USP 36 General Information / ⟨1058⟩ Analytical Instrument Qualification 1

⟨1058⟩ ANALYTICAL INSTRUMENTQUALIFICATION

INTRODUCTION

A large variety of laboratory equipment, instruments, andcomputerized analytical systems, ranging from simple nitro-gen evaporators to complex multiple-function technologies(see Instrument Categories), are used in the pharmaceuticalindustry to acquire data to help ensure that products aresuitable for their intended use. An analyst’s objective is toconsistently obtain reliable and valid data suitable for theintended purpose. Depending on the applications, users val-idate their procedures, calibrate their instruments, and per-form additional instrument checks, such as system suitability

Figure 1. Components of data quality.tests and analysis of in-process quality control check samplesto help ensure that the acquired data are reliable. With theincreasing sophistication and automation of analytical instru-ments, an increasing demand has been placed on users toqualify their instruments. Analytical Instrument Qualification

Unlike method validation and system suitability activities,analytical instrument qualification (AIQ) currently has no AIQ is the collection of documented evidence that an in-specific guidance or procedures. Competing opinions exist strument performs suitably for its intended purpose. Use ofregarding instrument qualification and validation procedures a qualified instrument in analyses contributes to confidenceand the roles and responsibilities of those who perform in the validity of generated data.them. Consequently, various approaches have been used forinstrument qualification, approaches that require varying Analytical Method Validationamounts of resources and generate widely differing amountsof documentation. This chapter provides a scientific ap- Analytical method validation is the collection of docu-proach to AIQ and considers AIQ as one of the major com- mented evidence that an analytical procedure is suitable forponents required for generating reliable and consistent data. its intended use. Use of a validated procedure with qualifiedNote that the amount of rigor applied to the qualification analytical instruments provides confidence that the proce-process will depend on the complexity and intended use of dure will generate test data of acceptable quality. Additionalthe instrumentation. This approach emphasizes AIQ’s place guidance on validation of compendial procedures may bein the overall process of obtaining reliable data from analyti- found in the general information chapter Validation of Com-cal instruments. pendial Procedures ⟨1225⟩.

Validation versus Qualification System Suitability TestsIn this chapter, the term validation is used for manufac- System suitability tests verify that the system will perform

turing processes, analytical procedures, and software proce- in accordance with the criteria set forth in the procedure.dures and the term qualification is used for instruments. These tests are performed along with the sample analyses toThus, the phrase “analytical instrument qualification” (AIQ) ensure that the system’s performance is acceptable at theis used for the process of ensuring that an instrument is time of the test. USP general chapter Chromatography ⟨621⟩suitable for its intended application. presents a more detailed discussion of system suitability tests

as related to chromatographic systems.COMPONENTS OF DATA QUALITY

Quality Control Check SamplesThere are four critical components involved in the genera-

tion of reliable and consistent data (quality data). Figure 1 Many analysts carry out their tests on instruments stan-shows these components as layered activities within a qual- dardized using reference materials and/or calibration stan-ity triangle. Each layer adds to the overall quality. Analytical dards. Some analyses also require the inclusion of qualityinstrument qualification forms the base for generating qual- control check samples to provide an in-process or ongoingity data. The other components essential for generating assurance of the test’s suitable performance. In this manner,quality data are analytical method validation, system suita- AIQ and analytical method validation contribute to the qual-bility tests, and quality control check samples. These quality ity of analysis before analysts conduct the tests. System suita-components are described below. bility tests and quality control checks help ensure the quality

of analytical results immediately before or during sampleanalysis.

