Chapter 3

Qualification
of Analytical
Instruments
3
Qualification of Equipment qualification and validation of computerized systems cover the
entire life of a product. It starts when somebody has a need for a specific
Analytical product and ends when the equipment is retired. For computer systems
Instruments validation ends when all records on the computer system have been
migrated and validated for accuracy and completeness on a new one.
Because of the length of time and complexity the process has been broken
down into shorter phases, so called lifecycle phases. Several lifecycle models
have been described for qualification and validation. Most common ones
are the V and 4Q model. The V model includes code development and
code testing for software, which is important when validation also covers
software development. For the purpose of this primer, where we deal
with commercially available instruments and systems, we have selected
the 4Q model with phases such as design qualification (DQ), installation
qualification (IQ), operational qualification (OQ), performance qualification
(PQ). The process is illustrated in figure 2.

Good to know! • Compare user requirements

Design Qualification with supplier specifications
All activities are defined in a • Supplier assessment
validation or qualification plan
• Verify environment

Qualification Report
and results are documented in
Installation Qualification • Verify arrival as purchased
Qualification Plan

a summary report.
• Check proper installation of
hardware and software
• Test of operational functions
Operational Qualification • Performance testing
• Test of security functions
• Test for specified application
Performance Qualification • Preventive maintenance
• On-going performance tests

Figure 2
Qualification phases – 4Q model.

In the DQ phase user requirements are compared with the vendor’s

specification. In addition, users conduct an assessment of the vendor. In
the installation qualification the selected user’s environment is checked
whether it meets the vendor’s environmental specifications. The instrument

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is installed according to vendor’s recommendations and correct installation
is verified and documented. Operational qualification checks if the instrument
conforms to the functional specifications, as defined in the DQ phase.
Performance qualification verifies that the complete system works for
selected applications. Preventive maintenance activities and controlled
changes also are part of this phase. All activities are defined in a validation
or qualification plan and results are documented in a summary report.
Figure 3 illustrates the timeline for the four qualifications.

Design Installation Operational Performance

Qualification Qualification Qualification Qualification

• Before • At • After • Whenever the

Purchasing installation installation instrument
• After major is used, e.g.,
changes, daily
e.g., repair,
updates
• At regular
intervals
(risk based)

Figure 3
Qualification time line.

3.1 Qualification Planning Qualification activities should be described in a master plan. The plan
documents a company’s approach for specific activities, for example, how
to qualify analytical instruments, how to assess vendors or what to test for
commercial computer systems. A master plan serves two purposes: when
implemented right, it ensures consistent and efficient implementation of
equipment qualifications, and it answers an inspector’s question for a
company’s approach for instrument qualification and system validation.
A validation master plan is also officially required by Annex 1522 to the

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European GMP directive: “All validation activities should be planned.
The key elements of a validation program should be clearly defined and
documented in a Validation Master Plan (VMP) or equivalent documents”.
FDA regulations and guidelines do not specifically require a validation
master plan. However, inspectors want to know what the company’s
approach towards validation is. The qualification master plan is an ideal
tool to communicate this approach both internally and to inspectors. In
case there are any questions as to why things have been done or not
done, the master plan should provide the answers.
Good to know! Within an organization a validation master plan can be developed for:
A validation master plan is the entire company at a corporate level
officially required by Annex 15
multiple or single sites
to the European GMP directive.
departments
system categories
The master plan is a framework for individual project plans and should be
written at the highest level possible. This ensures consistent implementation
across an organization.
Equipment and computer validation master plans should include:
1. Introduction with a scope of the plan, e.g., sites, systems, processes
2. Responsibilities, e.g., user departments, QA, IT
3. Related documents, e.g., risk master plan
4. Products/processes to be validated and/or qualified
5. Qualification/validation approach
6. Risk assessment
7. Steps for equipment qualification and computer system validation
with examples on type and extent of testing
8. Vendor assessment
9. Handling existing systems
10. Change Control procedures and templates
11. Instrument obsolescence and removal
12. Training plans (system operation, GMP)
13. Templates and references to SOPs
14. Glossary
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For each individual project a validation project plan should be developed.
This plan is derived from the validation master plan.
Figure 4 shows the link between the master plan and project plan. Ideally
master plans are developed at a corporate level. Project plans are written
in departments specifically for an instrument or system. Depending on
the size, structure and geographic distribution there also may be a site
or country specific master plan that is derived from the corporate master
plan but has been customized according to specific circumstances and
requirements of that site.

