calibration and metrology

7Calibration and Metrology

Go

ran Bringert

Independent Consultant, North Andover, Massachusetts, U.S.A.

INTRODUCTION

The regulatory authorities in the U.S.A. and Europe have

expanded the scope of regulations by reference to inter-

national standards for Quality and Risk Management.

The GMP regulations are still in effect, however the

enforcement focuses on the critical risk factors

determined by risk assessments.

In September 2004, FDA issued three documents

describing the FDAs current thinking:

&

Draft Guidance for IndustryQuality Systems

Approach to Pharmaceutical Current Good Manufac-

turing Practice Regulations (1)

&

Guidance for IndustrySterile Drug Products

Produced by Aseptic ProcessingCurrent Good

Manufacturing Practice (2)

&

Pharmaceutical CGMPs for the 21st CenturyA Risk-

Based Approach Final Report (3)

And Medical Devicespecic international

standards:

&

ANSI/AAMI/ISO 13485:2003 Medical Devices

Quality management systemsRequirements for

regulatory purposes (4)

&

ANSI/AAAMI/ISO 14971:2000/A1: 2003 Medical

devicesApplication of risk management to

medical devices (5)

All of the above documents refer either directly or

indirectly to the following documents as standard

requirements for calibration:

&

ISO 9001:2000 Quality management systems

Requirements (6)

&

ISO 10012: 2003 Measurement management

systemsRequirements for measurement processes

and measuring equipment (7)

&

ISO/IEC 17025:2005 General requirements for

the competence of testing and calibration labora-

tories (8)

&

GUM Guide to the Expression of Uncertainty in

Measurement, (corrected and reprinted 1995)

issued by BIPM, IEC, IFCC, ISO, IUPAC, IUPAP,

and OIML (9)

&

ANSI/NCSL Z540-2-1997 U.S. Guide to the

Expression of Uncertainty in Measurement (10)

The GMPs in Europe and the U.S.A. have common

objectives but differ to some degree in their approaches

and have specic regulatory requirements for human and

veterinary drugs and medical devices.

Validation veries that processes perform to speci-

cations. Specications serve to denewhat performance is

needed for a consistent quality output from the process.

Measurements of critical parameters are needed to judge

theperformance of theprocess. Themeasurements have to

be accurate and repeatable. Accurate and repeatable

measurements require adequately calibrated good

quality measurement equipment. Current regulations

and standards do not specify accuracy requirements as

processes and accuracy specications vary widely across

the industry. The regulations hold the organizations of the

regulated industries responsible to set specications and

tolerances for calibrations and to verify that calibration

laboratories/providers have the competency required for

compliance. The reader should keep in mind that the

standards and regulations cover implementation

of Quality Management Systems and that calibration is

only one of the several components of the Quality

Management System.

Validation of Pharmaceutical Processes is not

possible without reliable and repeatable measurements.

The Predicate Rules (G!Ps) require that critical

measurements be performed with adequately calibrated

measuring devices.

Heat Penetration Studies are performed to calculate

the accumulated lethality, F

0

, in the load. The accumulated

F

0

is the time integral of the lethality function:

LZ 10

TKT

b

=z

At a base temperature T

b

Z1218C and zZ108C, the

effect of 18C error in measured temperature at 1218C

results in approximately 26% error in the lethality

calculation.

This is why in section IX sub-clause C 2 Equipment

Controls and Instrument Calibration, of the 2004 Guidance

for IndustrySterile Drug Products Produced by

Aseptic ProcessingcGMPs Validation of Aseptic

Processing and Sterilization (2), FDA states:

For both validation and routine process control,

the reliability of the data generated by sterilization

cycle monitoring devices should be considered to be

of the utmost importance. Devices that measure cycle

parameters should be routinely calibrated. Written

procedures should be established to ensure that these

devices are maintained in a calibrated state.