ANALYTICAL INSTRUMENT QUALIFICATIONPROCESS

The following sections address in detail the AIQ process.The other three components of building quality into analyti-cal data—analytical method validation, system suitability

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Table 1. Timing, Applicability, and Activities for Each Phase of Analytical Instrument Qualification*

Operational PerformanceDesign Qualification Installation Qualification Qualification Qualification

Timing and ApplicabilityPrior to purchase of a new At installation of each instrument After installation or Periodically at specified intervalsmodel of instrument (new, old, or existing major repair of for each instrument

unqualified) each instrumentActivities

Assurance of manufacturer’s Description Fixed parameters Preventive maintenance andDQ repairs

Assurance of adequate support Instrument delivery Establish practices to addressavailability from manufacturer operation, calibration,

maintenance, and change controlUtilities/facility EnvironmentInstrument’s fitness for use in

laboratory Assembly and installationNetwork and data storage Secure data

storage, backup,and archive

Installation verification Instrument function Performance checkstests

* Activities under each phase are usually performed as given in the table. However, in some cases, it may be more appropriate to perform orcombine a given activity with another phase. Such activities spanning more than one qualification phase are shown as connected by doublearrows. If an activity listed under a given phase is performed under another phase, it is not necessary to repeat the activity under the phase wherethe activity is listed. Performing the activity is far more important than the phase under which the activity is performed.

tests, and quality control check samples—are not within the the selected environment, and that this environment is suit-scope of this chapter. able for the instrument. IQ applies to an instrument that is

new or was pre-owned, or to any instrument that exists onsite but has not been previously qualified. Relevant parts ofQualification Phases IQ would also apply to a qualified instrument that has beentransported to another location or is being reinstalled forInstrument qualification is not a single continuous pro- other reasons, such as prolonged storage. The activities andcess, but instead results from several discrete activities. For documentation typically associated with IQ are as follows.convenience, these activities can be grouped into four

Description—Provide a description of the instrument orphases: design qualification (DQ), installation qualificationthe collection of instrument components, including its man-(IQ), operational qualification (OQ), and performance quali-ufacturer, model, serial number, software version, and loca-fication (PQ).tion. Use drawings and flow charts where appropriate.Some AIQ activities cover more than one qualification

Instrument Delivery—Ensure that the instrument,phase, and analysts potentially could perform them duringsoftware, manuals, supplies, and any other instrument ac-more than one of the phases (see Table 1). However, incessories arrive as specified in the purchase order and thatmany instances there is need for specific order to the AIQthey are undamaged. For a pre-owned or existing instru-activities; for example, installation qualification must occurment, manuals and documentation should be obtained.first in order to initiate other qualification activities. The AIQ

activities will be defined and documented. Utilities/Facility/Environment—Verify that the installa-tion site satisfactorily meets manufacturer-specified environ-mental requirements.DESIGN QUALIFICATION Assembly and Installation—Assemble and install the in-strument, and perform any preliminary diagnostics and test-Design qualification (DQ) is the documented collection of ing. Assembly and installation may be done by the manu-activities that define the functional and operational specifica- facturer, vendor, specialized engineers, or qualified in-housetions of the instrument and criteria for selection of the ven- personnel. Manufacturer-established installation tests anddor, based on the intended purpose of the instrument. De- guides provide a valuable baseline reference for determiningsign qualification (DQ) may be performed not only by the instrument acceptance. Any abnormal event observed dur-instrument developer or manufacturer but also may be per- ing assembly and installation merits documenting. Installa-formed by the user. The manufacturer is generally responsi- tion packages purchased from the manufacturer or the ven-ble for robust design and maintaining information describ- dor may, however, need to be supplemented with user-ing how the analytical instrument is manufactured (design specific criteria.specifications, functional requirements, etc.) and tested

Network and Data Storage—Some analytical systemsbefore shipment to users. Nonetheless, the user should en-require users to provide network connections and data stor-sure that commercial off-the-shelf (COTS) instruments areage capabilities at the installation site. When required, con-suitable for their intended application and that the manufac-nect the instrument to the network, and check its function-turer has adopted a quality system that provides for reliableality.equipment. Users should also determine the manufacturer’s

capability for support installation, services, and training. This Installation Verification—Perform the initial diagnosticsdetermination might be aided by the user’s previous interac- and testing of the instrument after installation.tion with the manufacturer.