Frame work
Corporate Master forms, templates,
examples

Frame work
Site Master forms, templates,
(optional) examples
master list

Schedule
Project tasks, owners
deliverables
test plan

Figue 4
Link between master plan and project plan.

The project plan outlines what is to be done in order to get a specific

system into compliance. For inspectors it is a first indication of the control
a laboratory has over a specific instrument or system and it also gives a
first impression of the qualification quality.

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For simple equipment qualification a template in table form can be used
to outline planned activities. A template example is shown in Figure 5.
The left column can be the same for all instruments in the same category,
which makes the whole qualification process very efficient.

Scope of the Plan

Product Description
Validation Strategy
Responsibilities
Supplier Assessment
Risk Assessment
Testing Strategies
DQ
IQ
OQ
PQ
Traceability Matrix
Procedures
Documentation Control
Approval

Figure 5
Template for instrument qualification project plan.

3.2 Design Qualification “Design qualification (DQ) is the documented collection of activities that
define the functional and operational specifications of the instrument and
criteria for selection of the vendor, based on the intended purpose of the
instrument“2.
Design qualification is a shared responsibility between the vendor and
the user of an instrument.

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The vendor’s responsibilities are to:
Design, develop and manufacture instruments in a quality control
environment.
Develop functional and operational product specifications.
Provide information on how software and instruments are validated.
during development and supported during the entire life of the products.
Allow user audits, if required, and share approaches for development
and testing.
The user’s responsibilities are to:
Describe the analysis problem and selection of the technique.
Describe the intended use of the equipment.
Describe the intended environment (including computer environment).
Select and document the functional and performance specifications
(technical, environmental, safety).
Select and assess the vendor.

Specifications
DQ should ensure that instruments have all the necessary functions and
performance criteria that will enable them to be successfully implemented
for the intended application and to meet business requirements. Errors in
DQ can have a tremendous technical and business impact, and therefore
a sufficient amount of time and resources should be invested in the DQ
phase. For example, setting wrong operational specifications for an
HPLC system can substantially increase the workload for OQ testing,
and selecting a vendor with insufficient support capability can decrease
instrument up-time with a negative business impact.
Figure 6 shows a template that can be used to document design qualifi-
cation. User requirements for an HPLC system should not only have a
section to define chromatographic functions and performance but also
for physical requirements, construction and vendor requirements to the
vendor. A physical requirement could be that all modules should have the
same dimensions to allow stackability for optimal use of the lab’s bench

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Function/ User Supplier
Performance Requirements Specification Pass/Fail
Function 1
Function 2
Physical
Requirements
Construction
Requirements
Vendor
Requirements

Figure 6
Template for design qualification.

space. An example of a construction requirement are accessibility of the

detector lamp and flow cell from the front of the instrument for easy
maintenance.
Figure 7 shows an example of selected functional and performance
specifications of an HPLC system. The user defines his/her requirement
specifications and compares them with the vendor’s specifications. To set
the functional and performance specifications, the vendor’s specification
sheets can be used as guidelines. However, it is not recommended to
simply copy the vendor’s specifications, because compliance to the
functional and performance specifications must be verified later in the
process during operational qualification and also when re-qualifying
the instrument at a later time. Specifying too many functions and setting
the values too stringently will significantly increase the workload for OQ.
For example, if a company has a need for an isocratic HPLC system, but
plans to purchase a gradient system for future use, only an isocratic sys-
tem should be formally specified for regulatory purposes. This means, as
long as the instrument is not used for gradient runs no gradient test need
to be conducted. Later on, when the system is used for gradient analysis,
the specifications should be changed through a change control procedure.
The specifications should be set so that there is a high likelihood that the
instrument conforms to them, not only during initial OQ but also during
requalification, for example, a year later. Otherwise users may be expected

