〈1058〉 ANALYTICAL INSTRUMENT QUALIFICATION.

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1058

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ANALYTICAL INSTRUMENT

QUALIFICATION

INTRODUCTION

A large variety of laboratory equipment, instruments, and computerized analytical systems, ranging from simple nitro-gen evaporators to complex multiple-function technologies (see Instrument Categories), are used in the pharmaceutical industry to acquire data to help ensure that products are suitable for their intended use. An analyst’s objective is to consistently obtain reliable and valid data suitable for the intended 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 samples

to help ensure that the acquired data are reliable. With the increasing sophistication and automation of analytical instru-ments, an increasing demand has been placed on users to

qualify 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 of regarding instrument qualification and validation procedures a qualified instrument in analyses contributes to confidence and the roles and responsibilities of those who perform in the validity of generated data.

them. Consequently, various approaches have been used for

instrument qualification, approaches that require varying

_{Analytical Method Validation}

amounts of resources and generate widely differing amounts

of 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 for} ponents required for generating reliable and consistent data. _{its intended use. Use of a validated procedure with qualified} Note 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. Additional} the instrumentation. This approach emphasizes AIQ’s place _{guidance on validation of compendial procedures may be} in 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 Tests}

In 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 to} Thus, the phrase “analytical instrument qualification” (AIQ) _{ensure that the system’s performance is acceptable at the} is 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 Samples

There 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 qualstan-ity. Analytical dards. Some analyses also require the inclusion of quality instrument qualification forms the base for generating qual- control check samples to provide an in-process or ongoing ity 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 sample analysis.

ANALYTICAL INSTRUMENT QUALIFICATION

PROCESS

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

Operational Performance Design Qualification Installation Qualification Qualification Qualification

Timing and Applicability

Prior to purchase of a new At installation of each instrument After installation or Periodically at specified intervals model of instrument (new, old, or existing unquali- major repair of for each instrument

fied) each instrument

Activities

Assurance of manufacturer’s Description Fixed parameters Preventive maintenance and

re-DQ pairs

Assurance of adequate support Instrument delivery Establish practices to address oper-availability from manufacturer ation, calibration, maintenance,

and change control Utilities/facility Environment

Instrument’s fitness for use in

laboratory Assembly and installation

Network and data storage Secure data stor-age, backup, and archive

Installation verification Instrument function Performance checks tests

* Activities under each phase are usually performed as given in the table. However, in some cases, it may be more appropriate to perform or combine a given activity with another phase. Such activities spanning more than one qualification phase are shown as connected by double arrows. If an activity listed under a given phase is performed under another phase, it is not necessary to repeat the activity under the phase where the 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

_I

_NSTALLATION

_Q

_UALIFICATION scope of this chapter.

Installation qualification (IQ) is the documented collection of activities necessary to establish that an instrument is

de-Qualification Phases

livered as designed and specified, and is properly installed in the selected environment, and that this environment is suit-Instrument qualification is not a single continuous

pro-able for the instrument. IQ applies to an instrument that is cess, but instead results from several discrete activities. For

new or was pre-owned, or to any instrument that exists on convenience, these activities can be grouped into four

site but has not been previously qualified. Relevant parts of phases: design qualification (DQ), installation qualification

IQ would also apply to a qualified instrument that has been (IQ), operational qualification (OQ), and performance

quali-transported to another location or is being reinstalled for fication (PQ).

other reasons, such as prolonged storage. The activities and Some AIQ activities cover more than one qualification

documentation typically associated with IQ are as follows. phase, and analysts potentially could perform them during

Description—Provide a description of the instrument or

more than one of the phases (see Table 1). However, in

the collection of instrument components, including its man-many instances there is need for specific order to the AIQ

ufacturer, model, serial number, software version, and loca-activities; for example, installation qualification must occur

tion. Use drawings and flow charts where appropriate. first in order to initiate other qualification activities. The AIQ

activities will be defined and documented. Instrument Delivery—Ensure that the instrument, software, manuals, supplies, and any other instrument ac-cessories arrive as specified in the purchase order and that

D

ESIGN

Q

UALIFICATION _{they are undamaged. For a pre-owned or existing}

instru-ment, manuals and documentation should be obtained. Design qualification (DQ) is the documented collection of _{Utilities/Facility/Environment—Verify that the} installa-activities that define the functional and operational

specifica-tion site satisfactorily meets manufacturer-specified environ-tions of the instrument and criteria for selection of the ven- _{mental requirements.}

dor, based on the intended purpose of the instrument.

