GAMP Good P r a c t i c e Gu i d e :

Calibration Management

Preface to the GAMP Good PracticeGuide: Calibration ManagementCalibration is an essential element in ensuring compliance in the pharmaceutical industry. To ensure success, calibration should bemanaged effectively by appropriately qualified and trained personnel with good technical knowledge and practical understanding.If neglected, calibration is capable of compromising both product and plant, and dramatically increasing costs.

The GAMP Good Practice Guide: Calibration Management provides guidance in setting up a calibration management system,which will give a structured approach required to set up instrument criticality assessment, management, documentation, andcorrective actions essential to regulatory compliance. It is intended to cover process and laboratory instrumentation.

The process of setting up clear procedures and carrying out formal criticality assessment will allow calibration activities to bemanaged to concentrate the most resource where it is most needed. This Guide offers a pragmatic approach, based on a criticalityassessment, to provide effectiveness and regulatory compliance as cost effectively as possible.

This Guide offers both general guidance and examples of documentation and ways of working. The general approach to calibrationmanagement should follow the format described below.

1. Production of a full list of all instruments as the basis for a criticality assessment.

2. Categorization of the criticality of all instruments listed.

3. All instruments should be operable, as required. Those deemed critical to product quality should be calibrated according todocumented processes at suitable frequencies, to ensure that predetermined accuracy and operating parameters are met.

4. A system described by written procedures should exist to:

Identify and label instruments critical to product qualityCalibrate instruments to traceable standards at defined frequenciesDocument the calibrationFollow up any out of tolerance resultsAudit the effective completion of the above

The process of investigation of any out of tolerance results is of equal importance to the calibration itself. A formal investigationshould take place and be documented. To aid this, it is strongly recommended that any instrument found to be out of toleranceshould not be adjusted until the investigation is complete.

In regulatory terms, a system is only as good as its documentation. Good calibration management ensures that the process ofcalibration is in compliance with regulatory requirements. Control may be demonstrated in the most cost effective way byconcentrating resources in the most important areas.

GAMP Forum

The GAMP Forum was established in 1991 to help promote the understanding of how computer systems validation should becarried out in the pharmaceutical industry. It did this by developing a guide to validation taking input from not only theindustry, but also from its suppliers and the regulators, particularly the Medicines Control Agency in the UK.

The first draft was issued for comment in 1994 and since then three subsequent revisions have been published as “The GAMPGuide to Validation of Automated Systems in Pharmaceutical Manufacture.” Each addition has built on previous versionsadding details of best practice as they evolve.

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AcknowledgementsThe following members of the GAMP Forum Process Control Special Interest Group (SIG) worked on one or more of the sectionsof this document and volunteered countless hours to attend meetings and review the many drafts, which were produced over atwelve month period.

Mark Foss Boehringer Ingelheim (Chairman)Jim Fox SB R&D UKColin Moss Aventis PharmaStefano Giorgi CAMRClive Edwards Eli LillyPeter Wilson Glaxo WellcomeBill Hewlett Johnson & JohnsonAlan Halstead KvaernerNick Garrett Fisher RosemountRoger Golding PfizerIan Hall PfizerGeorgia Smart PfizerBill Roberts Johnson Controls Systems (secretary)Jack Buck Boehringer Ingelheim

The GAMP Forum Process Control SIG would like to acknowledge the support of their direct management and companies in thisendeavor.

The GAMP Forum Process Control SIG would like to thank all those involved in reviewing this Guide for providing valuablecomment, including regulatory authorities within Europe and several organizations in the Americas, Australia, Europe, Japan, andNew Zealand.

Members of the GAMP Forum Industry Board and Steering Committee, along with the ISPE Technical Documents SteeringCommittee are thanked for their participation in the review of this Guide.

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Disclaimer:This Guide is meant to assist pharmaceutical companies in managing calibration. The GAMP Forum Process ControlSpecial Interest Group cannot ensure and does not warrant that a system managed in accordance with this Guide will beacceptable to regulatory authorities. Further, this Guide does not replace the need for hiring professional engineers ortechnicians.