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Function/ User Vendor
Performance Requirement Specification Pass/Fail

Autosampler >90 x 2 mL vials 100 x 2 mL vials passed

capacity
Injection volume <1 % with 10 μL <0.5 % with passed
precision injection volume 10 μL injection
volume
Flow rate range 1-5 mL/min 0.1-10 mL/min passed

Baseline noise <± 2 x 10-5 AU <± 4 x 10-6 passed

Keyboard Control through Control through passed

control local user local user
interface interface

Figure 7
Selected HPLC specifications for design qualification.

to initiate an investigation to determine if the non-qualified instrument

could have had a negative impact on the quality of the product. For
example, these possibilities are expressed in ICH Q7A19:
“Deviations from approved standards of calibration on critical instruments
should be investigated to determine if these could have had an impact
on the quality of the intermediate(s) or API(s) manufactured using this
equipment since the last successful calibration”.

Vendor Assessment
Good to know!
Vendors of analytical instruments should be qualified through a formal
Vendors of critical analytical process. The objective is to ensure that vendors provide high quality
instruments should be qualified products and can give adequate support. For basic equipment, such as
through a formal process. pH-meters or a balance, this can be a single page statement describing
why the vendor XY has been selected. Certification for a recognized
quality system is sufficient for simple instruments. The formal assessment
statement should be supported by the quality systems certificate. Figure 8
shows a template with examples to document vendor assessment criteria
for analytical instruments.

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Requirements Results Passed
A Leader in the Market Place yes no
Good Experience with the Vendor yes no
Quality Assurance
ISO Certification yes no
Documented Software Development yes no
Support
Provide Specifications List yes no
Installation Service yes no
IQ/OQ Services yes no
Phone and Onsite Support yes no

Figure 8
Selected criteria for vendor assessment.

For more complex systems especially for critical computer systems such as
chromatographic data systems a more detailed assessment is recommended.
Depending on the complexity and criticality of the system this can be a
mail audit, 3rd party audit and a direct audit through the user firm.
The purpose of the vendor assessment is to ensure that products
are designed, developed and manufactured in a documented quality
environment. The assessment should also verify that the vendor provides
the right services and can maintain the instrument through phone and
on-site support.

3.3 Installation Qualification “Installation qualification (IQ) is the documented collection of activities
necessary to establish that an instrument is delivered as designed and
specified, is properly installed in the selected environment, and that this
environment is suitable for the instrument”2.

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Responsibility for IQ lies with the user but activities should be supported
Good to know! and can be carried out by the vendor. For example, before the instrument
Responsibility for IQ lies with arrives, the vendor should provide the user with environmental specifications
the user but activities should be so that the user can prepare the installation site accordingly.
supported and can be carried
out by the vendor.
Tasks performed for IQ include:
Prepare the laboratory facility according to vendor environmental
specifications.
Control and record environmental conditions, if critical. For example,
temperature and humidity.
Compare equipment received with the purchase order (including,
accessories and spare parts).
Check equipment for any damage.
Verify that the instrument conforms with physical and construction
Good to know! requirements, as specified by the user.
Agilent Technologies provides Check documentation for completeness (operating manuals,
documentation and services maintenance instructions, standard operating procedures for testing,
for installation qualification. safety and validation certificates).
Install hardware (instrument, fittings and tubing for fluid connections,
columns in HPLC and GC, power cables, data flow and instrument
control cables).
Switch on the instruments and ensure that all modules power up and
perform an electronic self-test.
List equipment manuals and SOPs.
Record firmware revision.
Prepare an installation report.
Enter instrument data into an inventory data base.
Prepare, review and sign formal IQ documentation.