OPERATIONAL QUALIFICATIONINSTALLATION QUALIFICATION

After a successful IQ, the instrument is ready for OQ test-Installation qualification (IQ) is the documented collection ing. Operational qualification (OQ) is the documented col-

of activities necessary to establish that an instrument is de- lection of activities necessary to demonstrate that an instru-livered as designed and specified, and is properly installed in ment will function according to its operational specification

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in the selected environment. Testing activities in the OQ ment is used. It may also be scheduled for regular intervals.phase may consist of these test parameters. Experience with the instrument can influence this decision.

It may be useful to repeat the same PQ tests each time theFixed Parameters—These tests measure the instrument’sinstrument is used so that a history of the instrument’s per-nonchanging parameters such as length, height, weight,formance can be compiled. Alternatively, the instrumentvoltage inputs, acceptable pressures, and loads. If the manu-may be incorporated into an integrated support system tofacturer-supplied specifications for these parameters satisfyassure that it remains continually qualified. Some systemthe user, the test requirements may be waived. However, ifsuitability tests or quality control checks that are performedthe user wants to confirm the parameters, testing can beconcurrently with the test samples also imply that the in-performed at the user’s site. Fixed parameters do notstrument is performing suitably.change over the life of the instrument, and therefore never

need redetermination. [NOTE—These tests could also be per- Preventive Maintenance and Repairs—When an instru-formed during the IQ phase (see Table 1); if so, fixed pa- ment fails to meet PQ test specifications, it requires mainte-rameters need not be redetermined as part of OQ testing.] nance or repair. A periodic preventive maintenance may also

be recommended for many instruments. The relevant PQSecure Data Storage, Backup, and Archiving—Whentest(s) should be repeated after the needed maintenance orapplicable, test secure data handling such as storage,repair to ensure that the instrument remains qualified.backup, audit trails, and archiving at the user’s site accord-

ing to written procedures. Practices for Operation, Calibration, Maintenance, andChange Control—Establish practices to maintain and cali-Instrument Function Tests—Instrument functions re-brate the instrument. Each maintenance and calibration ac-quired by the user should be tested to verify that the instru-tivity should be documented.ment operates as intended by the manufacturer. Manufac-

turer-supplied information is useful in identifyingspecifications for these parameters and in designing tests to ROLES AND RESPONSIBILITIESevaluate the identified parameters. Users, or their qualifieddesignees, should perform these tests to verify that the in-strument meets manufacturer or user specifications in theuser’s environment. Users

The extent of OQ testing that an instrument undergoesdepends on its intended applications. Therefore, no specific Users are ultimately responsible for instrument operationsOQ tests for any instrument or application are offered in and data quality. The user’s group encompasses analysts,this chapter. their supervisors, instrument specialists, and organization

Routine analytical tests do not constitute OQ testing. OQ management. Users should be adequately trained in the in-tests are specifically designed to verify the instrument’s op- strument’s use, and their training records should be main-eration according to specifications in the user’s environ- tained as required by the regulations.ment, and repeating the testing at regular intervals may not Users should also be responsible for qualifying their instru-be required. However, when the instrument undergoes ma- ments because their training and expertise in the use ofjor repairs or modifications, relevant OQ and/or PQ tests instruments make them the best-qualified group to designshould be repeated to verify whether the instrument contin- the instrument test(s) and specification(s) necessary for suc-ues to operate satisfactorily. If an instrument is moved to cessful AIQ. Consultants, equipment manufacturer or ven-another location, an assessment should be made of what, if dors, validation specialists, and quality assurance (QA) per-any, OQ test should be repeated. sonnel can advise and assist as needed, but the final

OQ tests can be modular or holistic. Modular testing of responsibility for qualifying instruments lies with the users.individual components of a system may facilitate interchang- The users must also maintain the instrument in a qualifieding of such components without requalification. Holistic state by routinely performing PQ.tests, which involve the entire system, are also acceptable.

Quality UnitPERFORMANCE QUALIFICATION

The role of the Quality Unit in AIQ remains the same asfor any other regulated activity. Quality personnel are re-Performance qualification (PQ) is the documented collec-sponsible for assuring that the AIQ process meets compli-tion of activities necessary to demonstrate that an instru-ance requirements, that processes are being followed, andment consistently performs according to the specificationsthat the intended use of the equipment is supported bydefined by the user, and is appropriate for the intended use.valid and documented data.After IQ and OQ have been performed, the instrument’s

continued suitability for its intended use is demonstratedthrough performance qualification. The PQ phase may in- Manufacturersclude the following parameters.

