Calibration in the Laboratory - · PDF fileCalibration in the Laboratory ... Calibration Procedure Laboratory Calibration Program ... Temperature measuring device in stability chamber

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.


3

Each laboratory should implement

procedures that provide the highest

level of assurance of the quality of

the data reported.


4

Components of Data Quality

Analytical Instrument Qualification

Analytical Method Validation

System

Suitability Tests

Quality

Control

Check Samples

© 2015 The Lanese Group, Inc.5

Components of Analytical Instrument Qualification

Design Qualification

Installation Qualification

Operational Qualification

Performance Qualification

4 Qs

Define your terms


The boundaries of qualifications activities are

fuzzy.

IQ

PQ

OQDQ

Define your terms


• Why calibrate?

• What is calibration?

• Where do we find the requirements for

calibration?

• Who in the organization is responsible

for calibration?

© 2015 The Lanese Group, Inc.8

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


Guidance on calibration requirements

USP<1251>

USP<41>


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)


Calibration

• Suitable intervals

• Written program

– Specific directions

– Schedules

– Limits of accuracy and precision

– Remedial action


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


Calibration goes beyond a regulatory

requirement – it is good business, good

science.

Calibration is an element of –

the Quality System


Life cycle

Intended use


17

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).


Personnel shall have

Education

Experience

Training

• GMP

• Skill

Personnel qualifications

21CFR211.25



or

Calibration


Calibration

Actions designed to provide

assurance that a measuring

device gives accurate results.


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.



is used as synonymous with

Calibration

After initial qualification


23

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


Relationship

Laboratory program to corporate

program.

Laboratory program to site 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:

• 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

• Scheduling

• Remedial action


Responsibility

• Review and approval of calibration

records

• Maintenance of calibration records


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


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.




program.• Form

– User responsibility

• Instrument description– Make

– Model

• Identification – Serial number

– Internal Identification

Intended use Location

Range of use

Process tolerance

Other




program.

• Form

– Calibration Manager

• Establish

– Classification

– Calibration points

– Calibration tolerance

– Calibration interval



• Remove instrument from system



• 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


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


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

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



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


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)


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


Test Accuracy Ratio

Process Tolerance

Process Calibration

Tolerance

Calibration Limit

Standard Accuracy

±1°C

±0.25°C

±0.06°C

±0.15°C



• Process for establishing and changing

intervals.

• Interval will drive the schedule.


Calibration Interval

Based on:

• Calibration tolerance

• Data

First interval


Time

Process Calibration

Tolerance

Instrument response

compared to standard

Instrument response with time


Time

Process Calibration

Tolerance

Instrument response

compared to standard

Instrument response with time

Calibration Limit


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

• Interval

• Range

• Test points

• Standards

• Limits for accuracy and precision

• Remedial action

• Work sheet



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


Additional considerations

• Traceable standards

• Known uncertainty

• Suitable

• Maintain records

• Status known

• Do not use equipment not

meeting standards


Impact of new guidance


Some things to consider

• USP <41>

• USP <1251>

• ICH Q10

• ICH Q8

• ICH Q9

• USP Stimulus Article on Test Method

Validation

• EU Chapter 15


Questions


64

Calibration

in the

Laboratory

Jerry Lanese

Ph.D.

The Lanese Group, Inc.

IVT

Validation Week

2015


65

Contact Information

• Jerry LaneseThe Lanese Group, Inc.

12401 Catalina, Leawood Kansas 66201

913 491 9234

[email protected]


mailto:[email protected]

Calibration in the Laboratory - · PDF fileCalibration in the Laboratory ... Calibration Procedure Laboratory Calibration Program ... Temperature measuring device in stability chamber

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