Calibration
in the
Laboratory
Jerry Lanese
Ph.D.
The Lanese Group, Inc.
IVT
Validation Week
2015
© 2015 The Lanese Group, Inc.
1
Outline
Overview of laboratory data integrity
Elements of the Laboratory Instrument
Calibration Program
The impact of new guidances on instrument
calibration
© 2015 The Lanese Group, Inc. 2
It is the goal of every analyst and every
quality control laboratory to report data
that accurately reflect the measured
parameters of the material under test.
© 2015 The Lanese Group, Inc.
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Each laboratory should implement
procedures that provide the highest
level of assurance of the quality of
the data reported.
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Components of Data Quality
Analytical Instrument Qualification
Analytical Method Validation
System
Suitability Tests
Quality
Control
Check Samples
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Components of Analytical Instrument Qualification
Design Qualification
Installation Qualification
Operational Qualification
Performance Qualification
4 Qs
Define your terms
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The boundaries of qualifications activities are
fuzzy.
IQ
PQ
OQDQ
Define your terms
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• Why calibrate?
• What is calibration?
• Where do we find the requirements for
calibration?
• Who in the organization is responsible
for calibration?
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Regulations and standards
requiring calibration and providing
limited guidance on what should be
in a calibration program
21CFR58
21CFR211
21CFR111
21CFR820
ICH-Q7A
ISO 9001ISO 10012ISO 13485ISO 17025
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Guidance on calibration requirements
USP<1251>
USP<41>
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General requirement
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.21CFR211.68(a)
© 2015 The Lanese Group, Inc. 11
Laboratory controls include:
The calibration of instruments, apparatus,
gauges, and recording devices at suitable
intervals in accordance with an established
written program containing specific
directions, schedules, limits for accuracy and
precision, and provisions for remedial action
in the event accuracy and/or precision limits
are not met. Instruments, apparatus,
gauges, and recording devices not meeting
established specifications shall not be used.
21CFR211.160(b)(4)
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Calibration
• Suitable intervals
• Written program
– Specific directions
– Schedules
– Limits of accuracy and precision
– Remedial action
© 2015 The Lanese Group, Inc. 13
The message is consistent
Program should include:
–Schedule
–Specific procedures
–Intervals
–Limits of accuracy and precision
–Status identification
–Standard traceability
–Measurement uncertainty
–Training
–Records© 2015 The Lanese Group, Inc. 14
Program should include remedial action
• Calibrate
• Investigate product impact
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Calibration goes beyond a regulatory
requirement – it is good business, good
science.
Calibration is an element of –
the Quality System
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Life cycle
Intended use
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Warning letter
10-9
Your SOP ***, requiring the Quality
Control Manager to ensure that in-house
calibration of all scales and balances is
performed *** at an interval*** with ***a
class*** standard weights was not
followed. Calibrations of the ***a brand
name*** scale used to weigh active
ingredients were performed with only
***a class*** weights for a period of 11
months (February 2007 to January 2008).
© 2015 The Lanese Group, Inc. 18
Personnel shall have
Education
Experience
Training
• GMP
• Skill
Personnel qualifications
21CFR211.25
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Operational Qualification
or
Calibration
© 2015 The Lanese Group, Inc. 20
Calibration
Actions designed to provide
assurance that a measuring
device gives accurate results.
© 2015 The Lanese Group, Inc. 21
Operational Qualification (OQ)
Establishing the documentary
evidence that a sub-system or set of
equipment is capable of repeated
operation within the limits defined in
the specifications.
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Operational Qualification
is used as synonymous with
Calibration
After initial qualification
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Calibration
The comparison of a measurement
system of unverified uncertainty to a
measurement system of quantified
uncertainty to detect or correct any
deviation from required performance
specifications. ….
© 2015 The Lanese Group, Inc. 24
… More specifically, calibration is the
practice of verifying critical
measurement equipment performance
(accuracy/ precision) using NIST
traceable standards.
Calibration
© 2015 The Lanese Group, Inc. 25
Relationship
Laboratory program to corporate
program.
Laboratory program to site program.
© 2015 The Lanese Group, Inc. 26
1
2
3
4
5
6
Records
Corporate
Guidance Site
Calibration
Procedure
Laboratory
Calibration
Program
Specific
Calibration
Procedures
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Relationship
• Calibration to maintenance.
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Responsibility
When contract calibration service is
involved:
• Procedure preparation
• Procedure approval
• Training
• Assuring contractor follows procedures
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Responsibility
• Procedure
– Format
– Preparation
– Review
– Approval
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Responsibility
• General test equipment– Thermometers
– Recorders
– Weighing devices
• Laboratory specific equipment– Chromatographs
– Spectrophotometers
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Responsibility
• Scheduling
• Remedial action
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Responsibility
• Review and approval of calibration
records
• Maintenance of calibration records
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Responsibility
• Assuring that appropriate
instrumentation is used.
• Assuring that instrumentation that
is not calibrated is not used.
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Calibration Program
Getting instruments into the system
Decommissioning instruments TAR
Establishing intervals
Remedial Actions Instrument classification
Scheduling Establishing Tolerances
© 2015 The Lanese Group, Inc. 35
Calibration Program - Element 1
Process to get all instruments into the
program.
User:
• Receives new
instrument.
• Completes instrument
data form.
Calibration manager
• Completes form.
• Assures procedures
in place.
• Places instrument
into calibration
program.
© 2015 The Lanese Group, Inc. 36
Calibration Program - Element 1
Process to get all instruments into the
program.• Form
– User responsibility
• Instrument description– Make
– Model
• Identification – Serial number
– Internal Identification
Intended use Location
Range of use
Process tolerance
Other
© 2015 The Lanese Group, Inc. 37
Calibration Program - Element 1
Process to get all instruments into the
program.