Performance Checks—Set up a test or series of tests to Manufacturers and developers are responsible for DQverify the acceptable performance of the instrument for its when designing the instrument. They are also responsibleintended use. PQ tests are usually based on the instrument’s for validation of relevant processes used in manufacturingtypical on-site applications and may consist of analyzing and assembly of the instrument. Manufacturers should testknown components or standards. The tests should be based the assembled instruments before shipping them to users.on good science and reflect the general intended use of the Finally, it is desirable that manufacturers and vendorsinstrument. Some system suitability tests or quality control should notify all known users about hardware defects dis-checks that are performed concurrently with the test sam- covered after a product’s release; offer user training, service,ples can be used to demonstrate that the instrument is per- repair, and installation support; and invite user audits asforming suitably. PQ tests may resemble those performed necessary.during OQ, but the specifications for their results may beset differently if required. Nevertheless, user specificationsfor PQ tests should demonstrate trouble-free instrument op- SOFTWARE VALIDATIONeration for the intended applications. As is the case with OQtesting, PQ tests may be modular or holistic. Software used for analytical work can be classified into

Testing frequency depends on the ruggedness of the in- three categories: firmware; instrument control, data acquisi-strument and the criticality of the tests performed. Testing tion, and processing software; and stand-alone software. Al-may be unscheduled—for example, each time the instru- though software validation is not the primary focus of this

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chapter, the following sections describe in which cases this addition as a result of the installed change. Where theactivity is under the scope of the analytical instrument change calls for additions, deletions, or revisions to the OQqualification. or PQ tests, follow the procedure outlined below.

Operational Qualification—Revise OQ tests as necessi-tated by the change. Perform the relevant tests affected byFirmwarethe change. This ensures the instrument’s effective operationafter the change is installed.Computerized analytical instruments contain integrated

Performance Qualification—Revise PQ tests as necessi-chips with low-level software (firmware). Such instrumentstated by the change. Perform the PQ testing after installa-will not function without properly operating firmware, andtion of the change if similar testing is not already performedusers generally cannot alter firmware design or function.during OQ. In the future, perform the revised PQ testing.Firmware is therefore considered a component of the instru-

For changes to firmware and to software for instrumentment itself. Indeed, the qualification of hardware is not pos-control, data acquisition, and processing, change control issible without operating it via its firmware. Thus, when theperformed through DQ/IQ/OQ/PQ of the affected instru-hardware (that is, the analytical instrument) is qualified atment. Change control for stand-alone software requiresthe user’s site, the integrated firmware is also essentiallyuser-site testing of changed functionality.qualified. No separate on-site qualification of the firmware is

needed. Whenever possible, the firmware version should berecorded as part of the IQ activities. Any changes made to AIQ DOCUMENTATIONfirmware versions should be tracked through change controlof the instrument (see Change Control, below).

Documents obtained during instrument qualificationshould be retained in an accessible manner. Where multiple

Instrument Control, Data Acquisition, and instruments of one kind exist, documents common to allinstruments and documents specific to an instrument mayProcessing Softwarebe stored separately. During change control, additional doc-uments may supplement those obtained during the qualifi-Software for instrument control, data acquisition, and pro-cation process, and both sets of documents should be re-cessing for many of today’s computerized instruments istained and maintained in a suitable manner that allows forloaded on a computer connected to the instrument. Opera-appropriate protection and access.tion of the instrument is then controlled via the software,

leaving fewer operating controls on the instrument. Also,the software is needed for data acquisition and postacquisi- INSTRUMENT CATEGORIEStion calculations. Thus, both hardware and software, theirfunctions inextricably intertwined, are critical to providing