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Figure 9 shows a template with selected examples that can be used
to document completeness of shipment. Figure 10 shows an example
of how to check if construction requirements such as stackability and
accessibility of flow cells are met.

Purchase Order Item Complete yes/no,

Comment
UV Detector
10 μL Flow Cell

Manual Item Complete yes/no,

Comment
Operating Manual yes
Lamp yes
Power Cord yes
LAN Cable yes
2 x Tubings with Fittings yes

Figure 9
Template and examples to document completeness of shipment for IQ.

Requirement Expected Result Pass/Fail

Accessibility of Flow cell and lamp Pass
flow cell and lamp must be accessible
from front from front

Detector must be All modules have the Pass

stackable with other same width and depth
1200 Series HPLC modules

Figure 10
Verification of construction requirements for IQ.

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All instruments should be entered into the IQ protocol and/or into a data-
base. An example of this documentation is shown in figure 11. The IQ
documents should be updated whenever there is a change made to any
entry in the IQ documents. Examples of changes are a firmware revision
and the location of the instrument within a building or site.

Identification

Manufacturer Best HPLC

Model D4424A

Firmware revision 1.00

Serial Number E4431A

Internal ID (Asset number) D33243

Current location Glab4

Size (w x b x h) (cm) 30 x 22 x 7

Condition when installed New

Supplier contact phone for services 1+541-64532

Figure 11
Equipment documentation for IQ.

Testing for Installation Qualification

Installation should verify that the instrument hardware and software are
properly installed. It does not verify that the instrument conforms to the
functional and performance specification. This is done later in the OQ
phase. For individual modules, testing is limited to perform and document
the instruments self diagnostics when it is switched on.
For systems comprised of multiple modules, correct connection between
the modules should be verified. For a modular analytical system, this can
be easily achieved by running a test sample and comparing the output
with a reference plot. An example of test specifications and results are
shown in figure 12.

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Actions Expected Result Pass/Fail

1) Set instrument A chromatogram similar as in the

conditions according to installation manual is obtained.
the installation manual
for analyzing the
installation verification
sample
2) Inject the installation 1. Chromatogram must include 1) pass
verification sample four peaks.
2. First two peaks are higher than 2) pass
the last two a peaks
3. Retention time of 3rd peak should 3) pass
be between 2.5 and 3.5 minutes

Figure 12
Verification of correct system installation for IQ.

3.4 Operational Qualification (OQ) “Operational qualification (OQ) is the documented collection of activities
necessary to demonstrate that an instrument will function according to its
operational specification in the selected environment“2 Emphasis should
be placed on “in the selected environment”. Testing of instrument hard-
ware at the user’s site is required because instrument characteristics can
change when shipped from the vendor to the user, for example through
Good to know! mechanical vibration.
Users, or their qualified designees, The most frequently asked questions related to OQ testing are: what
should perform OQ tests to verify should be tested, which are the acceptance criteria, and who should
that the instrument meets manu- perform the tests? USP answers all the questions in a single sentence:
facturer or users specification “Users, or their qualified designees, should perform these tests to verify
in the user’s environment that the instrument meets manufacturer or user specifications in the user’s
(USP <1058>). environment. Designees could be, for example, vendor representatives.”
If a system is comprised of several modules, it is recommended to perform
system tests (holistic testing), rather than performing tests module by
module (modular testing). Individual module tests should be performed