• Form
– Calibration Manager
• Establish
– Classification
– Calibration points
– Calibration tolerance
– Calibration interval
© 2015 The Lanese Group, Inc. 38
Calibration Program - Element 2
• Remove instrument from system
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Calibration Program - Element 3
• Classify the devices– GMP
• Critical
• Non-critical
• Utility
– Non-GMP
• Safety
• Environmental
• Other
© 2015 The Lanese Group, Inc. 40
GMP Critical Device
• Potential direct impact on product (test results)
quality
• Recorded in GMP record
• Used to make decisions that can impact quality
• Used to release product
• Not business, environmental or safety critical
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GMP Non-Critical Device
• No potential direct impact on product (test
result) quality
• Used to make decisions to improve laboratory
test efficiency
• May be redundant, or up-stream of final critical
device
• Not recorded in batch or QC record
• Calibrated same as critical
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GMP Utility Device
• Used only by maintenance technicians
• Used only for troubleshooting equipment
operation
• May have little stated accuracy or reading
resolution (color coded; on/of)
• Includes output control circuits
• May not need to be calibrated
© 2015 The Lanese Group, Inc. 43
Microbiological
testing area
Example – Sterile HVAC(simplified)
DPI
1
DPI
2
Sterile
SuiteGo
wn
ing
OA
RA
Damper Coil HEPARoughing
FilterPre- Filter
TI
2
FT
1
Damper
Operator
Heat
Transfer
Fluid
TR
2
TI
1
TI
3DO
1
V 1
FIT
1
Utility
Non-critical
Critical
DPI
1TI
2
FT
1
DO
1
V 1
DPI
1TI
2
FT
1
J Busfield© 2015 The Lanese Group, Inc. 44
Calibration Program Element 4
• Limits of accuracy
• Limits of precision
Process calibration tolerance
Limit beyond which product (test result) quality may be compromised
Trigger an out-of-tolerance
Dependent upon process tolerance
© 2015 The Lanese Group, Inc. 45
Process calibration tolerance
How much error are you willing to accept in the
measurement?
Risk analysis
Should be based on science and the knowledge of
the process.
A factor in determination of interval
© 2015 The Lanese Group, Inc. 46
Process calibration tolerance
• Limit beyond which product (test result) quality
may be compromised
• Assigned to GMP critical instruments only
• Greater than calibration limits
• Trigger out-of-tolerance event
• Based on process requirements
– Process limits
– Process studies
– Development studies
– Design space
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Test Accuracy Ratio
• TAR
• Test Uncertainty Ratio (TUR)
• Most programs require at least 4:1
• Process calibration tolerance should be less
than 1/4th process tolerance
• Standard should be at least 4 x accuracy of
calibrated instrument (4 x process calibration
tolerance)
© 2015 The Lanese Group, Inc. 48
Test Accuracy Ratio
Process Tolerance
Process Calibration
Tolerance
Calibration Limit
Standard Accuracy
±5°C
±1.25°C
±0.31°C
±0.75°C
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Temperature measuring device in stability
chamber
Stability SOP states:
control temperature to 27° C ± 1° C
Calibration procedure states:
Process calibration tolerance: ± 1° C
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Test Accuracy Ratio
Process Tolerance
Process Calibration
Tolerance
Calibration Limit
Standard Accuracy
±1°C
±0.25°C
±0.06°C
±0.15°C
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Calibration Program - Element 5
• Process for establishing and changing
intervals.
• Interval will drive the schedule.
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Calibration Interval
Based on:
• Calibration tolerance
• Data
First interval
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Time
Process Calibration
Tolerance
Instrument response
compared to standard
Instrument response with time
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Time
Process Calibration
Tolerance
Instrument response
compared to standard
Instrument response with time
Calibration Limit
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Calibration Program Element 6
• Scheduling and record keeping
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Calibration Program - Element 7
Specific procedures
– Each category of instrument
• Pressure gauge
• Thermometer
• HPLC
– Each specific instrument
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Suggestion
• Procedure for each category of
instrument
• Test sheet for each instrument in the
category
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Specific procedure considerations
• Format
• Test process
• Interval
• Range
• Test points
• Standards
• Limits for accuracy and precision
• Remedial action
• Work sheet
© 2015 The Lanese Group, Inc. 59
Calibration Program - Element 8
Remedial action
• Driven by an as-found, out-of-tolerance
observation.
• Should not be the responsibility of
the calibration unit
Sounds like Deviation Investigation
followed by CAPA
© 2015 The Lanese Group, Inc. 60
Additional considerations
• Traceable standards
• Known uncertainty
• Suitable
• Maintain records
• Status known
• Do not use equipment not
meeting standards
© 2015 The Lanese Group, Inc. 61
Impact of new guidance
© 2015 The Lanese Group, Inc. 62
Some things to consider
• USP <41>
• USP <1251>
• ICH Q10
• ICH Q8
• ICH Q9
• USP Stimulus Article on Test Method
Validation
• EU Chapter 15
© 2015 The Lanese Group, Inc. 63
Questions
© 2015 The Lanese Group, Inc.
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Calibration
in the
Laboratory
Jerry Lanese
Ph.D.
The Lanese Group, Inc.
IVT
Validation Week
2015
© 2015 The Lanese Group, Inc.
65
Contact Information
• Jerry LaneseThe Lanese Group, Inc.
12401 Catalina, Leawood Kansas 66201
913 491 9234
© 2015 The Lanese Group, Inc. 66