Limitation of Liability:In no event shall ISPE or any of its affiliates (including the GAMP Forum), or the officers, directors, employees,members, or agents of each of them, be liable for any damages of any kind, including without limitation any special,incidental, indirect, or consequential damages, whether or not advised of the possibility of such damages, and on anytheory of liability whatsoever, arising out of or in connection with the use of this information.

© Copyright ISPE 2002.

All rights reserved. No part of this document may be reproduced or copied in any form or by any means - graphic,electronic, or mechanical, including photocopying, taping, or information storage and retrieval systems - without writtenpermission of ISPE.

All trademarks used are acknowledged.

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Contents1 Introduction ................................................................................................................................................................. 9

2 Objective ....................................................................................................................................................................... 9

3 Scope ............................................................................................................................................................................... 9

4 Key Definitions and Responsibilities ...................................................................................................... 104.1 Key Definitions .................................................................................................................................................................. 104.2 Responsibilities .................................................................................................................................................................. 10

5 Key Regulatory Requirements ..................................................................................................................... 10

6 Criticality Assessment ...................................................................................................................................... 116.1 Criticality Assessment Team (CAT) .................................................................................................................................. 116.1.1 Team Meetings ................................................................................................................................................................... 126.2 Categorization .................................................................................................................................................................... 126.3 Ranges and Limits ............................................................................................................................................................. 126.4 Rationale ............................................................................................................................................................................ 126.5 Periodicity .......................................................................................................................................................................... 136.6 Process Change .................................................................................................................................................................. 13

7 Life Cycle Phases ................................................................................................................................................. 137.1 Project Phase ...................................................................................................................................................................... 137.2 Pre-Operational Calibration Phase .................................................................................................................................... 147.3 Operational Phase .............................................................................................................................................................. 147.4 Key Requirements for Life Cycle Phases .......................................................................................................................... 14

8 Project Phase ........................................................................................................................................................... 148.1 Responsibilities .................................................................................................................................................................. 148.1.1 Process ............................................................................................................................................................................... 148.1.2 Engineering ........................................................................................................................................................................ 158.1.3 Quality ............................................................................................................................................................................... 158.2 Specification of the Instrument ......................................................................................................................................... 158.2.1 Range ................................................................................................................................................................................. 158.2.2 Accuracy ............................................................................................................................................................................ 158.2.3 Hysteresis/Temperature Affects/Non-Linearity ................................................................................................................. 168.2.4 Uncertainties ...................................................................................................................................................................... 168.3 Labeling ............................................................................................................................................................................. 168.4 Calibration Process ............................................................................................................................................................ 168.4.1 Instrument Testing ............................................................................................................................................................. 168.4.2 Instrument Loop Testing .................................................................................................................................................... 168.5 Installation Qualification Sign Off .................................................................................................................................... 17

9 Pre-Operational Phase ...................................................................................................................................... 17

10 Operational Phase ................................................................................................................................................ 1710.1 Responsibilities .................................................................................................................................................................. 1710.1.1 Instrument Calibrator ......................................................................................................................................................... 1710.2 Cleaning and Decontamination ......................................................................................................................................... 1710.3 Calibration Process ............................................................................................................................................................ 1810.3.1 Instrument Calibration ....................................................................................................................................................... 1810.3.2 Loop Calibration ................................................................................................................................................................ 1810.3.3 Non-Conformance ............................................................................................................................................................. 1810.3.4 Third Party Calibration ...................................................................................................................................................... 1810.4 Documentation: Calibration Records ................................................................................................................................ 1910.4.1 Calibration Request Documents ........................................................................................................................................ 2010.4.2 Certificate of Calibration ................................................................................................................................................... 2010.4.3 Non-Conformance Documentation ................................................................................................................................... 2010.5 Removal: Decommissioning of the Instrument ................................................................................................................. 21

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11 Training ........................................................................................................................................................................ 2111.1 Training Records ................................................................................................................................................................ 21

12 Change Control ...................................................................................................................................................... 22

13 Documentation ....................................................................................................................................................... 23

14 Electronic Records .............................................................................................................................................. 23

15 Auditing ....................................................................................................................................................................... 2415.1 Calibration Management Auditing .................................................................................................................................... 2415.2 Third Party Auditing .......................................................................................................................................................... 24