Temperature and pressure monitoring devices for

heat sterilization should be calibrated at suitable

Abbreviations used in this chapter: CAPA, corrective action, preventive

action; CFR, Code of Federal Regulations; cGMPs, current good

manufacturing practices; FDA, Food and Drug Administration;

GMP, good manufacturing practice; GUM, Guide to the Expression

of Uncertainty in Measurement; NIST, National Institute of Stan-

dards and Technology; RTD, resistance temperature detector; SOP,

standard operating procedures; TUR, test uncertainty ratio.

intervals. The sensing devices used for validation

studies should be calibrated before and after validation

runs.

ANSI/ISO/DIS 17665:2004 Sterilization of health care

productsMoist heatDevelopment, validation and routine

control of a sterilization process for medical devices (11),

requires that calibration of the validation system, measuring

chain, shall be veried before and after each stage

of validation.

These statements are a clear indication that regulat-

ory authorities consider the integrity of temperature

measurements a critical part of the validation of thermal

sterilization processes. It is important that the validation

SOP reects the theoretical and practical aspects of how

to achieve and maintain high-accuracy temperature

measurements in conjunction with thermal validation.

Due to the large number of topics covered by the

current standards and regulations, this chapter will focus

on the practical issues of calibration based on the assump-

tion that the organization has a quality management

system that is compliant with applicable requirements.

The reader should refer to the complete regulatory

documents, referenced in this chapter, to fully assess

what has to be in place within the readers organization

for a competent and compliant calibration function for

the organizations specic application area. Depending

on the origin, some of these documents are available free

from the Internet while all ISO standards and regulations

are copyright protected and can be purchased as hard

copy or downloadable from any national ISO-afliated

organization.

APPLICATION SPECIFIC REGULATION

(PREDICATE RULES)

U.S. FDA GMP

&

21 CFR Part 58 Good Laboratory Practice for Noncli-

nical Laboratory Studies (12)

&

21 CFR Part 211 Current GoodManufacturing Practice

for Finished Pharmaceuticals (13)

&

21 CFR Part 606 Current Good Manufacturing Prac-

tice for Blood and Blood Components (14)

&

21 CFR Part 820 FDA, Subchapter HMedical

Devices, Quality System Regulation (15)

For full text, go to (16) and under Reference Room

select Code of Federal Regulation.

Europe GMP

&

The European GMP is published in EUDRALEX

Volume 4Medicinal Products for Human and Veter-

inary Use: GMP (17).

Medical Devices

There are three current standards specic to medical

devices recognized by the FDA and EU:

&

ANSI/AAMI/ISO 13485:2003 Quality System

Requirements for Medical Devices (4)

&

ANSI/AAMI/ISO 14971:2000/A1:2003 amendment,

Medical DevicesApplication of risk management

to medical devices (5)

&

ANSI/ISO/DIS 17665:2004 Sterilization of health care

productsMoist HeatDevelopment, validation and

routine control of a sterilization process for medical

devices (11); a draft standard expected to revise and

replace ISO 11134:1994, ISO 13683:1997, and CEN

554:1994 to keep current with technology and moist

heat sterilization practices

&

ISO 17025 has two main sections, Management

requirements and Technical requirements. Section 4,

Management requirements, has 15 sub-clauses

covering eight pages and Section 5, Technical require-

ments, has 10 sub-clauses covering 14 pages. It is

beyond the scope of this chapter to review the detailed

requirements, whichwill be left to the reader to review

as needed.

Corrective Action/Preventive Action (CAPA)

ISO 9001 (6), ISO 10012 (7), ISO 17025 (8), and GMPs have

mandatory requirements for CAPA.

GMPs (PREDICATE RULES)

Regulatory Requirements for Calibration in Europe

and the United States

In Guidance for IndustrySterile Products Produced by

Aseptic ProcessingcGMP, September 2004 (2), the

FDA has included text boxes with quotes from the CFR

and stated:

The quotes included in the text boxes are not intended

to be exhaustive. Readers of this document should

reference to complete CFR to ensure that they have

complied, in full, with all relevant sections of the

regulations.