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as part of the diagnosis if the system fails. USP does not give a detailed
answer on what exactly should be tested: “The extent of testing that an
instrument undergoes depends on its intended applications. Therefore,
no specific OQ tests for any instrument or application are offered in this
chapter”.
Good to know!
Our recommendation is to look at the vendor’s test procedures as a starting
If a laboratory uses the same
point and to only make adjustments if there is a specific reason. If a laboratory
type of instruments from different
uses the same type of instruments from different vendors, it is more efficient
vendors, it is more efficient to use
to use the same test procedures for all instruments than to use different
the same test procedures for all
ones for different vendor instruments. We also recommend using the same
instruments than to use different
test procedure for a specific instrument throughout the company, independent
ones for different vendor
from the location. This allows comparing instrument performance across
instruments.
the company and facilitates exchange of instruments and analytical methods.
The frequency of OQ depends on the type of instrument, on the stability
of the performance characteristics, but also on the specified acceptance
criteria. In general, the time intervals should be selected so that the
probability is high that all parameters are still within the operational
specifications. Otherwise, analytical results obtained with that particular
instrument are questionable. Here the importance of proper selection of
the procedures and acceptance limits becomes very apparent. For exam-
ple, if the baseline noise of a UV/Visible detector is set to the lowest
possible limit as specified by the vendor, the lamp will have to be
changed more frequently than when set at a factor of 5 higher.
Inspectors expect OQ tests to be quantitative. This means that the test
protocol should include expected results and actual results. Figure 13
includes an example for recording of test results of a balance. The header
includes three control weights and acceptable limits for the weight. The
daily protocol records actual weights and the name and signature of the
test person.

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Instrument BestBalance

Serial number 55235A

Maximal weight 110 g

Control weight 1 10,000 mg Limit: ±10 mg

Control weight 2 1,000 mg Limit: ±1 mg

Control weight 3 100 mg Limit: ± 0.1 mg

Test engineer
Date Weight 1 Weight 2 Weight 3 o.k.
Name Signature

2/3/06 9999.8 999.9 100.0 yes Hughes

Figure 13
OQ test example.

3.5 Performance Qualification “Performance qualification (PQ) is the documented collection of activities
necessary to demonstrate that an instrument consistently performs
according to the specifications defined by the user, and is appropriate
Good to know! for the intended use.”2
Important for consistent instrument Here emphasis is placed on the word ‘consistently’. Important for consistent
performance are regular preventive instrument performance are regular preventive maintenance, making changes
maintenance, making changes to to a system in a controlled manner and regular testing. The PQ test frequency
a system in a controlled manner is much higher than for OQ. Another difference is that PQ should always be
and regular testing. performed under conditions that are similar to routine sample analysis. For a
chromatograph system this means using the same column, the same analysis
conditions and the same or similar test compounds.
PQ should be performed on a daily basis or whenever the instrument is
used. The test frequency depends on the criticality of the tests, on the

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ruggedness of the instrument and on everything in the system that may
contribute to the reliability of analysis results. For a liquid chromatograph,
this may be the chromatographic column or a detector’s lamp.
In practice, PQ testing can mean system suitability testing or the analysis of
quality control samples. This is supported by USP <1058>: “Some system
Good to know! suitability tests or quality control checks that are performed concurrently
with the test samples can be used to demonstrate that an instrument is
PQ testing can mean system performing suitably.“ For system suitability testing critical system performance
suitability testing or the analysis characteristics are measured and compared with documented, preset limits.
of quality control samples. For example, a well characterized standard can be injected 5 or 6 times
and the standard deviation of amounts is then compared with a predefined
value. If the limit of detection and/or quantitation is critical, the lamp’s
intensity profile or the baseline noise should be tested. For chromatographic
equipment SST tests are recommended in USP chapter <621>23.
For ongoing quality control checks samples with known amounts are
interspersed among actual samples at intervals determined by the total
number of samples, the stability of the system and the specified precision.
The advantage of this procedure is that quantitative system performance is
measured more or less concurrently with sample analyses under conditions
that are very close to the actual application. Figure 14 shows a template
with examples for a PQ test protocol.

Test Test Expected Actual Pass/

Case Result Result Fail
Baseline T10 <0.5 x 10-4 AU <0.5 x 10-5 AU Pass
Noise
Resolution between T11 >2.0
Compound A and B
Tailing factor T12 <1.3
Precision of Amount T13 <1%
Compound A,
6 Replicate Injections
Precision of Amount T14 <1%
Compound B,
6 Replicate Injections

Figure 14
Documentation of PQ tests.

