Calibration in the Laboratory - CBI | Powering Thought ... 2 Breakfast...Outline Introductions...
Transcript of Calibration in the Laboratory - CBI | Powering Thought ... 2 Breakfast...Outline Introductions...
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© 2014 The Lanese Group, Inc. 1
Calibration
in the
Laboratory
Jerry Lanese
Ph.D.
The Lanese Group, Inc.
IVT
Validation Week - 20
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Goooo
Kansas City Royals
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Outline
Introductions
Requirements for Calibration in the
Laboratory
Elements of a Laboratory Instrument
Calibration Program
Calibration of common laboratory instruments
Interactive exercise
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Please share • Name
• Position
• Your involvement with a calibration program
• Type of program
– Site program
– Stand-alone laboratory program
– Laboratory program within site program
• Two biggest challenges of your calibration
program
• One thing you would like to take away © 2014 The Lanese Group, Inc. 4
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To assure he accuracy and integrity of
the test results we provide
Why do we calibrate
instruments?
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The need for accurate measurements
• Is not unique for to the laboratory.
• Is not unique to the pharmaceutical industry
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It is good science
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What are the regulatory requirements
for the calibration of laboratory
instruments?
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Regulations and standards
21CFR211
21CFR111
21CFR820
ICH Q7
ISO 9001
ISO 10012
ISO 13485
ISO 17025
USP<1251>
USP<41>
8
Things to
consider
for your
calibration
program
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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.
© 2014 The Lanese Group, Inc. 9
21CFR211.68(a)
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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.
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21CFR211.160(b)(4)
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Laboratory records:
Complete records shall be maintained of the
periodic calibration of laboratory instruments,
apparatus, gauges, and recording devices
required by 211.160(b)(4).
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21CFR211.194(d)
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USP 1251
“The tests described above also can be
included in formal periodic calibration in
order to fulfill applicable cGMP
requirements.”
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• Sensitivity
• Linearity
• Eccentricity
• Repeatability
USP 36 <1251> Weighing on an
Analytical Balance
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Unless otherwise specified, when
substances must be “accurately weighed”,
the weighing shall be performed using a
balance calibrated over the operating range
and meets the requirements defined for
repeatability and accuracy.
USP <41>
USP 36 <41>
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If you are assigned the task of writing a
calibration program, what would you
include?
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Calibration
• Suitable intervals
• Written program
– Specific directions
– Schedules
– Limits of accuracy and precision
– Remedial action
– Records
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The message is consistent
You must have a calibration program and it
should include:
Schedule
Specific procedures
Intervals
Limits of accuracy and precision
Status identification
Remedial action
Records
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Your program should also include:
Getting instruments into the system
Removing instruments from the system
Classification of instruments
Standard traceability
Measurement uncertainty
Training
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Your SOP ***, requiring the Quality
Control Manager to ensure that in-house
calibration of all scales and balances is
performed ****** with ****** standard
weights was not followed. Calibrations of
the ****** scale used to weigh active
ingredients were performed with only
****** weights for a period of 11 months
(February 2007 to January 2008).
Warning letter
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Your SOP ***, requiring the Quality
Control Manager to ensure that in-house
calibration of all scales and balances is
performed daily with Class A standard
weights was not followed. Calibrations of
the production scale used to weigh active
ingredients were performed with only
class C weights for a period of 11 months
(February 2007 to January 2008).
Warning letter – an interpretation
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*
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FDA standard observation statement The calibration of
• [instruments]
• [apparatus]
• [gauges]
• [recording devices]
is not done at suitable intervals
• [in accordance with an established written
program]
• [with provisions for remedial action in the event
accuracy and/or precision limits are not met].
Specifically, ***
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What other contemporary concepts will
impact our calibration program?
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What other contemporary concepts will
impact our calibration program?
• Qualification
• Intended use
• Investigations/CAPA
• Quality system
• Lifecycle
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What is calibration?
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Calibration
Actions designed to provide
assurance that a measuring
device gives accurate results.
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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. ….
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… More specifically, calibration is the
practice of verifying critical
measurement equipment performance
(accuracy/ precision) using NIST
traceable standards.
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Calibration
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Operational Qualification
or
Calibration
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Operational Qualification
is synonymous with
Calibration
After initial qualification
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What responsibilities and relationships
impact the laboratory calibration
program?
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Relationship
Laboratory program to site program.
Laboratory program to corporate
program.
