implementing calibration program

Calibration

100 PHARMACEUTICAL ENGINEERING NOVEMBER/DECEMBER 2003

Recommendations for Implementing aCalibration Program

by Yefim S. Gudesblat, PE

This articlepresents theinfrastructure ofa GMPcompliantCalibrationProgram basedon technical andmetrologymythology.

Continued on page 102.

Introduction

This article is limited to the principles oforganization for calibration work inrelation to cGMP and other pharma-ceutical standards. Calibration and me-

trology methods related to actual calibrationtechniques, statistics, and theories are not ex-plored in our discussions.1 Each class of instru-ments requires specific techniques and ap-proaches to achieve stated accuracies. All mem-bers of the calibration team should be educatedin metrology techniques and skills necessaryfor the successful calibration work.

In pharmaceutical applications, perfor-mance and accuracy of instrumentation de-vices are governed by Current Good Manufac-turing Practices (cGMPs). Verification of properprocess instrumentation operation is an im-portant factor for finished product in Quality

Assurance (QA) programs. In GPM processes,outside of validated parameters weighing addi-tions, sterilization temperatures, compound-ing pressures, and other factors are most likelynot recoverable and costly to the business.Mistakenly released products within an estab-lished QA program could be detrimental topatients’ health and manufacturers’ reputa-tion, including legal implications.5

Proper operation of process systems andlaboratory equipment in the pharmaceuticalenvironment is critical for product quality,manufacturing cost, and research development.Processes controlled by instrumentation out-side of defined tolerances, presumably irre-versible, will lead to distraction of affectedmaterials and rise of production costs. Incor-rect data of laboratory instrumentation andmeasurements could delay development and

Figure 1. Facilityinstrumentationconfiguration diagram.

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release of new products resulting in potential losses of themarket share.

The Product Master File and Batch Records contain infor-mation concerning weighing specifications, sterilization re-quirements, compounding parameters, and other details ofscientifically developed process tolerances. Production reci-pes include sequential order of all process activities andpermitted fluctuations. Maximum and minimum tempera-

tures for sterilization, weights of each chemical addition,mixing time, and feeding rates are examples of windows forvalidated parameters critical in determination of final phar-maceutical product quality.2

Precision of data in research and development applica-tions is one of the requirements associated with current GoodLaboratory Practices (cGLPs). Good calibration record keep-ing and maintenance of standards and instruments are


Figure 2. Interactions between preventative maintenance and calibration programs.

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necessary for expected reliability of experimental outcomes.Introductions of new drugs to the market could be affected byfailures of upholding metrology standards in science labora-tories.

The purpose of this article is to review in a general format

a Calibration Program suitable for the pharmaceutical in-dustry. In addition, a discussion of engineering methods forprocess specifications and theory of calibration requirementsin reference to pharmaceutical process procedures, opera-tion/laboratory methods, and standards for instrumentation

Table A. Similarities and differences between calibration and preventative maintenance programs.

Functions of Preventative Maintenance Programin relation to Instrumentation and Measurements

Field calibrators are functional but not necessarilytraceable to NIST. Calibrators functional or calibrationfailures will be limited to equipment retests only.

Instruments and loops functional performance aredefined for control and monitoring processes of non-GMP areas.

Documentation of performed preventative maintenanceis filed under preventative maintenance calibrationprogram.

Preventative Maintenance schedules and frequenciesare under periodic review and approval.

Instruments, loops and systems functional failures willnecessitate repairs and possible notifications.

Selected Functions of CalibrationProgram

Field calibrators are certified astraceable to NIST. Failures of fieldcalibrators will result in product holdand investigations.

Calibration and process tolerancesare specified for the processoperating range and instrumentoperating range.

Documentation of performedcalibration is filed under calibrationprogram.

Calibration schedules and frequen-cies are under periodic review andapproval.

Instruments, loops and systemscalibration failures will triggernotification, investigations, producthold, etc.

Description of Differences or Comments

Instruments subjected to calibration program require greaterfunctional analysis than devices under preventative maintenanceprogram. For example, failure of calibrators used for sterilizationprocesses and calibrators used for balancing temperature inoffice areas will generate different responses.

Product quality could be directly or indirectly affected by out oftolerance instruments in the Calibration program. Instrumentsunder preventative maintenance program have functions ofconvenience, energy cost, effectiveness or comforts.

There should be no difference in documentation filing andretrieval between calibration and preventative maintenanceprograms.

Both programs could be defined by one database and divided byCritical, non-Critical and Maintenance categories.