16 Other Considerations ......................................................................................................................................... 2416.1 Automation and Smart Instrumentation ............................................................................................................................ 2416.2 Automation ........................................................................................................................................................................ 2516.3 Diagnostic and Calibration Development Trends in Smart Instrumentation .................................................................... 2516.3.1 Measurement Integrity Validation and Self Calibration .................................................................................................... 25

17 Calibration Management Software ........................................................................................................... 25

18 Smart Calibrators and Test Equipment .................................................................................................. 26

19 References ................................................................................................................................................................. 26

20 Glossary ...................................................................................................................................................................... 2620.1 Acronyms ........................................................................................................................................................................... 2620.2 Definitions ......................................................................................................................................................................... 27

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Appendices

Appendix 1 Worked Example Showing Calibration Failure Limits

Appendix 2 Example Calibration Master List

Appendix 3 Example Declaration of Decontamination Status

Appendix 4 Example Non-Conformance Report

Appendix 5 Example Calibration Certificate

Appendix 6 Example Standard Operating Procedure: Calibration By Work Order

Appendix 7 Example Calibration Report Standard Operating Procedure

Appendix 8 Example Calibration Work Instruction Standard Operating Procedure

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1 IntroductionThe GAMP Good Practice Guide: Calibration Management describes a system of calibration management, which defines whatneeds to be done, when, by whom, and why. This Guide also describes the principles and suggests a prioritized, effective methodfor meeting the calibration needs of the pharmaceutical industry and satisfying the requirements of the regulators.

The importance of being in control cannot be overemphasized, and making the correct decisions depends largely on whether thecorrect information is acquired. This information is often gathered through measurement and it is, therefore, critical that it is bothreliable and accurate.

For example, it is essential that during the steam sterilization of a fermenter, clean saturated steam at a temperature of 121°C±2°C is maintained for the appropriate amount of time, as temperatures of 121°C or greater are required to kill off the bacteria. Inmanufacturing, however, temperatures in excess of 123°C may denature the medium within the fermenter. Instrumentation usedfor monitoring and controlling the temperature should, therefore, be both reliable and accurate.

The calibration of process control instruments may drift, due to the complexity of their construction and the environmentalconditions in which they operate. This drift may be significant within a short time frame and accounts for the requirement forperiodic recalibration.

Concentrating resources in the most important areas will maximize their effectiveness. The process of risk and criticalityassessment will help in achieving this and in reducing costs.

This document provides education in the importance of calibration and the need to prioritize. The assurance of control andcompliance within stated parameters can be achieved only through the implementation of effective calibration management.Simply put, if a parameter is not measured, control cannot be assured.

The importance of the measurement error depends on what is being measured, i.e., assurance that a temperature measurementinstrument is accurate to, e.g., ± 0.5°C during the critical step of a process is more important than an instrument measuring thetemperature of an office where a ± 3°C error is acceptable.

The key message is that the performance of the instrument is such that there is high confidence that the process has remainedwithin the desired range, i.e., indicated value plus possible error will remain within desired limits.

An assessment needs to be made on the criticality, accuracy, and stability of all instruments that can be calibrated to give a highdegree of confidence that the process has remained within the desired range, and accuracy within tolerance.

2 ObjectiveThe objective of the GAMP Good Practice Guide: Calibration Management is to provide a practical approach to calibrationmanagement designed for the pharmaceutical industry, to satisfy relevant regulatory bodies, and improve operationaleffectiveness.

3 ScopeThe scope of the Guide includes quality, safety, and environmental issues as well as the regulatory requirements of thepharmaceutical industry. The methodology considers the full life cycle of instrument management, covering the requirementsto satisfy regulators, and giving guidance on best industry practice. It is not, in itself, validation but is a building block for usein qualification and validation.

The document is structured to follow the life cycle of validation and is intended to cover initial calibration as well as periodicinspection, testing and calibration. The Guide does not cover the detail of test methodology but concentrates on calibrationmanagement.

The GAMP Good Practice Guide: Calibration Management is intended for use by engineers, Quality Assurance (QA), andpersonnel involved in the management of calibration in a regulated environment.