Transcript Slide 1

US & EU GMP Guidelines
on Analytical Instrument
Qualification and Related
Warning Letters
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Confidentialit
Overview
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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/agilent
Available until March 10, 2014
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Regulations and Quality Standards
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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 Guidelines
Europe
• 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)
Perform Operational Qualification Equipment
Ref: www.fdawarningletter.com
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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)
Perform IQ/OQ/PQ for Equipment
Ref: www.fdawarningletter.com
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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.
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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)
Perform Operational Qualification for all
equipment functions
Ref: www.fdawarningletter.com
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FDA Warning Letters
• No chromatographic system suitability testing
(W-016)
1. Develop written procedures for type and frequency of
system suitability testing
2. Ensure that the procedure is followed
Ref: www.fdawarningletter.com
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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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Qualification/Validation Phases
4Q Model
Design Qualification
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Installation Qualification
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Operational Qualification
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Performance Qualification
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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
Comment
yes/no
Function 1
Function 2
Physical
Requirements
Construction
Requirement
Vendor
Requirement
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Documenting Equipment Supplier Selection
Items
Required
Results
Passed
Recognition in the market place
□ yes □ no
Experience with the vendor
Reliability, 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 documentation
User
• 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 1+541-64532
services
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 requalification
User
• 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
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
Date
Weight 1 Weight 2
2/3/06 9999.8
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999.9
Weight 3
100.0
o.k.
Test engineer
Name
Signature
yes Hughes
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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 charts
User
• 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
Baseline
Noise
T10
<1x10-4 AU
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%
Actual
Result
Pass/
Fail
Pass
Example: HPLC System
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Summary Report Template
Scope 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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Validation Phases – 4Q Model
APPROACH FOR EXISTING EQUIPMENT
Define System Use
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Installation Qualification
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Operational Qualification
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Performance Qualification
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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)
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Slide 24
Thank You
I would like to thank
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All attendees for your attention
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Agilent Technologies for invitation and organization
Dr. Ludwig Huber
[email protected]
For links to Analytical Instrument Qualification references, please check
www.labcompliance.com/agilent
(Available until March 10, 2014)
Ludwig Huber
Labcompliance
Sponsored by
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