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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:
• Contractor certification
• On-site/off-site
• Contact for contractors
• 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
• 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
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Personnel shall have
Education
Experience
Training
• GMP
• Skill
Personnel qualifications
21CFR211.25
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Calibration SOPs
Corporate
Site
Laboratory
Contractor qualification SOP
Specific laboratory calibration procedures
Measurement uncertainty
Traceability
Skill Training should include:
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Calibration Program - Element 1
Process to get all instruments into the program.
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• A form
• The origin of the Master Instrument List
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Get new instrument into the system
• Instrument description – Make
– Model
• Identification – Serial number
– Internal Identification
• Intended use – Location
– Range of use
– Process tolerance
– Classification
– Other
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Form - User responsibility
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Get new instrument into the system
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Form – Calibration Manager responsibility
Verify information
– Classification
Identify calibration SOP and/or data sheet
Assign
– Identification /control number
Enter instrument into the calibration
management system
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Calibration Program - Element 2
• Remove instrument from system
– Interface with Change Control System
– Requires final calibration
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Calibration Program - Element 3
• Classify the devices – GMP
• Critical
• Non-critical
• Utility
– Non-GMP
• Safety
• Environmental
• Other
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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
• OOT requires an investigation
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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
• OOT does not require an investigation
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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
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Microbiological
testing area
Example – Sterile HVAC(simplified)
DPI
1
DPI
2
Sterile
Suite Go
wn
ing
OA
RA
Damper Coil HEPA Roughing
Filter Pre- Filter
TI
2
FT
1
Damper
Operator
Heat
Transfer
Fluid
TR
2
TI
1
TI
3 DO
1
V 1
FIT
1
Utility
Non-critical
Critical
DPI
1 TI
2
FT
1
DO
1
V 1
DPI
1 TI
2
FT
1
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Calibration Program Element 4
• Limits of accuracy
• Limits of precision
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Process calibration tolerance
Limit beyond which product (test result) quality may be compromised
Trigger an out-of-tolerance
Dependent upon process tolerance
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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
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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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Process calibration tolerance
• Accuracy
• Sometimes it is defined for us
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Unless otherwise specified, when
substances must be “accurately weighed”,
the weighing shall be performed using a
balance calibrated over the operating range
and meets the requirements defined for
repeatability and accuracy.
Balance – accurately weigh
USP 36 <41>
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Accuracy of a balance is satisfactory if its weighing
value, when tested with a suitable weight(s) is
within 0.10% of the testing value.
A test weight is suitable if it has a mass between
5% and 100% of the balance’s capacity.
A test weight’s maximum permissible error (mpe)
(calibration uncertainty) shall be NMT one-third of the
applied test limit of the accuracy test.
Accuracy
USP – 36 <41>
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Test Accuracy Ratio
• TAR
• Test Uncertainty Ratio (TUR)
• Most programs require at least 4:1
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Metrology will utilize a 4 to 1 accuracy ratio
where possible, with a 1 to 10 ratio preferred
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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 (1/4th of the process
calibration tolerance)
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58
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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60
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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“accurately weigh” expects a tolerance of
0.10% for the weighing process
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Repeatability is satisfactory if two times
the standard deviation of the weighed
value, divided by the nominal value of
the weight used, does not exceed 0.10%
2 x SDW/W ≤ 0.0010
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USP 36 <41>
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Weigh one test weight no less than 10
times. Must be within the balance range
Need not be calibrated
Repeatability = standard deviation.
Repeatability is independent of mass.
Repeatability
USP – 36 <41>
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If
• The weight = 100 mg
• The standard deviation of 12 weighings = 0.05 mg
2 x 0.05mg./100mg. = 0.001 = 0.1%
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If the standard deviation is less than
0.41d, where d is the scale interval,
replace the standard deviation with
0.41d.
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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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68
Time
Process Calibration
Tolerance
Instrument response
compared to standard
Instrument response with time
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69
Time
Process Calibration
Tolerance
Instrument response
compared to standard
Instrument response with time
Calibration Limit
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Process for changing intervals
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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
• Work sheet
• Interval
• Range
• Test points
• Standards
• Limits for accuracy and precision
• Remedial action
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Calibration Program - Element 8
Remedial action
• Driven by an as-found, out-of-tolerance
observation.
• Should not be the responsibility of
the calibration unit
75
Sounds like Deviation Investigation
followed by CAPA
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Additional considerations
• Traceable standards
• Known uncertainty
• Suitable
• Maintain records
• Status known
• Do not use equipment not
meeting standards
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Specific Calibration
Procedures
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– Electronic calibration
– Calibration
– Verification
– Who calibrates
– Interval
– Weights
Balance
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USP 1251
“The tests described above also can be
included in formal periodic calibration in
order to fulfill applicable cGMP
requirements.”
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• Sensitivity
• Linearity
• Eccentricity
• Repeatability
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Unless otherwise specified, when
substances are to be “accurately weighed”
for Assay the weighing is to be performed
with a weighing device whose measurement
uncertainty (random plus systematic error)
does not exceed 0.1% of the reading.
Measurement uncertainty is satisfactory if
three times the standard deviation of not
less than ten replicate weighings divided by
the amount weighed, does not exceed 0.001
Balance – accurately weigh
USP – prior <41>
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Unless otherwise specified, when
substances must be “accurately weighed”,
the weighing shall be performed using a
balance calibrated over the operating range
and meets the requirements defined for
repeatability and accuracy.
Balance – accurately weigh
USP 36 <41>
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Weigh one test weight no less than 10
times. Must be within the balance range
Need not be calibrated
Repeatability = standard deviation.
Repeatability is independent of mass.
Repeatability
USP – 36 <41>
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Repeatability is satisfactory if two times
the standard deviation of the weighed
value, divided by the nominal value of
the weight used, does not exceed 0.10%
SDW/W ≤ 0.0010
© 2014 The Lanese Group, Inc. 83
USP 36 <41>
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If
• The weight = 100 mg
• The standard deviation of 12 weighings = 0.05 mg
2 x 0.05mg./100mg. = 0.001 = 0.1%
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If the standard deviation is less than
0.41d, where d is the scale interval,
replace the standard deviation with
0.41d.
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Accuracy of a balance is satisfactory if its weighing
value, when tested with a suitable weight(s) is
within 0.10% of the testing value.
A test weight is suitable if it has a mass between
5% and 100% of the balance’s capacity.
A test weight’s maximum permissible error (mpe)
(calibration uncertainty) shall be NMT one-third of the
applied test limit of the accuracy test.
Accuracy
USP – 36 <41>
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Minimum weight
Minimum weight = k S/A
k – expansion factor (2)
S – standard deviation
A – Required accuracy (as %) (0.10% = 0.001)
Minimum weight = 2000 S
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If
• S = 0.05mg
• Minimum weight = 2000 x 0.05 mg. = 100 mg
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Assessment questions
• Is the weighing uncertainty (reproducibility)
appropriate for the weighing operation?
• Have you determined the minimum
amount that should be weighed on this
balance?
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Weighing references
• USP <41>
• USP<1251>
• ASTM E617
• GWP® - The Standard – Science
Based Weighing; Mettler Toledo
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• Temperature monitoring devices
• Melting point apparatus
• Standards
Temperature
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How often should dissolution test
apparatuses be calibrated when they are
used with both baskets and paddles?
Dissolution
cGMP Notes
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The CGMP regulations call for apparatus
calibration at suitable intervals. Although
specific time periods are not given,
apparatuses should be calibrated every six
months as part of a firm's routine SOP.
Dissolution
cGMP Notes
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• Dissolution apparatus
– wobble
– level
– rotation
– temperature
– Calibrator tablets
Dissolution
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• Spectrophotometers
– Visible/UV
• Wavelength
• Absorbance
– IR
• Wavelength
– NIR
• Wavelength
Spectrophotometers
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Warning letter
© 2014 The Lanese Group, Inc. 96 10-9
Failure to follow written procedures applicable
to the quality control unit and to establish
adequate procedures in writing as required buy
21CFR211.22(d). Specifically, your SOP ****
requires that the Quality Control manager or
designee calibrate ***brand name*** FT-IR
spectrometer with an internal reference standard
on a ***time period*** basis. This was not
done for the six months following the last
calibration on November 9, 2007.
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Glassware
• Accuracy
• Precision
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Volumetric glass pipettes
Micro pipettes
Accuracy
Precision
Pipettes
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Pipettes
In the case of pipettes, for example, it
would not be suitable to calibrate at
intervals since under normal
conditions of use their capacity does
not fluctuate.
Preamble to the cGMPs
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Chromatographic equipment
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HPLC
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Qualification of HPLC Systems
Modules
Modular
System
Holistic
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Qualification of HPLC Systems
Pump
Injector
Oven
Detector
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Qualification of HPLC Systems
Pump Injector Oven Detector
Critical HPLC Q Parameters:
• Injection volume precision (< 1% RSD)
• Injection volume linearity (in some cases)
• Injection carryover (using a blank; method specific)
• Flow rate precision (< 0.5% RSD RT)
• Column oven temperature (< 0.5% RSD RT)
• Linearity of detector response (using standards; method specific)
• Signal to noise ratio (using dilute standards and blank; method specific)
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Qualification of HPLC Systems
Pump Injector Oven Detector
• Precision of flow rate • Precision of retention times
• Acceptance criteria: Within 5%
• Accuracy of flow rates
• Digital flow meter/volumetric flask and stop
watch
• 1 ml/min with water
• Acceptance criteria: ±10%
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Qualification of HPLC Systems
Pump Injector Oven Detector
• Accuracy of gradient • Increase %B from 0 to 100%, in steps.
• Measure absorbance
• Compare with theoretical value
• Acceptance criteria: ±2% total
• Precision of gradient • Repeat step gradient
• Acceptance criteria: Within 5%
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Qualification of HPLC Systems
Pump Injector Oven Detector
• Ripple • Peak to Peak noise
• Limit: <0.2
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Qualification of HPLC Systems
Pump Injector Oven Detector
• Precision of flow rate
• Accuracy of flow rate
• Accuracy of gradient
• Precision of gradient
• Ripple
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Precision of Injection Volume •Six injections of a standard
•85% water
•15% ACN,
•0.050 mg/ml Caffeine
•10 ul volume •Acceptance criteria: RSD <1%
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Linearity of Injection Volume (optional)
• Analysis with different sample volumes
• Regression analysis
• Acceptance criteria: >0.999
•Carry over • Injection of high concentration followed
by solvent
• Acceptance criteria: <0.2%
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Thermostatted Autosampler •Accuracy of thermostat
•Monitor tempeature over extended period
•Acceptance criteria: -1 to +4
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Precision of Injector Volume
•Linearity of injector Volume
•Carry Over
•Thermostat accuracy
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Precision of temperature •Set tempearture to 40°C •Run water; 1ml/min; 20 min. •-254 nm •Acceptance criteria: ±1°C
•Accuracy of temperature •Comparison with standard •40°C •5 min •Acceptance criteria: ± 2°C
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1 2 3 4 5 6
Qualification of HPLC Systems
Pump Injector Oven Detector
UV
•Baseline noise
–ASTM
–Restriction capillary or column
–Acceptance criteria: <1 x 10-4 AU
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Holmium oxide filter
361.0 nm
453.7 nm
536.7 nm
Wavelength accuracy
Caffeine-Sandard
(0.050 mg/ml)
85% water / 15%
acetonitrile
205 nm
244 nm
272 nm Acceptance criteria: ±2 nm:
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Qualification of HPLC Systems
Pump Injector Oven Detector
UV
Wavelength accuracy
Acceptance criteria: ±2 nm:
Caffeine
205
245
273
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Qualification of HPLC Systems
Pump Injector Oven Detector
•Linearity
–Caffeine standards
–Five Standards,
–0.5 - 50 ug/mL Limit:
–Acceptance criteria: 0.99900
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Qualification of HPLC Systems
Vis/UV Detector
Baseline noise
Wavelength accuracy
Linearity
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Qualification of HPLC Systems
Flow Control
Injector
Oven
Detector
Flow precision and accuracy
Gradient precision and accuracy
Ripple
Volume precision and linearity
Carry over
Temperature precision and accuracy
Temperature precision and
accuracy
Baseline
Signal linearity
λ accuracy
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Qualification of HPLC Systems
System suitability
Injector Precision
Retention time
Detector/injector linearity
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Qualification of GC Systems
Flow Control
Injector
Oven
Detector
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Chromatographic equipment
• Data handling
– A/D Converter
– Integrator
– Recorder
• Curve generator
• Voltage source
• Stop watch
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Particle Counters
• Variable between instruments
• Elements
– Counting efficiency
– Sizing resolution
– False count ratio
– Sampling flow rate
– Sampling time
– Sampling volume
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What is critical?
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Intended use
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What are the challenges you have
experienced in developing, implementing
and maintaining a compliant instrument
calibration program?
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Bonus Material
• Instrument Data Form
– Thanks to Joe Busfield
• Model Calibration SOP
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Questions
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Calibration
in the
Laboratory
Jerry Lanese
Ph.D.
The Lanese Group, Inc.
IVT
Validation Week - 20
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Contact Information
Jerry Lanese Ph.D.
The Lanese Group, Inc.
12401 Catalina, Leawood, Kansas 66209
913 491 9234
© 2014 The Lanese Group, Inc. 131