Calibrated instruments and loops are traceable to calibrators andstandards. It is a good practice to use calibrated instrument inpreventative maintenance work. However, strict instrumentationtraceablilety is not necessary.

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NOVEMBER/DECEMBER 2003 PHARMACEUTICAL ENGINEERING 105

tolerances will be outlined.Weighing additions of chemical components, process tem-

peratures, pressures, flows, etc., will naturally fluctuate frombatch to batch. Therefore, cGMP requires that StandardOperating Procedures (SOPs) for validated pharmaceuticalprocesses will cover maximum allowed fluctuations for speci-fied parameters. Products made outside of critical controldefined specifications will oblige sanctions of product “onhold” for investigation. An almost certain outcome frominvestigations will lead to destruction or rework of manufac-tured material.

Permitted variations in processes need to agree with theequipment and instrumentation capabilities. Qualificationtests and procedures for instruments in validated processeswill provide the necessary assurance of accurate processexecutions. Verification of the instrument’s compliance to theprocess requirements is an important phase for the systemqualification and validation. Selections of calibration proce-dures, calibration frequencies, and certification methods forinstruments, sensors, control loops, and systems depend onapplications, accuracies, and characteristics of instrumentsstability.

Data of pharmaceutical manufacturing processes and labo-ratory testing are limited by the instrumentation accuracy.Product quality compliance requires calibration standardcertification traceable to National Institute of Standards andTechnology (NIST). Calibration procedures work with for-

mats of records to establish documentation layout and flowdesigned to assure traceability of collected data. Verificationof instrumentation measuring devices performance is com-prised from two parts. One is a calibration certification andthe other is a calibration check. The calibration certificationsummarizes a methodical process defined by a written andapproved procedure developed for a range of measurements.A calibration check is a simplified confirmation of the instru-ment, loop, or device performance. Usually calibration checksare represented by one or two test measurements.

A successfully executed calibration procedure confirmsthat manufacturing processes and laboratory experimentsare not affected by the tested instrument within the lastcalibration time interval. Calibration failure in the “as found”data will necessitate an investigation of the product producedwithin the last calibration period. In the laboratory environ-ment, all tested lots will be affected by an instrument calibra-tion failure. Strict procedures are required for notification ofcalibration failures. Adjustments of the instruments foundout of tolerance should be controlled by Standard OperatingProcedures (SOPs). Each SOP should contain instructions foradjustments or reference them to published literature. Forinvestigation purposes, some instruments could require ad-ditional testing and may not be adjusted or repaired inimita-bly. Investigational tests may be needed to determine amagnitude of losses or requirements for application/design/replacement of an instrument.


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Figure 3. Process of calibration request approval.

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NOVEMBER/DECEMBER 2003 PHARMACEUTICAL ENGINEERING 107

Properly established instrumentation tolerances, calibra-tion procedures, and instruments functional tests are veryimportant issues for product development, quality assuranceprograms, and production costs. CGMP/cGLP metrology pro-gram issues related to laboratory instruments, manufactur-ing capabilities, process tolerances, and calibration method-ology are addressed in this article. Actual calibration tech-niques and metrology requirements related to standards,uncertainty rations, instruments bias, precision, and accu-racy are outside of the scope of work for this article.

Managing a Calibration ProgramA modern pharmaceutical facility is dependant on thousandsof instruments installed in operations, utilities, laboratories,and development areas. Proper functions and accuracies ofthose instruments are maintained by a Calibration Program.Tasks of a Calibration Program are interfaced with a Preven-tative Maintenance Program and Quality Assurance activi-ties.6

The process of review and approval of Preventive Mainte-nance activities needs to address requirements of pre andpost calibration data. The critical path formula of Pre-Cali-bration, Preventive Maintenance work, and Post-Calibrationis necessary for the system integrity assurance. Calibrationand Preventive Maintenance programs cannot function asindependent programs. In many cases, Preventive Mainte-nance could disturb instrumentation and unfortunate discov-

eries during Calibration work will lead to quality investiga-tions, production loses, and poor business reviews.

Interfacing of Calibration and Preventive Maintenancework requires maintenance, engineering, and quality re-views. Preventive Maintenance and Calibration tasks for allsystems and devices need initial and periodic evaluations forassurances of production/experimental consistency and re-peatability. The outcome of these reviews should be outlinedin specific procedures. For example, Preventive Maintenancework associated with control valves, removal, and reinstalla-tion of instruments will necessitate coordination with cali-bration activities. Bearing greasing, belts replacements, andother mechanical work may not require links to the calibra-tion program.

An established Calibration Program needs to address thefollowing functions:

I. Documentation records of instruments for traceabilityand application requirements in accordance with theindustry standards of metrology.

II. Continued enforcement of approved calibration SOPs.Reviews and recommendations for modifications of cali-bration SOPs based on the inputs from PreventativeMaintenance and Quality Assurance. Development ofnew SOPs.


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III. Notification of calibration failures to appropriate depart-ments. Investigations of calibration failures and assis-tance to affected departments by providing technicalexpertise and improvements.

IV. Maintaining calibration schedules and coordination withproduction and maintenance activities.

Each of the above functional topics represents specific re-sponsibilities and procedures of a comprehensive calibrationprogram.3 Descriptions of internal and external configura-tion correlated to functional topics are very important forunderstanding the scope of calibration work.

I. Documentation Records of Instrumentsfor Traceability and Application

Requirements in Accordance with theIndustry Standards of Metrology

All instruments should be recorded on an approved singleformat Instrument Data Form. The form should be able todescribe and identify a single instrument, sensor, loop, dis-play, system, etc. The information from the manuals andcutsheets of instruments include manufacturing model, serialnumber, input/output units of measurement, resolution, andaccuracy. This information should be properly placed on anInstrument Data Form. Consequences of instrument perfor-mances and failures related to processes should be provided

by engineering, process development groups, and technicalservices. This information is needed to identify each instru-ment as critical or not critical, calibration frequency, andtolerances in reference to the final product quality require-ments.

Each of the critical and non-critical instrumentation could bedivided into several subcategories. That division may benecessary to establish multi-level procedures for calibrationfailure notification and actions. The following sections of thisarticle will provide a general discussion of critical and non-critical categories without subcategories.

Instrument review procedures in a calibration programneed to identify each device, loop, and system with a calibra-tion number. This number will stay with each instrument,loop, or system and will be retired from the program afterremoval of the instrument or loop/system modification. Cali-bration numbers need to work within an establish databaseto assure historical traceability (replacements and modifica-tions) for all control elements of production and researchequipment. Figure 1 represents a sample diagram for con-figuration of facility instrumentation. The Instrument DataForm requires the location of an instrument, loop, and system(including interconnected references) to be recorded. Forexample, a form for a temperature sensor, transmitter, orcontroller should identify the location in the loop, system, andplant area (factory). Each loop or system needs to referenceinstruments and devices employed in the application. Bi-directional referencing is a very important factor for effectiveperformance of a calibration program.

Instrument calibration numbers need to be interfaced orin many cases integrated with the preventative maintenanceprogram for production machines and devices. It is accept-able for the function verification of non-critical instrumentsto be addressed by the plant preventative maintenance pro-gram. Non-critical gauges and displays utilized for referenceonly could be checked or periodically replaced within a pre-ventative maintenance program. The Calibration Programcould employ a separate category of maintenance devices. Forexample, some HVAC control loops may be covered by thepreventative maintenance (calibration) program. Table Ademonstrates similarities and differences between calibra-tion and preventative maintenance functions in relation toinstrumentation testing.

The process of an instrument calibration review flowchart is presented in Figure 2. The Maintenance and Calibra-tion work need integration for the following reasons:

• Calibration schedules must be coordinated with preventa-tive maintenance schedules. Preventative maintenance ofa system immediately after calibration will void all cali-bration efforts. Calibration should be a conclusion ofpreventative maintenance work.

• All instruments require performance verification. How-ever, the detailed periodic calibration with documentedtraceable standards is not necessary for maintenance


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gauges, HVAC controls, and many other devices. Thepreventative maintenance functions within the Calibra-tion Program can satisfy the need for verification for suchdevices without traceable documentation for standardsand detailed records.

Figure 3 summarizes the necessary steps for finalizing andapproving calibration documentation. In the process of devel-opment or modification of a calibration program, those stepscould be subdivided or combined to satisfy company policies,personal need of technical staff, or availability of equipmentand software. A brief description for each step is presentedbelow:

1. The first step is dedicated for instrument identificationwith cross-reference to control loops, systems, and loca-tions. References of the instruments to loops and systemshould be bi-directional. In this step, information is re-corded about manufacturing operational data, devicesmodels, operating software, serial numbers, I/O inputs,etc.

2. The second step requires review of the instrument’s im-pact on product quality. This step will collect informationnecessary to determine instruments, loops, and systemalliance and placement under calibration or preventativemaintenance programs.

3. This step is allocated for instruments under calibrationprogram and will require coordination of tolerances. Cali-bration limits will be determined from coordination oftolerances. Recorded and approved calibration limits willbe used to initiate suitable procedures to notify appropri-ate departments of calibration failures.

Coordination of tolerances is a very important factor forsetting process calibration limits.4 This information shouldbe extracted from engineering and process development in-formation. Based on instrument/loop capabilities and pro-cess requirements, calibration procedures should include twosets of limits. After exceeding the first set of limits theinstrument or loop should be subjected to adjustments. Nocalibration failure notices will be necessary. If the instru-ment or loop calibration data exceeds the second level oflimits then calibration failure notifications will be necessary.For graphical interpretations see Figure 4. Calibration limitsusually are determined by experience, but process limits areestablished from the process requirements and engineeringcalculations.

II. Continued Enforcement of ApprovedCalibration SOPs. Reviews and

Recommendations for Modifications ofCalibration SOPs Based on the Inputs From

Preventative Maintenance and QualityAssurance. Development of new SOPs.

Periodic SOP reviews and GMP training are very importantfactors for a successful calibration program. SOP reviewsshould reflect changes in facility processes, quality assur-

ance, and preventative maintenance programs. GMP train-ing is a requirement for maintaining personnel qualificationsat an acceptable level.

New and modified processes will require creation or modi-fications of specific SOPs. Periodic reviews will assure thatsingle changes of one SOP have not created contradictionsand discrepancies in the integrity of the calibration program.Those reviews or audits should be conducted by quality,engineering, and production representatives.

Training of personnel should be focused on actual docu-mentation procedures and metrology techniques. It is advis-able for members of a calibration team to join professionalsocieties. Participation in the Instrument Society of Americaand National Conference of Weights and Measurements willimprove and broaden technical skills of technicians andengineers. The staff responsible for implementation of tech-nical tasks within the frame of a calibration program mustmaintain and continuously improve their knowledge in in-strumentation and metrology.3

III. Notification of Calibration Failures toAppropriate Departments. Investigations of

Calibration Failures and Assistance toAffected Departments by Providing

Technical Expertise and Improvements.Procedures of a calibration program for pharmaceutical ap-plications should be able to categorize instruments, loops,and systems in several levels of criticality. Instrumentsinvolved in the final product quality tests will be the mostcritical and devices collecting duplicate data will be lesscritical. Different organizations may adapt specific and mostappropriate terminology for a system to categorize instru-ments.

The majority of calibration programs choose the use ofprimary standards. Primary standards are instruments,materials, and devices utilized for testing (calibrating) fieldcalibrators. Primary standards are directly traceable to NISTtraceable laboratories. Field calibrators are traceable toprimary standards. Sometimes primary standards are usedfor field calibration also. All instruments, loops, and devicesmust be traceable to calibrators. Calibration failures of pri-mary or field calibrators will trigger investigations of pro-cesses affected by instruments traceable to failed calibrators.

A failure of an instrument or a loop calibration indicatesthat all product or testing material affected by the instru-ment requires investigation for quality of compliance. Inves-tigation periods will be extended to the date of the previouscalibration. All products manufactured and tested betweenthe last acceptable calibration and the current failure ofcalibration require an investigation.

Instruments of a failed calibration in different applica-tions will require:

a) immediate adjustment, repair, or replacement, orb) no adjustment or repairs until additional testing of the

failed instrument and process is conductedThe actions above must be pre-selected for each instrument,


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Figure 4. Limits of calibration process and tolerances.

loop, and system, and clearly identified by specific SOPs. Theactions ‘a’ and ‘b’ could be associated with the level of critical-ity of instruments and processes. Therefore, instrumentcalibration frequencies should be set with considerations andrisk assessments of processes.

Calibration failures will affect all processes and instru-ments calibrated with the defective calibrator. Calibrationfailure of instruments in a quality assurance laboratory couldhave the same or larger specter of issues. Calibration failuresof critical instrumentation could put product on hold, recalland/or destruction.

Properly engineered systems with correctly selected in-struments and a practical calibration program will effec-

tively minimize nuisance calibration failures. One part of thecalibration program consists of continuous/periodic evalua-tions of the processes and instrumentation to assure goodcGMP compliance.

IV. Maintaining Calibrations Schedules andCoordination with Production and

Maintenance ActivitiesCalibration instruments, loops, and system must be carefullyscheduled for calibration. Calibration work requires shut-down of production and laboratory testing. In productionenvironments, calibration of water systems, continuous ster-ilizers, and other systems will necessitate a major shutdown.

Concludes on page 114.