GMP Calibration Requirements

This section will identify calibration requirements, as of

April 2004, dened by CGMP regulations, the Predicate

Rules including the 21CFR 820 Quality System

Regulations, and EU regulations.

&

21 CFR part 58Good Laboratory Practice for Noncli-

nical Laboratory Studies (12)

&

21 CFR part 211Current Good Manufacturing Prac-

tices for Finished Pharmaceuticals (13)

&

Sec. 211.68 Automatic, mechanical, and electronic

equipment.

&

Sec. 211.160 Laboratory ControlsGeneral require-

ments.

&

Sec. 211.165 Testing and release for distribution.

&

Sec. 211.194 Laboratory records.

&

21 CFR part 606Current Good Manufacturing

Practice for Blood and Blood Components (14)

&

Sec. 606.60 Equipment

&

Sec. 606.100 Standard Operating Procedures

&

Sec. 606.160 Records

&

21 CFR part 820 Quality System Regulation (15)

&

Sec. 820.72 Inspection, measuring and test equipment

ISO/DIS 17665:2004

Sterilization of health care productsMoist heat

Development, validation and routine control of a ster-

ilization process for medical devices (11).

100 II: SUPPORT AND UTILITY SYSTEMS

Summary, Standards, and Regulations

The standards and regulations, in the preceding

summary, require that organizations, involved in the

validation of processes, have personnel with a thorough

knowledge and understanding of what is needed to

achieve and maintain compliance. Calibration is critical,

as reliability of the data generated by sterilization cycle

monitoring devices should be considered to be of the utmost

importance. (FDA 2004 Guidance for IndustrySterile

Drug Products Produced by Aseptic ProcessingcGMP

Validation of Aseptic Processing and Sterilization) (2).

ISO 17025-2005 (8) provides general requirements

for the competence of testing and calibration laboratories

and the GUM (9) clause 1.1 states:

This Guide establishes general rules for evaluating

and expressing uncertainty in measurement that can be

followed at various levels of accuracy and in many

eldsfrom the shop oor to fundamental research.

Therefore, the principles of this Guide are intended to be

applicable to a broad spectrum of measurements,.

An organization that intends to comply has to

dene and document, in SOP, how the organization

achieves and maintains compliance.

Estimation and Expression of Uncertainty

(An Overview)

The Guide (9) is a complex document that covers

far reaching requirements and it should be the responsi-

bility of the metrology function within the organization to

dene the criteria for uncertainties in measurement that

are needed for specic compliance requirements. Cali-

bration is used to maintain measurement errors within

acceptable limits needed to ensure that product quality

consistently meets predened product quality speci-

cations. Historically this was done by the comparison of

howmuch ameasured value differed from a true value.

The difference was dened as the measurement error.

The international metrology community has agreed that

true values are by nature indeterminate and that is why

the term true value is not used in the ISO GUM (9). In

other words, there will always be a degree of uncertainty

in any measurement.

GUM 2.3.1 denes standard uncertainty as:

uncertainty of the result of a measurement expressed

as a standard deviation.

This illustrates standard deviation in a normal

distribution, based on denitions in the U.S. GUM

ANSI/NCSL Z540-2-1997 (10).

ANSI/ISO/DIS 17665:2004 (11) requires, and FDA

Guidance for IndustrySterileDrugProductsProducedby

Aseptic Processing 2004 (2) recommends that the measure-

ment systemused forvalidationshouldbe calibratedbefore

and after validation runs. Calibration requires the use of a

temperature standard and a stable thermal source. Each of

these items contributes some degree of uncertainty to the

calibration result in addition to the uncertainties that are

inherent in each of the components of the measuring chain

(the measurement system used for validation). The Guide

(10) denes how to combine these uncertainties into a

combined standard uncertainty for the measurement

system after calibration. A coverage factor is then used as

a multiplier of the combined standard uncertainty in order

to obtain an expanded uncertainty. If Figure 1 represents

the combined standard uncertainty of a measurement

system with normal distribution, the three condence

intervals shown in the graph represent coverage factors 1,

2 and 2.57 for 68%, 95% and 99% condence intervals

respectively.

European Standard EN 554:1994 required a

minimum TUR of 3:1 for the validation of thermal

sterilization processes. This means that the validation

system should have an expanded uncertainty that is

at least three times less than the process specication

limits. This is illustrated in Figure 2. The process under

validation has specication limitsG0.58C which, with an

assumed normal distribution, can be represented by the

standard uncertainty 1sZ0.16678C. The validation

0

0.1

0.2

0.3

0.4

0.5

-4 -3 -2 -1 0

-2.57 2.57

Measured

Value

Total Uncertainty 2.57 at the

99% Confidence Interval

Standard Deviation

Probability

Density

1 Uncertainty at the


2 Uncertainty at the


1 2 3 4

Figure 1 Standard deviation in a normal

distribution.

7: CALIBRATION AND METROLOGY 101

system has to have a standard uncertainty at least three

times smaller or 1sZ0.0558C. This is an example of an

adequate TUR for validation of a thermal sterilization

process.

A larger expanded uncertainty of the validation

standard increases the probability for an erroneous vali-

dation result that could have severe consequences. This is

illustrated by Figure 3.

TheU.S. version ofGUM,ANSI/NCSLZ540-2-1997,

U.S. GUM (10), is an adaptation of the ISO GUM (9) to

promote consistent international methods in the

expression of measurement uncertainty within the U.S.

standardization, calibration, laboratory accreditation, and

metrology services. The U.S. Guide is identical to the ISO

Guide (corrected and printed, 1995) with the exception of

minor editorial changes to facilitate its use in the

United States.

ISO 17025:2005 (8) makes reference to GUM for

further information on estimation of uncertainty in

measurement.

ISO 10012:2003 (7) Guidance to clause 7.3.1

Measurement uncertainty refers to the GUM for

methods that can be used to combine uncertainties and

present the results. It also states that other documented

and accepted methods may be used.

To fully understand and master the methods

referred to above, it is necessary to study the documen-

tation and integrate the information and requirements into

the users Quality Management and Risk Management

Systems, a topic beyond the scope of this chapter.

Practical Discussion of How to Calibrate the

Measuring Chain

The integrity of temperature measurements is a critical

part of validation of thermal sterilization processes. It is

important that the validation SOP reects the theoretical

and practical aspects of how to achieve and maintain

high-accuracy temperature measurements in conjunction

with thermal validation.

Heat penetration studies are performed to calculate

the accumulated lethality, F

0

, within the load items. The

accumulated F

0

is the time integral of the lethality

function:

LZ 10

TKT

b

=z

At a base temperature T

b

Z1218C and zZ108C, the

effect of 18C error in measured temperature at 1218C

results in approximately 25% error in the

lethality calculation.

The FDA denition of Process Validation is:

Establishing by objective evidence that a process

consistently produces a result or product meeting its

predetermined specications.

a

The required temperature uniformity in the

chamber, according to contemporary industry standards

for terminal sterilization, should be better than or equal to

18C or 0.58C depending on the application. The combined

standard uncertainty for the instrument used for vali-

dation measurements, including temperature sensors,

should be at least three times less than the specied for

the process variable. This means that the overall system

combined standard uncertainty should be better than or

equal to G0.338C or G0.178C, respectively. All com-

ponents involved with the measurement, (from the tip

of each sensor, via the connecting wires, cold junction

reference, signal interface, analog to digital conversion,

conversion from mill volts to temperature, to display and

printout of the measured values) are referred to as the

measuring chain. Figure 4 shows ameasuring chain using

thermocouples.

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

120.00 120.50 121.00 121.50 122.00

Temperature C

Pro

ba

bility

Disrib

utio

n

Standard

2

= 120.70C:

2

= 0.055C

Process

1

= 121.10C:

1

= 0.1667C

Figure 2 Adequate test uncertainty ratio

for validation.

a

(GMP/Medical Device Quality System Manual, 4. Process Vali-

dation, 1997).


Error Sources

Several variable error sources can affect the temperature

measurement accuracy in validation. Control and

management of these error sources should be recognized

as the responsibility of the people who perform the

validation. Individuals responsible for validation should

have the competency to adequately perform the

validation studies.

It is important to distinguish between systematic

and random errors. Systematic errors are eliminated by

calibration, while random errors are not eliminated by

calibration, and can only be minimized through the

application of knowledge and proper procedures. The

operator has to understand how to minimize the inu-

ence of random temperature measurement errors to

consistently achieve the accuracy required for thermal

validation of steam sterilization processes. Procedures

documented in the validation SOP and individual

training of validation personnel are necessary to main-

tain competency of the validation team.

Electronic temperature measurements for valida-

tion are acquired using temperature sensors connected

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

120.00 120.50 121.00 121.50 122.00

Temperature C

Pro

ba

bility

Distrib

utio

n

Standard

2

= 120.70C;

2

= 0.11C

Process

1

= 121.1C;

1

= 0.1667C

Figure 3 Inadequate test uncertainty ratio

for validation.

121C

Autoclave

T/C

121C

Cold

Junction

Scanner A/D conv.

CPU

Feedthrough

Process Measurement

Overall System Accuracy

Figure 4 The measuring chain is

composed of all components

involved in the measurement

system.


to an electronic data logger or recorder. The components

of the measuring chain contribute errors, systematic or

random, that contribute to the Overall System Accuracy.

Figure 5 identies the most signicant Random Error

Sources (in red) in the measuring chain.

Signicant random errors can occur in the following

areas:

&

Sensor design

&

Sensor location

&

Sensor wire nonhomogeneity

&

Thermal scatter at the cold junction reference

Temperature Sensors

Thermocouple type T (copper/constantan) is the

most commonly used thermocouple for temperature

measurements in validation applications due to its high

accuracy and low cost. Temperature measurement is

affected by several ambient conditions, that is why the

ASTMManual on The Use of Thermocouples in Tempera-

ture Measurement, Series MNL 12, 1993 (18) has the

following statement on its rst page:

Regardless of how many facts are presented herein

and regardless of the percentage retained, all will be

for naught unless one simple important fact is kept

rmly in mind. The thermocouple reports only what it

senses. This may or may not be the temperature of

interest. Its entire environment inuences the thermo-

couple and it will tend to attain thermal equilibrium

with this environment, not merely part of it. Thus, the

environment of each thermocouple installation should

be considered unique until proven otherwise. Unless

this is done, the designer will likely overlook some

unusual, unexpected, inuence.

Calibration

The measuring chain shall be calibrated prior to and after

calibration runs. Adequate calibration equipment shall be

used when in calibration of the measuring chain. A

temperature transfer standard, traceable to a primary

standard, and a stable thermal source are required to

perform calibration of the measuring chain. The

combined expanded uncertainty of all components of

the measuring chain, temperature transfer standard and

stable thermal source shall be determined by a competent

calibration facility and documented to be adequate for the

validation of the process equipment.

Measurement standards are classied based on

metrological qualities.

&

The primary standard has the highest metrological

qualities and is accepted without reference to other

standards of the same quantity. Primary standards are

normally kept in national measurement laboratories

and designated as national standards.

&

The secondary standard has its value assigned

by comparison with a primary standard of the same

quantity.

&

The transfer standard is used for the comparison of

standards of the same quantity.

This means that the validation study has to have

documented evidence that the measuring chain was

in calibrated state before and after the validation

study was performed. The documented procedures

shall describe the criteria chosen for the calibration

procedures. This should be backed by historical docu-

mentation that gives the rationale for the procedure. The

regulations require three consecutive successful vali-

dation runs for a successful validation. Based on the

companys risk assessment and risk management it

seems realistic to calibrate before the validation study

begins and to verify that the measuring chain remains in

calibration at the end of the third successful run.

Be patient. A frequent mistake in calibrating instru-

mentation is to takemeasurements andmake adjustments

before conditions have stabilized. Itmay takemuch longer

than expected for a system to become completely stable,

because thermal equilibration takes place exponentially

and the outputmay seem to be stable even though it is still

changing slowly. Automatic detection of stability to preset

stability criteria, offered bymodern calibration equipment

and software, is the most reliable and repeatable method

for stability determination.

Sensitivity

Long Termdrift

Temperature Coefficient

A/D Conversion Error

121C

Autoclave

T/C

121C

Sensor Design

Position

Non Homogeneity

Linearization

Thermal Scatter at Cold Junction Reference

Cold

Junction

Scanner A/D Conv. CPU

Figure 5 Random and systematic error

sources in the measuring chain.


Temperature Transfer Standard

The accuracy of the transfer standard must be better

than that of the instrument being calibrated. This would

seem obvious, but it is amazing how often a voltage

calibrator is used that has a greater error than the

system being calibrated. It is important to recognize

that the accuracy of the calibration can be no better than

the standard used, and it is a mistake to change the

adjustment of a measuring system if it is already more

accurate than the standard.

The characteristics of the transfer standard must

have been determined by a procedure that is traceable to

accepted primary standards. In the U.S.A., NIST is the

accepted source of primary standards. The transfer

standards need to be calibrated by NIST relative to

their primary standards or by a qualied Standards

laboratory relative to standards calibrated by NIST.

In either case, the test results and test numbers should

be known so the calibration procedure can be traced to

the primary standards.

The transfer standard must be independent of the

measuring system. Because the output of a thermo-

couple depends on the entire circuit, it is not a

desirable transfer standard. An RTD is a device that

indicates changes of temperature by a change of

resistance. Because the resistance of an RTD is only a

function of its temperature, and the resistance can

be measured independently of the system being

calibrated, RTDs are ideal temperature transfer

standards.

The transfer standard must be stable in shipment

and tolerate other handling. As its name implies, the

purpose of the transfer standard is to transfer a

measured characteristic from one laboratory to

another. The characteristics of the standard must be

the same when received from NIST as when it was

calibrated relative to their standards. Liquid in glass

thermometers may be damaged or develop small voids

in the liquid during shipment, and therefore are not

reliable temperature transfer standards. RTDs are sensi-

tive devices that maintain their characteristics only

with careful handling and shipment.

Stable Thermal Source

Signicant random calibration errors that can occur in a

dry block temperature reference:

&

Transfer calibration

&

Stem conduction

&

Uneven heat transfer

&

Immersion depth

&

Well inserts not used

&

Stability

&

Time needed for stabilization

Reference Error, Using Thermocouples

When calibrating a thermocouple T

1

, against an

RTD transfer standard T

2

, a key contribution to error is

the difference in temperature between these devices

when placed in the reference (Fig. 6). This difference

is called transfer calibration error and is potentially the

largest contribution to calibration errors in dry block

references.

Transfer calibration error contains two components:

1. Stem conduction error, which cools the thermocouple

tip (Fig. 7).

2. Uniformity of the reference wells relative to the

standard well.

A dry block with one common large diameter well

is not suitable for calibration of a measuring chain using

multiple thermocouples (Fig. 8). The stem conduction

will cause heat losses that are greater than the heat

radiated from the walls of the single well. Figure 8

illustrates this inadequacy.

