used;
- Calibration frequency;
- Limits for accuracy and precision;
- Calibration range;
- Calibration test points;
- Specific environmental conditions for calibration, if applicable;
- Calibration records; and
- Repairs and service records.
- The Instrument History File should be retained in accordance with the Site record retention procedure.
3. Instrument Identification should be unique and permanently assigned to each instrument. The instrument identification should allow complete traceability of the instrument and should be permanently displayed on the instrument in a manner that does not interfere with use of the instrument. The instrument’s identification label should be suitable for the environmental conditions where the instrument is installed. If the Instrument Identification cannot be placed directly on the instrument without interfering with the use of the instrument or due to the size of the instrument, an alternate system may be used provided that the instrument traceability can be assured.
4. Calibration Records include, and are not limited to, the following:
- Instrument or equipment identification;
- Calibration data including initial (as found), and final (as left) results;
- Comparison of results against specifications;
- Units of measure;
- Identification of any standard(s) used;
- Identification of the procedure used for the calibration;
- Date calibration performed;
- Signature of person performing work;
- Signature of second person reviewing and approving the data and date of approval; and
- Environmental conditions, if required by the calibration procedure (e.g.,temperature, humidity, atmospheric pressure).
- Calibration records should be retained in accordance with the Site record retention procedure.
5. Calibration Records should be reviewed by the System Owner to identify potential out-of-tolerance conditions. In addition, calibration records should also be reviewed to support modifying tolerances and to obtain data to support changing calibration frequencies.
6. Calibration Status Labels should be placed on instruments in a conspicuous location, if possible, and should include, but not be limited to, the following information:
- Date calibrated,
- Next due date, and
- Initials of person performing calibration.
Instrument Calibration Status may be tracked using other systems besides labels such as validated computerized systems or manual paper-based systems provided the system allows the operator of the instrument to determine the instrument’s calibration status.
7. Instrument Calibration Status should be verified prior to use of the instrument.
8. Calibrations should be completed by the due date or the instrument is considered overdue and should be identified as being past due. An investigation should be conducted and documented on the impact of the past due calibration on product or the process, if the instrument was used subsequent to becoming overdue.
9. Instruments [except those that require calibration prior to each use (e.g., pH meters) should be removed from service or designated out of service (e.g., not used and/or removed from work areas) because of, and not limited to, the following reasons:
- Inability to calibrate;
- An out-of-tolerance condition is determined on the initial check, and the adjustments cannot be made; or
- Past due calibration, if the instrument was subsequently used after becoming past due, unless documented approval to use the instrument is granted by the Site Quality Team.
10. For Calibrations Affected by Environmental Conditions, the conditions should be suitable for both the instrument and the standard being used for the calibration, prior to performing the calibration.
11. Changes in the Calibration Frequency or Instrument Tolerances should be approved by the Site Quality Team and should be based on, and not limited to:
- In-use reliability,
- Experience, and
- Calibration history.
- Rationale for changes should be documented.
12. Instruments and Standards should be calibrated, stored, and used in an environment controlled to the extent necessary to ensure continued measurements of the required accuracy. Calibration should be performed in a location other than where the instrument is used only if the instrument is unaffected by relocation or the locations have been shown to be equivalent. Consideration should be given to, and not limited to, the following environmental conditions that can potentially affect the instrument:
- Temperature,
- Humidity,
- Vibration,
- Cleanliness,
- Electromagnetic Forces (EMF), and
- Radio frequencies.
13. Calibration Standards, when not in use, should be stored in a controlled manner that prevents unauthorized adjustments, and meets the storage requirements for the standard.
14. A System should be established for notification of the Site Quality Team and the responsible System Owner when an instrument is found to be out-of-tolerance.
15. An Investigation should be conducted to determine the potential impact of an out-of- tolerance condition on the product. The investigation should be documented by the System Owner and approved by the Site Quality Team.
16. Transfer Standards should be certified against primary standards either at the Site or by an approved calibration service contractor.
17. The Accuracy of the Calibration Standard should be, at least, equal to the accuracy of the instrument being calibrated.
18. A Calibration Certificate and the Supporting Raw Data should be obtained from the calibration service contractor for each certification of a primary or secondary standard. The System Owner should review the certification for completeness and accuracy and document the results of the review. For In-House standards, a calibration certificate should be prepared based on supporting raw data. The certificate should include, and should not be limited to:
- Description of the standard;
- Date the standard was established;
- Signature of person preparing the standard;
- Date standard must be recertified or replaced;
- Handling or storage conditions for the standard;
- Reference to a method or SOP used to establish the standard; and
- Accuracy (or purity for chemical substance) and precision of the standard.
19. Calibration Service Contractor Quality System SOPs should be reviewed and documented evidence should be available to indicate that the Site Quality Team approved the SOPs for use at the Site. Specific instrument calibration SOPs should be reviewed when possible. If specific instrument calibration SOPs are proprietary and unavailable for review, an alternative method for ensuring acceptability of the SOPs should be established by the Site Quality Team.
20. Initial “As Found” Data should be recorded prior to removing an instrument from the calibration schedule, performing an upgrade, or before an instrument is moved. If the instrument is not calibrated prior to a move, the justification should be documented and approved by the Site Quality Team.
21. The Calibration Range Selected should include the normal process parameter values and expected variability. The instrument calibration should demonstrate that the instrument can reproducibly measure across the selected range.
22. Loop Calibration, in lieu of calibrating individual instruments in the loop, is justified under the following circumstances:
A documented evaluation of the Instrument Loop is conducted by the Site Calibration Principals. The instrument loop evaluation should include, but is not limited to:
(a) The instrument loop design;
(b) Operating characteristics of the individual loop elements; and
(c) Reliability or experience with the technologies incorporated into the instrument loop; or
(d) An assessment of the historical data from the specific instrument loop;
Calibration Service Contractor Quality System SOPs should be reviewed and documented evidence should be available to indicate that the Site Quality Team approved the SOPs for use at the Site. Specific instrument calibration SOPs should be reviewed when possible. If specific instrument calibration SOPs are proprietary and unavailable for review, an alternative method for ensuring acceptability of the SOPs saIndividual instruments to be incorporated into an instrument loop have been calibrated as required by and demonstrated to be functioning properly, prior to the placement into the instrument loop; The instrument loop is periodically calibrated and documented using a loop calibration. If an instrument loop is found to be outside the expected variability, then the individual component instruments should be examined and calibrated individually to return the loop to specification; and All other aspects of the loop calibration methodology and system (e.g., systems, documentation, schedules, tolerances, labeling, change control) meet the site requirements. hould be established by the Site Quality Team.
23. Calibration should be conducted at a minimum of three points (e.g., upper operational range, lower operational range, and NOR), if possible. For instruments that cannot be calibrated at three points, the points to be included in the calibration should be defined and justified.