April 21, 2023

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US & EU GMP Guidelines on Analytical Instrument Qualification and Related Warning Letters

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Overview

• FDA/EU/USP Requirements and enforcement practices

• Examples of FDA warning letters• The 4Q model for equipment qualification• Essential steps and example templates for Instrument

Qualification: DQ, IQ, OQ, PQ• Validation of existing systems• Requalification: what, when

Reference material: www.labcompliance.com/agilentAvailable until March 10, 2014

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Regulations and Quality Standards

• Good Laboratory Practices

• GMP Manufacturing Practices

• Good Clinical Practices

• 21 CFR Part 11: E-Records&signatures

• IS0 17025

• Equipment should be suitable for its intended use• Equipment should be calibrated and maintained

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US FDA; 21 CFR Part 211 - 211.68• Automatic, mechanical, or electronic equipment or other

types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product

• If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.

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Other Regulations and GuidelinesEurope•EU GMP Annex 15 (draft February 2014)

– Validation and qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment

– Steps include: User requirement specifications, design qualification, installation qualification, operational qualification and performance qualification (4Q model)

United States Pharmacopeia

•.USP general chapter <1058>: “Analytical Instrument Qualification”

– Global standard for laboratory equipment qualification

– Follows the 4Q model (see Annex 15 above)

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FDA Warning Letters• Failure of your quality control unit/laboratory to

ensure that analytical instrumentation and test equipment used to assure the quality of your APIs has been appropriately qualified and calibrated for their intended use.

• All laboratory instrumentation and equipment that you use to test material manufactured for the U.S. market should have an Operational Qualification (OQ) and should be calibrated to include applicable operating ranges (W-288)

Ref: www.fdawarningletter.com

Perform Operational Qualification Equipment

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FDA Warning Letters• Lacks documentation of installation and operation qualification of equipment (160)

• The Validation Master Plan does not contain an operational qualification for xxx (164)

• There is no requirement for a Performance Qualification protocol (164)

Ref: www.fdawarningletter.com

Perform IQ/OQ/PQ for Equipment

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FDA Warning Letter/483/EIR• The calibration program for your stability chambers is

deficient ill that it does not include specific directions and schedules.

• You do not perform re-qualification of the stability chambers.

1. Develop a program for equipment calibration and calibration. Include a schedule

2. Conduct regular requalification of equipment

–

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FDA Warning Letters

• Failure to have a complete calibration program for the HPLCs in that the gradient accuracy and detector linearity is not being verified (W-110)

Ref: www.fdawarningletter.com

Perform Operational Qualification for all equipment functions

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FDA Warning Letters

• No chromatographic system suitability testing (W-016)

Ref: www.fdawarningletter.com

1. Develop written procedures for type and frequency of system suitability testing

2. Ensure that the procedure is followed

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Analytical Instrument Qualification and and other Quality Checks

• Quality control checks– Verifies accuracy of sample analysis

• System suitability tests– Verifies that the system performs according to

analysts expectations• Analytical methods validation

– Proof that analytical procedure does what it purports to do

• Analytical instrument qualification– Forms the base for generating quality data– Proof suitability of the instrument for intended

use

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Design Qualification

Installation Qualification

Operational Qualification

Performance Qualification

Qualification/Validation Phases 4Q Model

User requirement specifications Functional specifications Operational specifications Vendor qualification

Check arrival as purchased Check proper installation of

hardware and software Test of operational functions Performance testing Test of security functions

Test for specified application Preventive maintenance On-going performance tests

Required by FDA, Europe and USP

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Design Qualification (DQ) Activities and Documentation

• Vendors– Design, develop and manufacture instruments in quality control environment, e.g., ISO 9001:2008– Develop functional and operational product specifications

• Users– Develop user requirement specifications– Verify that the vendor’s instrument meets user’s requirements: product specifications, delivery

and support– Verify that the vendor operates in a quality system environment

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Design Qualification - Template