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(Preventive) Maintenance and Repair
Analytical instruments should be well maintained to ensure proper
ongoing performance. Procedures should be in place for regular preventive
maintenance of hardware to detect and fix problems before they can
have a negative impact on analytical data. The procedure should
describe:
The maintenance to be done.
When it is to be done.
What should be re-qualified after maintenance is done. For example,
a PQ test should always be performed after instrument maintenance.
How to document maintenance activities.
Instruments should be labeled with the dates of the last and next scheduled
maintenance.
Planned maintenance activities should follow a documented instrument
maintenance plan. Some vendors offer maintenance contracts with
services for preventive maintenance at scheduled time intervals. A set
of diagnostic procedures is performed and critical parts are replaced to
ensure ongoing reliable system uptime.
Unplanned activities that are necessary in addition to the planned activities
should be formally requested by the user of the instrument or by the person
who is responsible for the instrument. An example of a request form is
shown in figure 15.

Equipment Owner:
System ID:
Location of Equipment:
Requester:
Date:
Reason for Maintenance:
Describe Observation
Priority: High Medium Low
Comment:

Figure 15
Request form for unplanned maintenance.

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The reason for the requested maintenance should be entered as well as a
priority. All maintenance activities should be documented in the instrument’s
logbook. A template with examples is shown in figure 16.

Log Date Type of Person Instrument Comment

ID Maintenance Performing Owner
Maintenance

From E.g., routine/ Printed Name Printed Name E.g.,

non routine recalibrated
To Signature Signature

From Printed Name Printed Name

To Signature Signature

Figure 16
Good to know! Maintenance logs.

Defective instruments should

be either removed from the
laboratory or clearly labeled as Defective instruments should be either removed from the laboratory area
being defective. or clearly labeled as being defective. Procedures should be available for
most common problems such as defective UV detector lamps. Procedures
should also include information if and what type of requalification is
required. Uncommon problems, for example, if an HPLC pump becomes
defect without any obvious reason, should be handled through a special
procedure that guides users of instruments through the repair process
and reinstallation. In this case the impact of the failure on previously
generated data should be evaluated.

Change Control
Analytical instruments and systems go through many changes during their
lifetime. New hardware modules may be added to enhance functionality,
for example, an automated sampling system replaces a manual one for
unattended operation. Vendors may change the firmware to a new revision
to remove software errors or application software may be upgraded to be

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compatible with a new operating system. Or a complete system is moved
to a newly designed laboratory. Some changes are also initiated when
new technologies are introduced, for example, a standard HPLC pump is
replaced by a rapid resolution pump for higher sample throughput.
Any changes to instrument hardware, firmware and software should
follow written procedures and be documented. Requests for changes
should be submitted by users and authorized by the user’s supervisor or
department manager and by QA. Before any change request is approved,
business benefits should be compared with the risks a change may bring.
Good to know! USP chapter <1058> states: “Implementing changes may not always
benefit users. Users should therefore adopt changes they deem useful or
Any changes to instrument necessary and should also assess the effects of changes to determine
hardware, firmware and what, if any, requalification is required”.
software should follow written
USP also recommends following the same 4Q model for changes as for
procedures and be documented.
initial qualifications. This means:
Specifications should be updated, for example in case a new automated
sampling system replaces a manual one.
IQ documents should be updated, if a new firmware revision is installed.
Installation documents should also be updated when a system is moved
to a new laboratory.
OQ documents with new test cases and test protocols should be added
if the software is upgraded with new functionality and,
PQ tests need to be updated to verify ongoing system suitability of a
new rapid resolution HPLC pump.
Before any change is approved and implemented a thorough evaluation
should be made if OQ tests should be repeated. Depending on the change,
an instrument may need no, partial or full testing of a system.

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