De-Assembly and Installation—Assemble and install the

in-sign qualification (DQ) may be performed not only by the

strument, and perform any preliminary diagnostics and test-instrument developer or manufacturer but also may be

per-ing. Assembly and installation may be done by the manu-formed by the user. The manufacturer is generally

responsi-facturer, vendor, specialized engineers, or qualified in-house ble for robust design and maintaining information

describ-personnel. Manufacturer-established installation tests and ing how the analytical instrument is manufactured (design

guides provide a valuable baseline reference for determining specifications, functional requirements, etc.) and tested

instrument acceptance. Any abnormal event observed dur-before shipment to users. Nonetheless, the user should

en-ing assembly and installation merits documenten-ing. Installa-sure that commercial off-the-shelf (COTS) instruments are

tion packages purchased from the manufacturer or the ven-suitable for their intended application and that the

manufac-dor may, however, need to be supplemented with user-turer has adopted a quality system that provides for reliable

specific criteria. equipment. Users should also determine the manufacturer’s

capability for support installation, services, and training. This Network and Data Storage—Some analytical systems determination might be aided by the user’s previous interac- require users to provide network connections and data stor-tion with the manufacturer. age capabilities at the installation site. When required,

con-nect the instrument to the network, and check its function-ality.

set differently if required. Nevertheless, user specifications

O

PERATIONAL

Q

UALIFICATION

for PQ tests should demonstrate trouble-free instrument op-eration for the intended applications. As is the case with OQ After a successful IQ, the instrument is ready for OQ

test-testing, PQ tests may be modular or holistic. ing. Operational qualification (OQ) is the documented

col-Testing frequency depends on the ruggedness of the in-lection of activities necessary to demonstrate that an

instru-strument and the criticality of the tests performed. Testing ment will function according to its operational specification

may be unscheduled—for example, each time the instru-in the selected environment. Testinstru-ing activities instru-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.

Fixed Parameters—These tests measure the instrument’s

It may be useful to repeat the same PQ tests each time the nonchanging parameters such as length, height, weight, _{instrument is used so that a history of the instrument’s} per-voltage inputs, acceptable pressures, and loads. If the

manu-formance can be compiled. Alternatively, the instrument facturer-supplied specifications for these parameters satisfy _{may be incorporated into an integrated support system to} the user, the test requirements may be waived. However, if

assure that it remains continually qualified. Some system the user wants to confirm the parameters, testing can be _{suitability tests or quality control checks that are performed} performed at the user’s site. Fixed parameters do not

concurrently with the test samples also imply that the in-change over the life of the instrument, and therefore never _{strument is performing suitably.}

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

Secure Data Storage, Backup, and Archiving—When _{be recommended for many instruments. The relevant PQ}

applicable, test secure data handling such as storage,

test(s) should be repeated after the needed maintenance or backup, audit trails, and archiving at the user’s site accord- _{repair to ensure that the instrument remains qualified.} ing to written procedures.

Practices for Operation, Calibration, Maintenance, and

Instrument Function Tests—Instrument functions re- _{Change Control—Establish practices to maintain and}

cali-quired by the user should be tested to verify that the

instru-brate the instrument. Each maintenance and calibration ac-ment operates as intended by the manufacturer. Manufac- _{tivity should be documented.}

turer-supplied information is useful in identifying

specifications for these parameters and in designing tests to

evaluate the identified parameters. Users, or their qualified

_{ROLES AND RESPONSIBILITIES}

designees, should perform these tests to verify that the

in-strument meets manufacturer or user specifications in the user’s environment.

Users

The extent of OQ testing that an instrument undergoes depends on its intended applications. Therefore, no specific

Users are ultimately responsible for instrument operations OQ 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 of jor repairs or modifications, relevant OQ and/or PQ tests

instruments make them the best-qualified group to design should 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 qualified ing of such components without requalification. Holistic

state by routinely performing PQ. tests, which involve the entire system, are also acceptable.

Quality Unit

P

ERFORMANCE

Q

UALIFICATION

The role of the Quality Unit in AIQ remains the same as Performance qualification (PQ) is the documented

collec-for any other regulated activity. Quality personnel are re-tion of activities necessary to demonstrate that an

instru-sponsible for assuring that the AIQ process meets compli-ment consistently performs according to the specifications

ance requirements, that processes are being followed, and defined by the user, and is appropriate for the intended use.

that the intended use of the equipment is supported by After IQ and OQ have been performed, the instrument’s

valid and documented data. continued suitability for its intended use is demonstrated

through performance qualification. The PQ phase may

in-clude the following parameters.

_{Manufacturers}

Performance Checks—Set up a test or series of tests to

Change control may follow the DQ/IQ/OQ/PQ

classifica-SOFTWARE VALIDATION

tion process. For DQ, evaluate the changed parameters, and determine whether need for the change warrants imple-Software used for analytical work can be classified into

menting it. If implementation of the change is needed, in-three categories: firmware; instrument control, data

acquisi-stall the changes to the system during IQ. Evaluate which of tion, and processing software; and stand-alone software.

Al-the existing OQ and PQ tests need revision, deletion, or though software validation is not the primary focus of this

addition as a result of the installed change. Where the chapter, the following sections describe in which cases this

change calls for additions, deletions, or revisions to the OQ activity is under the scope of the analytical instrument

or PQ tests, follow the procedure outlined below. qualification.