Function/Performance

User Requirement

Supplier Specification

Commentyes/no

Function 1

Function 2

Physical Requirements

Construction Requirement

Vendor Requirement

Documenting Equipment Supplier Selection Items Required Results Passed

Recognition in the market place □ yes □ no

Experience with the vendorReliability, response to problems

□ yes □ no

Quality assurance

ISO 9001:2008 Certification □ yes □ no

Documented Software Development. □ yes □ no

Support

Provide specifications list □ yes □ no

Installation service □ yes □ no

IQ/OQ services with Certificates □ yes □ no

Phone and onsite support □ yes □ no

Equipment functionality

Products has required functions □ yes □ no

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Installation Qualification (IQ)Vendor•Provides the user with environmental specifications and a site prep document•Provides •Offers services for IQ with inspection ready documentationUser •Verify that facilities, utilities, and environment meet vendor requirements•Assemble and install equipment•Perform initial diagnostics and testing•For complex equipment: run reference sample •Document installation, including drawings

Equipment lacks documentation of installation and operation qualification (160)

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Equipment Documentation for IQ

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) 30x22x7

Condition when installed New

Supplier contact phone for services

1+541-64532

Example: HPLC detector

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Operational Qualification (OQ)

Vendor• Provides services for OQ with traceable tools• Delivers inspection ready OQ documentation• Makes recommendations for frequency of requalificationUser• Test functions to verify that the instrument operates in the

user’s environment as intended by the manufacturer and required by the user.

• Test secure data handling, storage, back-up and archiving• Tests can be holistic or modular. • Tests can be done by users or qualified designees.

Conductivity meters not calibrated to a NIST traceable device (156)

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OQ Test - Example

Date Weight 1Weight 2 Test engineerName Signature

Weight 3 o.k.

yes9999.8 999.9 100.0 Hughes2/3/06

Instrument BestBalance

Serial number 55236A

Maximal weight 11 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

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Performance Qualification (PQ) Vendor• Provides recommendation for PQ tests, e.g., for system suitability

testing• Provides software for PQ testing, e.g., for system suitability and quality

control chartsUser • Preventive maintenance to ensure trouble free operation for the

intended application• Performance checks, based on the instrument’s typical on-site

applications– Test frequency depends on the ruggedness of the instruments and

the criticality of the tests– System suitability and QC tests can imply suitable performance

There is no requirement for a Performance Qualification protocol (164)

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Documentation of PQ Testing

Test Test Case

Expected result Actual Result

Pass/Fail

BaselineNoise

T10 <1x10-4 AU Pass

Resolution between compound A and B

T11 >2.0

Tailing factor T12 <1.3

Precision of amount compound A, 6 replicate injections

T13 <1%

Precision of amount compound B, 6 replicate injections

T14 <1%

Example: HPLC System

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Summary Report TemplateScope of the report

Product Description

Qualifiaction Strategy

Responsibilities

Supplier Assessment

Risk assessment

Testing Strategies

DQ

IQ

OQ

PQ

Traceability matrix

Procedures

Deviations

Approval

Documentation control

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Define System Use

Installation Qualification

Operational Qualification

Performance Qualification

Validation Phases – 4Q Model APPROACH FOR EXISTING EQUIPMENT

Document equipment use Document applications Document used functions

Enter all modules and systems in a database

Hardware, Firmware, Software

Document past tests Test of functional specifications Test of performance functions

System test (system suitability testing)

Preventive maintenance

+ Change Control

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OQ - Requalification

• Required – when the instrument undergoes major

repairs or modification– After transport to an other location, if the

move ‘disturbs’ instrument operation• May not be required to be repeated at

regular intervals

No recalibration after equipment move (154)The calibration program for your stability chambers is deficient in that it does not include specific directions and schedules.(231)

Ludwig HuberLabcompliance Sponsored by Slide 25

Thank YouI would like to thank • All attendees for your attention• Agilent Technologies for invitation and organization

For links to Analytical Instrument Qualification references, please checkwww.labcompliance.com/agilent(Available until March 10, 2014)

Dr. Ludwig HuberLudwig_huber@labcompliance.com