Compliant Calibration Program

Explanation of compliant calibration programs in Pennsylvania and terms and definitions.

PA Compliant Calibration Program

By Pharmaceutical Technical Services (PTS)

The terms used in this paper are examples and are used throughout this document as points of reference.

CHARACTERIZATION AND CLASSIFICATION

  • All facility, process, utility, and laboratory instruments used in the manufacturing, processing, packing, holding or testing of drug products, biologicals, medical devices, or nutritional products must be characterized as GMP or Non-GMP according to their use in the GMP environment. This characterization must recognize that in a pharmaceutical, biological, diagnostic or related area the majority of instruments exist to monitor or control some aspect of the manufacturing operation and are therefore GMP.
  • Instruments characterized as GMP should be further classified regarding their potential for direct impact on product quality. One such classification scheme would be:
    • GMP Critical: Potential direct impact on product quality
    • GMP Non-critical: No potential direct impact, but potential indirect impact or equipment efficiency impact
    • GMP Utility: No potential for direct impact on product, rather are used primarily for troubleshooting equipment functioning.
    • Non-GMP Instruments must be handled in accordance with good engineering practices and are not subject to the requirements of this program.
    • Note: All instruments must be evaluated and all GMP instruments included in the calibration program for calibration or operational verification/maintenance.
           
  • Instrument classifications must be used to determine calibration parameters such as frequency of calibration, Out-of-Tolerance investigations, limits and tolerances. These parameters should recognize the criticality of the instrument, for example:
    • GMP Critical instruments should be calibrated more frequently than GMP Non-critical instruments to ensure product quality.
    • Out-of-Tolerance investigations can be limited to GMP Critical instruments
    • Process Calibration Tolerances (a secondary calibration limit set to initiate an Out-of-Tolerance investigation based on process tolerance – e.g. Action Limit) can be established for only GMP Critical instruments.
    • GMP Utility instruments may have their maintenance limited to functional operational checks on a regular basis, rather than a quantitative calibration performer

STANDARDS

  • Calibration Standards (instruments and equipment) must be traceable to a national or international certified standard, where applicable. If national or international standards are not practical or available, an independent reproducible standard must be used. If no applicable standard exists, an in-house standard must be maintained. Calibration Standards must be part of a formal, written certification program to assure their calibrated status prior to use in calibrating other instrumentation.
        
  • There must be a system of Reverse Traceability to track where standards were used to calibrate specific instruments
         
  • In all cases the accuracy of a calibration standard must be greater than the accuracy of the device under calibration, generally by a 4:1 ratio, and this ratio must be verified. By default, all standards used to calibrate GMP instruments are Critical GMP Instruments.

GENERAL PROGRAM ELEMENTS

  • GMP Instruments must be assigned Calibration Limits to determine when adjustment is required. Critical GMP Instruments may also be assigned Process Calibration Tolerances to trigger Out-of-Tolerance notification. These Process Calibration Tolerances must be based on the requirements of the process and products and supplied by Process Development, Technical Services, or Operations personnel.
          
  • All GMP Instruments must be calibrated and maintained according to a written program designed to ensure and demonstrate ongoing accurate performance. This program must include the following elements:
    • Each GMP Instrument must be identified by a unique identification number and included on the Master GMP Instrument List. The Master GMP Instrument List must identify, at a minimum, instrument classifications, locations, unique identifying numbers, manufacturers and model numbers.
    • There must be a procedure for establishing and maintaining Instrument History Files, which will include hard copies of all hand recorded procedures, forms, and hand recorded calibration records for each instrument.
    • Calibration Parameters, e.g. characterization, classifications, calibration points, limits and tolerances, etc., must be approved by the Quality Unit, the department responsible for calibration, and the applicable user group (Production, Facilities and Utilities, Technical Services, or Laboratory). There must be a procedure for adding, changing, deactivating, reactivating, and retiring instruments within the program requiring the same level as approval as originally required to establish the instrument in the program.
    • Procedures must be established for determining and changing calibration intervals, test points, Calibration Limits and, where required, Process Calibration Tolerances.
    • Where appropriate, procedures must be in place to verify and/or standardize accuracy and reliability of GMP Instruments such as analytical balances and pH meters.
    • Procedures prepared must determine when to challenge repeatability (precision) for each test point.
    • Procedures must be prepared describing the steps and forms required for the calibration and maintenance of a class or type of instrument.
    • A Calibration Sticker program must be defined, including requirements for a calibration sticker incorporating the instrument identification, calibration date, technician identification, next calibration due date. Auxiliary stickers, such as Out of Service stickers must be defined.
    • There must be a procedure for tracking scheduled calibration activities.
    • There must be a procedure for notifying users of calibration due dates, overdue calibrations and Out-of-Tolerance findings.
    • There must be a procedure for disallowing the use of an instrument after its calibration due date if it has not been calibrated successfully.
    • There must be a procedure to repair and record any repairs on an instrument.
    • The Quality Unit must review all systems and procedures.
    • Where a computerized calibration management system (CCMS) or computerized maintenance management systems (CMMS) is employed, it must be qualified for its intended use.
    • Calibration records and procedures must be reviewed regularly to identify any trends and the need to change frequencies or tasks.
    • The calibration program must include a procedure for reporting any GMP Critical instrument that is found outside the Process Calibration Tolerance during a calibration. This procedure must be invoked whether the device is returned to a calibrated state at the time of calibration or not.
    • There must be calibration forms developed to record the results of the calibration. These forms must include, at a minimum: 
      • Instrument Identification Number
                  
                or 
        • Manufacturer
        • Model number 
        • Serial number 
      • Calibration procedure identification (specific to instrument type)
      • Calibration due date.
      • Calibration standard(s) used.
      • Next due date for the calibration of each standard.
      • Predetermined test inputs and test points. Normally not less than 3 points must be tested to demonstrate linearity and precision (repeatability).
      • Test points must span the range of the instrument.
      • As-found result for each test point.
      • Acceptable calibration limits (accuracy) for each test point in engineering terms and percentages, as appropriate.
      • Process Calibration Tolerance for each test point, as required, for Critical GMP Instruments.
      • As-left results, including precision verification for each test point.
      • Calibration performed by/date.
      • Calibration reviewed by/date.
  • Exceptions to any of the preceding elements, e.g., two point calibration vs. the norm of three points, must be approved by a process outlined in a procedure designed to rigorously challenge the exception as necessary. These exceptions require approval by the Quality Unit, Responsible Operating, and Technical (Calibration) personnel
         
  • Laboratory instruments used in the manufacture, processing, packing, holding or testing of drug products must be incorporated into the process and facilities instrumentation calibration program or equivalent program.

RECORD KEEPING

  • Records of all calibrations must be complete, current and understandable.
  • Records of all calibration and maintenance of instruments must be maintained for a specified period beyond the longest expiration date of any product produced using the equipment. A chronological Instrument History File for each Instrument must be established. This file must include a complete history of all calibration data, documentation of all instrument repairs, replacements and modifications, demonstration of compliance with change control requirements, notifications of Out-of-Tolerance findings, and notifications of late calibrations.
  • There must be a procedure established to maintain current technical manuals specific to device make and model.
  • Notations in equipment logbooks by any calibration personnel must be completed in clear, understandable terms. This description must include the date, a brief description of the work performed described in complete sentences, reference to any work orders or preventive maintenance orders used, and a listing of any parts used, identified by part number. Logbook entries by calibration personnel must include the signature or identifiable initials of all personnel working on the system.

PERSONNEL QUALIFICATIONS

  • There must be a system for ensuring the qualification of technicians and mechanics employed in the calibration of GMP Instruments.
  • There must be a written system established to ensure technicians and mechanics are properly trained on any significant new equipment installed in the facility.
  • There must be a written procedure for the qualification of contracted mechanics and technicians used to supplement facility resources.
  • There must be regular training sessions for all calibration personnel covering both cGMP’s and operational issues.

These guides are offered as a basis for a Compliant Calibration Program and do not pretend to cover all the aspects of, e.g., when is a Test Accuracy Ratio not appropriate, relating calibration limits to readability of the Unit Under Test, instrument versus equipment considerations, guidelines for determining classifications, etc. Developing a calibration program is a significant undertaking, best done as comprehensively as possible in the early stages to avoid redoing classifications, etc., at later dates.

We at Pharmaceutical Technical Services stand ready to assist in your efforts to establish a compliant Calibration (or Maintenance or Engineering) Program. Contact us.