Operational Qualification—Revise OQ tests as

necessi-tated by the change. Perform the relevant tests affected by

Firmware

_{the change. This ensures the instrument’s effective operation}

after the change is installed. Computerized analytical instruments contain integrated

Performance Qualification—Revise PQ tests as

necessi-chips with low-level software (firmware). Such instruments

tated by the change. Perform the PQ testing after installa-will not function without properly operating firmware, and

tion of the change if similar testing is not already performed users 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 instrument ment itself. Indeed, the qualification of hardware is not

pos-control, data acquisition, and processing, change control is sible without operating it via its firmware. Thus, when the

performed through DQ/IQ/OQ/PQ of the affected instru-hardware (that is, the analytical instrument) is qualified at

ment. Change control for stand-alone software requires the user’s site, the integrated firmware is also essentially

user-site testing of changed functionality. qualified. No separate on-site qualification of the firmware is

needed. Whenever possible, the firmware version should be

recorded as part of the IQ activities. Any changes made to

_{AIQ DOCUMENTATION}

firmware versions should be tracked through change control

of the instrument (see Change Control, below). _{Documents obtained during instrument qualification} should be retained in an accessible manner. Where multiple instruments of one kind exist, documents common to all

Instrument Control, Data Acquisition, and

instruments and documents specific to an instrument may

Processing Software

be 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 is

tained and maintained in a suitable manner that allows for loaded 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 CATEGORIES}

tion calculations. Thus, both hardware and software, their

functions 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 this _{rators to complex automated instruments. Therefore,} apply-software, and provide users with a summary of validation. _{ing a single set of principles to qualifying such dissimilar} At the user site, holistic qualification, which involves the en- _{instruments would be scientifically inappropriate. Users are} tire instrument and software system, is more efficient than _{most capable of establishing the level of qualification} modular validation of the software alone. Thus, the user _{needed 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 to _{A, B, and C, as defined below. Examples of instruments in} the AIQ process. _{each group are provided. Note that the list of instruments} provided here is for illustration only and is not meant to be exhaustive. It does not provide the exact category for an

Stand-Alone Software

instrument at a user site. That category should be deter-mined by users for their specific instruments or applications. An authoritative guide for validating stand-alone software,

The exact grouping of an instrument must be determined such as LIMS, is available.1

The validation process is

adminis-by users for their specific requirements. Depending on indi-tered by the software developer, who also specifies the

de-vidual user requirements, the same instrument may appro-velopment model appropriate for the software. Validation

priately fall into one group for one user and another group takes place in a series of activities planned and executed

for another user. Therefore, a careful selection of groups by through various stages of the development cycle.

users is highly encouraged.

CHANGE CONTROL

Group 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, where defects. However, implementing all such changes may not

the manufacturer’s specification of basic functionality is ac-always benefit users. Users should therefore adopt changes

cepted as user requirements. Conformance of Group A they deem useful or necessary and should also assess the

equipment with user requirements may be verified and doc-effects of changes to determine what, if any, requalification

umented through visual observation of its operation. Exam-is required. The change control process enables them to do

ples of equipment in this group are nitrogen evaporators, this.

magnetic stirrers, vortex mixers, and centrifuges.

1_{General Principles of Software Validation: Final Guidance for Industry and FDA}

performance tests. Installing these instruments can be a complicated undertaking and may require the assistance of

Group B

specialists. A full qualification process, as outlined in this document, should apply to these instruments. Examples of Group B includes standard equipment and instruments

instruments in this group include the following: providing measured values as well as equipment controlling

• atomic absorption spectrometers physical parameters (such as temperature, pressure, or flow)

• differential scanning calorimeters that need calibration, where the user requirements are

typi-• dissolution apparatus cally the same as the manufacturer’s specification of

func-• electron microscopes tionality and operational limits. Conformance of Group B

• flame absorption spectrometers instruments or equipment to user requirements is

deter-• high-pressure liquid chromatographs mined according to the standard operating procedures for

• mass spectrometers the instrument or equipment, and documented during IQ

• microplate readers and OQ. Examples of instruments in this group are

bal-• thermal gravimetric analyzers ances, melting point apparatus, light microscopes, pH

me-• X-ray fluorescence spectrometers ters, variable pipets, refractometers, thermometers, titrators,

• X-ray powder diffractometers and viscometers. Examples of equipment in this group are

• densitometers muffle furnaces, ovens, refrigerator-freezers, water baths,

• diode-array detectors pumps, and dilutors.

• elemental analyzers • gas chromatographs

Group C

• IR spectrometers

• near-IR spectrometers Group C includes instruments and computerized analytical • Raman spectrometers systems, where user requirements for functionality, opera- • UV/Vis spectrometers

tional, and performance limits are specific for the analytical • inductively coupled plasma-emission spectrometers application. Conformance of Group C instruments to user