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Calibration work requires diligence, dedication, and objectiv-ity. Therefore, system shutdowns should be scheduled withadequate time delegated for calibration and coordinationwith other perhaps preventative maintenance activities.

Calibration schedules must be very closely monitored.Overdue scheduled calibrations should be considered asserious events and treated with commitments to avoid anypossible future delays. If an instrument calibration is over-due, then production/laboratory stop notices should be imme-diately forwarded to appropriate departments for shutdownof instruments and associated processes. Accidentally manu-factured products or laboratory work performed with instru-ments affected by a calibration overdue date will requireinvestigation and hold of products.

If a cGMP equipment or system is due for removal ormodification then calibration work should be scheduled be-fore work begins. Calibration should be conducted immedi-ately after production ends and before project work starts. Toassure product integrity calibration work is necessary toverify instrumentation performance as production ends. Af-ter project completion (in case of modification), calibrationwork will be part of commissioning or validation. If equip-ment is removed, then the last calibration report will be arecord that product manufacturing was performed underspecified controls.

ConclusionCalibration work in a pharmaceutical plant should be focusedon the specific applications and not on the capability ofinstruments in wide varieties of their potential performances.The rules of calibration cannot require that all instrumentsmust be calibrated over the full range of the instrument to theexpected manufacturing accuracies and with a completeignorance to the processes. Each system, loop, and instru-ment should be carefully reviewed for calibration methodol-ogy and applicable techniques.

Process instrument calibrations should be done in place,without instrument removal, and within the loops. Loopcalibration is one of the most desirable methods. Calibrationof instruments before installation and manufacturing certi-fication should be considered as a reference only and accept-able for commissioning. In regulatory environments, calibra-tion procedures of an approved program must be exercisedprior to the beginning of qualifications and validations.

The relationship between an instrument range, processlimit, and instrument tolerances is very important. Processlimits cannot exceed instrumentation ranges and range ofinstruments cannot exceed the required process resolution.For example, gauges with ranges of 0 to 1000 psi and 0 to 25psi cannot be used in the processes of 20- 30 psi.

In a large number of pharmaceutical processes, an appli-cation loop calibration at process limits is acceptable andconsidered as a reliable verification of the controlled accu-racy. Loop calibrations could be supplemented by individualdevice calibrations. For example, if frequency of a loop cali-bration is quarterly or semiannual then device calibrationscould be set for an annual schedule. After completion of

individual device calibrations, a loop calibration should bedone to assure proper operation of the loop. Functionalities ofalarms, emergency algorithmic, and sequence of operationsat critical points could be included in calibration procedures.

This article in a general format outlines an infrastructureof a Calibration Program dedicated to a pharmaceuticalfacility. The purpose of the program is an assurance ofinstrumentation integrity. A successful calibration programmust be interfaced and integrated with other functionalprograms of engineering, production, and quality depart-ments. At the present time, a facility calibration program isone of the most important factors in the plant compliance andbusiness performance.

References1. G.L. Squires, Practical Physics, McGraw-Hill, London,

1968.

2. Handbook 44, 2000 Edition, as adopted by 84th NationalConference of Weights and Measurements 1999.

3. Specific Technical Guidelines from NVLAP CalibrationLaboratories Technical Guide http://ts.nist.gov.

4. Gudesblat, Yefim S., “Specification and Calibration Re-quirements for Industrial Scales in Pharmaceutical Appli-cations,” Pharmaceutical Engineering, Vol. 21, No. 5, pp.82-89.

5. 21 CFR 210, MCA Rules and Guidance for PharmaceuticalManufacture and Distribution.

6. GAMP Good Practice Guide: Calibration Management,ISPE 2002.

About the AuthorYefim S. Gudesblat, PE is presently employed by Baxter,Inc. He is a Senior Process/Project Engineer responsible for

project management, construction, and de-sign of major engineering projects in ACCproduction/research facility. In 1971,Gudesblat completed his studies in physicsand electrical engineering technology inOdessa, Ukraine (Formally USSR). He is aregistered Professional Engineer in Penn-sylvania, North Carolina, and New Jersey.

Gudesblat has 23 years of experience in the pharmaceuticalindustry and has published several articles in leading tech-nical magazines, including Pharmaceutical Engineering. Hewas employed by Wyeth, Johnson & Johnson - Merck and aconsulting firm TCPI. He can be reached by tel: 1-856/489-2585 or by email: [email protected].

Wyeth, 2 Esterbrook Ln., Cherry Hill, NJ 08003.

implementing calibration program

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