Modern laboratories typically include a suite of instru-analytical results.ments and equipment varying from simple nitrogen evapo-The manufacturer should perform DQ, validate thisrators to complex automated instruments. Therefore, apply-software, and provide users with a summary of validation.ing a single set of principles to qualifying such dissimilarAt the user site, holistic qualification, which involves the en-instruments would be scientifically inappropriate. Users aretire instrument and software system, is more efficient thanmost capable of establishing the level of qualificationmodular validation of the software alone. Thus, the userneeded for an instrument. On the basis of the level needed,qualifies the instrument control, data acquisition, and pro-it is convenient to categorize instruments into three groups:cessing software by qualifying the instrument according toA, B, and C, as defined below. Examples of instruments inthe AIQ process.each group are provided. Note that the list of instrumentsprovided here is for illustration only and is not meant to be

Stand-Alone Software exhaustive. It does not provide the exact category for aninstrument at a user site. That category should be deter-

An authoritative guide for validating stand-alone software, mined by users for their specific instruments or applications.such as LIMS, is available.1 The validation process is adminis- The exact grouping of an instrument must be determinedtered by the software developer, who also specifies the de- by users for their specific requirements. Depending on indi-velopment model appropriate for the software. Validation vidual user requirements, the same instrument may appro-takes place in a series of activities planned and executed priately fall into one group for one user and another groupthrough various stages of the development cycle. for another user. Therefore, a careful selection of groups by

users is highly encouraged.

CHANGE CONTROLGroup A

Changes to instruments, including software, become inev-Group A includes standard equipment with no measure-itable as manufacturers add new features and correct known

ment capability or usual requirement for calibration, wheredefects. However, implementing all such changes may notthe manufacturer’s specification of basic functionality is ac-always benefit users. Users should therefore adopt changescepted as user requirements. Conformance of Group Athey deem useful or necessary and should also assess theequipment with user requirements may be verified and doc-effects of changes to determine what, if any, requalificationumented through visual observation of its operation. Exam-is required. The change control process enables them to doples of equipment in this group are nitrogen evaporators,this.magnetic stirrers, vortex mixers, and centrifuges.Change control may follow the DQ/IQ/OQ/PQ classifica-

tion process. For DQ, evaluate the changed parameters, anddetermine whether need for the change warrants imple- Group Bmenting it. If implementation of the change is needed, in-stall the changes to the system during IQ. Evaluate which of Group B includes standard equipment and instrumentsthe existing OQ and PQ tests need revision, deletion, or providing measured values as well as equipment controlling1General Principles of Software Validation: Final Guidance for Industry and FDA physical parameters (such as temperature, pressure, or flow)Staff, U.S. Department of Health and Human Services, Food and Drug Admin- that need calibration, where the user requirements are typi-istration, Rockville, MD, January 11, 2002. http://www.fda.gov/Medi- cally the same as the manufacturer’s specification of func-calDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085281.

tionality and operational limits. Conformance of Group Bhtm (accessed December 2012.instruments or equipment to user requirements is deter-

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mined according to the standard operating procedures for • atomic absorption spectrometersthe instrument or equipment, and documented during IQ • differential scanning calorimetersand OQ. Examples of instruments in this group are bal- • dissolution apparatusances, melting point apparatus, light microscopes, pH me- • electron microscopesters, variable pipets, refractometers, thermometers, titrators, • flame absorption spectrometersand viscometers. Examples of equipment in this group are • high-pressure liquid chromatographsmuffle furnaces, ovens, refrigerator-freezers, water baths, • mass spectrometerspumps, and dilutors. • microplate readers

• thermal gravimetric analyzers• X-ray fluorescence spectrometersGroup C • X-ray powder diffractometers• densitometersGroup C includes instruments and computerized analytical • diode-array detectorssystems, where user requirements for functionality, opera- • elemental analyzerstional, and performance limits are specific for the analytical • gas chromatographsapplication. Conformance of Group C instruments to user • IR spectrometersrequirements is determined by specific function tests and • near-IR spectrometersperformance tests. Installing these instruments can be a • Raman spectrometerscomplicated undertaking and may require the assistance of • UV/Vis spectrometersspecialists. A full qualification process, as outlined in this • inductively coupled plasma-emission spectrometersdocument, should apply to these instruments. Examples of

instruments in this group include the following: