Calibration in the Laboratory - CBI | Powering Thought ... 1 Breakfast...Outline Introductions...

© 2014 The Lanese Group, Inc. 1

Calibration

in the

Laboratory

Jerry Lanese

Ph.D.

The Lanese Group, Inc.

IVT

Validation Week - 20

Outline

Introductions

Requirements for Calibration in the

Laboratory

Elements of a Laboratory Instrument

Calibration Program

Calibration of common laboratory instruments

Interactive exercise


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. 3

To assure he accuracy and integrity of

the test results we provide

Why do we calibrate

instruments?


The need for accurate measurements

• Is not unique for to the laboratory.

• Is not unique to the pharmaceutical industry


It is good science

What are the regulatory requirements

for the calibration of laboratory

instruments?


Regulations and standards

21CFR211

21CFR111

21CFR820

ICH Q7

ISO 9001

ISO 10012

ISO 13485

ISO 17025

USP<1251>

USP<41>

7

Things to

consider

for your

calibration

program

© 2014 The Lanese Group, Inc.

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)

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)

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).


21CFR211.194(d)

USP 1251

“The tests described above also can be

included in formal periodic calibration in

order to fulfill applicable cGMP

requirements.”


• Sensitivity

• Linearity

• Eccentricity

• Repeatability

USP 36 <1251> Weighing on an

Analytical Balance


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>

If you are assigned the task of writing a

calibration program, what would you

include?


Calibration

• Suitable intervals

• Written program

– Specific directions

– Schedules

– Limits of accuracy and precision

– Remedial action

– Records


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

15 © 2014 The Lanese Group, Inc.

Your program should also include:

Getting instruments into the system

Removing instruments from the system

Classification of instruments

Standard traceability

Measurement uncertainty

Training


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

© 2014 The Lanese Group, Inc. 17 10-9

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


*

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, ***


What other contemporary concepts will

impact our calibration program?


What other contemporary concepts will

impact our calibration program?

• Qualification

• Intended use

• Investigations/CAPA

• Quality system

• Lifecycle


What is calibration?



Calibration

Actions designed to provide

assurance that a measuring

device gives accurate results.

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. ….


… More specifically, calibration is the

practice of verifying critical

measurement equipment performance

(accuracy/ precision) using NIST

traceable standards.


Calibration


Operational Qualification

or

Calibration


Operational Qualification

is synonymous with

Calibration

After initial qualification

What responsibilities and relationships

impact the laboratory calibration

program?



Relationship

Laboratory program to site program.

Laboratory program to corporate

program.


1

2

3

4

5

6

Records

Corporate

Guidance Site

Calibration

Procedure

Laboratory

Calibration

Program

Specific

Calibration

Procedures


Relationship

• Calibration to maintenance.


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


Responsibility

• Procedure

– Format

– Preparation

– Review

– Approval


Responsibility

• General test equipment – Thermometers

– Recorders

– Weighing devices

• Laboratory specific equipment – Chromatographs

– Spectrophotometers


Responsibility

• Assuring that appropriate

instrumentation is used.

• Assuring that instrumentation that

is not calibrated is not used.


Calibration Program

Getting instruments

into the system

Decommissioning

instruments

TAR

Establishing intervals

Remedial Actions

Instrument

classification

Scheduling Establishing

Tolerances

37

Personnel shall have

Education

Experience

Training

• GMP

• Skill

Personnel qualifications

21CFR211.25


38

Calibration SOPs

Corporate

Site

Laboratory

Contractor qualification SOP

Specific laboratory calibration procedures

Measurement uncertainty

Traceability

Skill Training should include:


Calibration Program - Element 1

Process to get all instruments into the program.


• A form

• The origin of the Master Instrument List

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


Form - User responsibility

Get new instrument into the system


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


• Remove instrument from system

– Interface with Change Control System

– Requires final calibration



• Classify the devices – GMP

• Critical

• Non-critical

• Utility

– Non-GMP

• Safety

• Environmental

• Other


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


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


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


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

J Busfield © 2014 The Lanese Group, Inc. 47

Calibration Program Element 4

• Limits of accuracy

• Limits of precision

48

Process calibration tolerance

Limit beyond which product (test result) quality may be compromised

Trigger an out-of-tolerance

Dependent upon process 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



• 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



• Accuracy

• Sometimes it is defined for us









Balance – accurately weigh

USP 36 <41>

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


USP 36 <41>


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>

If

• The weight = 100 mg

• The standard deviation of 12 weighings = 0.05 mg

2 x 0.05mg./100mg. = 0.001 = 0.1%


If the standard deviation is less than

0.41d, where d is the scale interval,

replace the standard deviation with

0.41d.

© 2014 The Lanese Group, Inc. 56 USP 36 <41>


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>


• Accuracy

• Many times we must define it.


Test Accuracy Ratio

• TAR

• Test Uncertainty Ratio (TUR)

• Most programs require at least 4:1


Metrology will utilize a 4 to 1 accuracy ratio

where possible, with a 1 to 10 ratio preferred


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)


62

Test Accuracy Ratio

Process Tolerance

Process Calibration

Tolerance

Calibration Limit

Standard Accuracy

±5°C

±1.25°C

±0.31°C

±0.75°C


Temperature measuring device in stability

chamber

Stability SOP states:

control temperature to 27° C ± 1° C

Calibration procedure states:

Process calibration tolerance: ± 1° C


64

Test Accuracy Ratio

Process Tolerance

Process Calibration

Tolerance

Calibration Limit

Standard Accuracy

±1°C

±0.25°C

±0.06°C

±0.15°C


“accurately weigh” expects a tolerance of

0.10% for the weighing process



Process for establishing and changing intervals.