A dry block with smaller diameter wells and inserts

provides closer thermal coupling between well walls and

sensors under calibration, minimizing the effect of stem

conduction and transfer calibration error. A dry block

designed for maximum transfer calibration accuracy has

small diameter wells with inserts that t the size of the

sensors under calibration (Fig. 9).

Temperature

Measurement

Standard

Thermocouple

Temperature

Reference

T

1

T

2

Figure 6 Transfer calibration error is the temperature

difference between thermocouple tip (T

1

) and the measurement

standard (T

2

).


Calibration Procedure

Calibration of the measuring chain (Fig. 3) should be

done with the sensors connected to the data logger/

recorder and installed in the sterilizer via the feed

through and out through the open sterilizer door.

The sensors should be inserted into the temperature

reference bath or dry block, just outside the open steri-

lizer. Calibration should be performed prior to a

validation study and a calibration check should be

performed at the conclusion of the validation.

Prestudy Calibration

A two-point calibration should be used with calibration

points bracketing the sterilization temperature for the

process under validation, e.g., 1008C and 1308C, and

calibration checkpoint should be, e.g., 1218C, between

the two calibration points to verify the calibration.

Poststudy Verification

A two-point comparison between the temperature stan-

dard and the temperature sensors should be performed to

verify that the calibration of the measuring chain is intact.

The calibration should be documented, to provide

evidence that the temperature of the reference, the

transfer standard, and the sensors were stable before

the determination of calibration correction values. The

calibration documentation should include data on the

deviation between the temperature standard and each

temperature sensor before and after calibration. To ensure

traceability, the documentation must list the calibration

parameters and equipment including serial numbers and

last calibration dates.

SUMMARY

Validation of thermal sterilization processes requires

accurate temperature measurements to provide reliable

results. In order to ensure measurement integrity it is

necessary that the validation personnel has adequate

training and well-dened processes to follow.

Risk assessment and risk management are now

mandatory for processes that are used for manufacture

or production of products with critical tolerances.

The result of the risk assessment should serve as a basis

for denition of process tolerances and the corresponding

measurement tolerances for the process control system.

Appropriate measurement tolerances vary by appli-

cation, while a moist heat sterilization process needs to

be measured toG0.58C a depyrogenation process would

be adequately measured with a tolerance of G1.08C.

Internationally accepted good metrological stan-

dards and process control engineering practice call for

the application of TUR between the equipment under

calibration/validation and the calibration equipment

itself. For most applications the minimum TUR should

be 3:1 and preferably higher (Figs. 12). The higher

the TUR the more expensive calibration equipment has

to be used. This is an area where risk assessment and

risk management is used to determine the level of

Sensor

Under Calibration

Heat Loss Through

Copper Wire

Air Gap Between

Sensor and Well

Transfer Standard

Figure 7 Stem conduction causes heat loss and generates

calibration error.

Top View

Side View

Figure 8 Dry well with large diameter wells.


compromise needed to balance the level of acceptable risk

versus the cost of more sophisticated calibration equip-

ment. According to ISO 17025 and ISO 10012

the management is responsible for the determination

and justication of the balance of risk versus cost.

Calibration/verication of the sensors monitoring

and controlling the process is as critical as the cali-

bration of the sensors used for validation of the

process. Each individual measuring chain has to be

calibrated/veried against a transfer standard, i.e.,

sensor, wiring, and measurement system, to at least the

same expanded uncertainty as required for the calibration

of the validationsystem.

The pressure sensor in the autoclave must be

calibrated in place under standard operating condi-

tions. A two-point comparison between the installed

pressure sensor and a temporarily connected pressure

transfer standard, traceable to a national standard,

should be performed. Based on the comparison, zero

and span adjustments are done on the installed

pressure sensor.

REFERENCES

1. FDA Draft Guidance for IndustryQuality Systems

Approach to Pharmaceutical Current Good Manufacturing

Practice Regulation, September 2004, U.S. Department of

Health andHumanServices FoodandDrugAdministration,

Center forDrug Evaluation andResearch (CDER) Center for

BiologicsEvaluationandResearch (CBER),Center forVeteri-

nary Medicine (CVM), Ofce of Regulatory Affairs (ORA).

2. FDA Guidance for IndustrySterile Drug Products

Produced by Aseptic ProcessingCurrent Good Manufac-

turing Practice, September 2004, U.S. Department of Health

and Human Services Food and Drug Administration

Center for Drug Evaluation and Research (CDER) Center

for Biologics Evaluation and Research (CBER) Ofce of

Regulatory Affairs (ORA).

3. FDA Pharmaceutical CGMPs for the 21st CenturyA Risk-

Based ApproachFinal Report, September 2004, Depart-

ment of Health and Human Services, U.S. Food and Drug

Administration.

4. ANSI/AAMI/ISO 13485:2003 Medical DevicesQuality

management systemsRequirements for regulatory

purposes. Association for the Advancement of Medical

Instrumentation, Arlington, VA.

5. ANSI/AAMI/ISO 14971:2002/A1:2003Application of

risk management to medical devices. Association for the

Advancement of Medical Instrumentation, Arlington, VA.

6. ISO 9001:2000 Quality management systemsRequire-

ments. International Organization for Standardization,

Central Secretariat, Geneva, Switzerland.

7. ISO 10012:2003 Measurement management systems

Requirements for measurement processes and measuring

equipment. International Organization for Standardization,

Central Secretariat, Geneva, Switzerland.

8. ISO/IEC 17025:2005 General requirements for the compe-

tence of testing and calibration laboratories. International

Organization for Standardization (ISO) and International

Electrotechnical Commission, Geneva, Switzerland.

9. ISOGuide to the Expression of Uncertainty inMeasurement

(GUM), issued by BIPM, IEC, IFCC, ISO, IUPAC, IUPAP.

International Organization for Standardization, Central

Secretariat, Geneva, Switzerland, 1995.

10. ANSI/NCSL Z540-2-1997 American National Standard for

Expressing UncertaintyU.S. Guide to the expression of

Uncertainty in Measurement. National Conference of Stan-

dards Laboratories, Boulder, CO.

11. ANSI/ISO/DIS 17665:2004 Sterilization of health care

productsMoist heatDevelopment, validation and

routine control of a sterilization process for medical

devices. International Organization for Standardization,

Geneva, Switzerland, 2004.

Top View

Transfer Standard

Well with Insert and

Three Thermocouples

Well with Insert

for Three T/Cs

Well with no

Insert

and One T/C

Side View

Figure 9 View of dry block with one large well and no insert.


12. FDA, Good Laboratory Practice for Nonclinical Laboratory

Studies, Title 21, Part 58.

13. FDA, Current Good Manufacturing Practice for Finished

Pharmaceuticals, Title 21, Part 211, Code of Federal

Regulations (U.S.A.).

14. FDA, Current Good Manufacturing Practice for Blood and

Blood Components, Title 21, Part 606, Code of Federal

Regulations (U.S.A.).

15. FDA, Subchapter HMedical Devices, Title 21, Part 820,

Quality System Regulation, Code of Federal Regulations

(U.S.A.).

16. http://www.fda.gov, 2006

17. European Good Manufacturing Practice, EDURALEX

Volume 4Medicinal Products for Human and Veterinary

Use, August 2004 (update of 1998 edition), European Com-

mission, Enterprise DirectorateGeneral Pharmaceuticals:

Regulatory Framework andMarket Authorizations. http://

ec.europa.eu/enterprise/pharmaceuticals/eudralex/

homev4.htm, 2006

18. ASTM Manual on the Use of Thermocouples in Tempera-

ture Measurement, Manual Series MNL 12, American

Society for Testing and Materials 1916 Race Street, Phila-

delphia, PA, 1993.


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