Interval will drive the schedule.


Calibration Interval

Based on:

• Calibration tolerance

• Data

First interval


68

Time

Process Calibration

Tolerance

Instrument response

compared to standard

Instrument response with time


69

Time

Process Calibration

Tolerance

Instrument response

compared to standard

Instrument response with time

Calibration Limit


Process for changing intervals


Calibration Program Element 6

• Scheduling and record keeping



Specific procedures

– Each category of instrument

• Pressure gauge

• Thermometer

• HPLC

– Each specific instrument


Suggestion

• Procedure for each category of instrument

• Test sheet for each instrument in the category


Specific procedure considerations

• Format

• Test process

• Work sheet

• Interval

• Range

• Test points

• Standards

• Limits for accuracy and precision

• Remedial action



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


Additional considerations

• Traceable standards

• Known uncertainty

• Suitable

• Maintain records

• Status known

• Do not use equipment not

meeting standards


Specific Calibration

Procedures



– Electronic calibration

– Calibration

– Verification

– Who calibrates

– Interval

– Weights

Balance

USP 1251

“The tests described above also can be

included in formal periodic calibration in

order to fulfill applicable cGMP

requirements.”


• Sensitivity

• Linearity

• Eccentricity

• Repeatability



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


USP – prior <41>









USP 36 <41>


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>

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


USP 36 <41>

If

• The weight = 100 mg

• The standard deviation of 12 weighings = 0.05 mg

2 x 0.05mg./100mg. = 0.001 = 0.1%


If the standard deviation is less than

0.41d, where d is the scale interval,

replace the standard deviation with

0.41d.

© 2014 The Lanese Group, Inc. 85 USP 36 <41>


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>

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


If

• S = 0.05mg

• Minimum weight = 2000 x 0.05 mg. = 100 mg


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?


Weighing references

• USP <41>

• USP<1251>

• ASTM E617

• GWP® - The Standard – Science

Based Weighing; Mettler Toledo



• Temperature monitoring devices

• Melting point apparatus

• Standards

Temperature


How often should dissolution test

apparatuses be calibrated when they are

used with both baskets and paddles?

Dissolution

cGMP Notes


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


• Dissolution apparatus

– wobble

– level

– rotation

– temperature

– Calibrator tablets

Dissolution


• Spectrophotometers

– Visible/UV

• Wavelength

• Absorbance

– IR

• Wavelength

– NIR

• Wavelength

Spectrophotometers

Warning letter


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.


Glassware

• Accuracy

• Precision


Volumetric glass pipettes

Micro pipettes

Accuracy

Precision

Pipettes


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


Chromatographic equipment


HPLC

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Qualification of HPLC Systems

Modules

Modular

System

Holistic



Pump

Injector

Oven

Detector



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)




• 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%




• 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%




• Ripple • Peak to Peak noise

• Limit: <0.2




• Precision of flow rate

• Accuracy of flow rate

• Accuracy of gradient

• Precision of gradient

• Ripple




•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%




•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%




•Thermostatted Autosampler •Accuracy of thermostat

•Monitor tempeature over extended period

•Acceptance criteria: -1 to +4




•Precision of Injector Volume

•Linearity of injector Volume

•Carry Over

•Thermostat accuracy




•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


1 2 3 4 5 6



UV

•Baseline noise

–ASTM

–Restriction capillary or column

–Acceptance criteria: <1 x 10-4 AU




•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:




UV

Wavelength accuracy

Acceptance criteria: ±2 nm:

Caffeine

205

245

273




•Linearity

–Caffeine standards

–Five Standards,

–0.5 - 50 ug/mL Limit:

–Acceptance criteria: 0.99900



Vis/UV Detector

Baseline noise

Wavelength accuracy

Linearity



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



System suitability

Injector Precision

Retention time

Detector/injector linearity


Qualification of GC Systems

Flow Control

Injector

Oven

Detector


Chromatographic equipment

• Data handling

– A/D Converter

– Integrator

– Recorder

• Curve generator

• Voltage source

• Stop watch

Particle Counters

• Variable between instruments

• Elements

– Counting efficiency

– Sizing resolution

– False count ratio

– Sampling flow rate

– Sampling time

– Sampling volume



What is critical?

Intended use



What are the challenges you have

experienced in developing, implementing

and maintaining a compliant instrument

calibration program?

Bonus Material

• Instrument Data Form

– Thanks to Joe Busfield

• Model Calibration SOP


Questions



Calibration

in the

Laboratory

Jerry Lanese

Ph.D.


IVT

Validation Week - 20

Contact Information

Jerry Lanese Ph.D.


12401 Catalina, Leawood, Kansas 66209

913 491 9234

[email protected]


mailto:[email protected]

Calibration in the Laboratory - CBI | Powering Thought ... 1 Breakfast...Outline Introductions...

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Transcript of Calibration in the Laboratory - CBI | Powering Thought ... 1 Breakfast...Outline Introductions...