CALIBRATION IN PHARMACEUTICAL INDUSTRY

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Osama Kamel
Egyptian Engineering Systems
www.ees9.com
 KEY WORDS
 CALIBRATION – Comparison
 METROLOGY – Science of Measurement
 TRACEABILITY – Unbroken Chain of Comparisons
 UNCERTAINTITY – Error in Measurement
 ACCREDITATION – Third Party Ascertain
 CALIBRATION INTERVAL – Equipment Remains Reliable
 CRITICAL PARMETERS

MEASUREMENTS

Experiment Uncertainty
Of measurment
or test
Traceability of
measurement

Conducting And
Allowing the
Analyzing Results process owner to
work with
confidence

within the acceptable limits or not

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 Calibration (Old Definition)

“Calibration
is the comparing of an unknown
measurement device against equal or better
known standard under specified conditions”

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 Calibration
“Operation that, under specified conditions, in a first step, establishes a
relation between the quantity values with measurement uncertainties
provided by measurement standards and corresponding indications
with associated measurement uncertainties, and in a second step, uses this
information to establish a relation for obtaining a measurement result from
an indication ” International Vocabulary of Metrology )
( JCGM 200:2012 – International Vocabulary of Metrology )

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 Units of Measurement
SI Units published by BIPM(Bureau of Weights and Measures)
Base Units…

Quantity Unit Symbol

Length metre m
Mass kilogram kg
Time second s
Temperature kelvin K
Electric current ampere A
Luminous intensity candela cd
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Amount of substance mole mol
 Some updates Of ISO 17025 : 2017
• Evaluation of measurement Uncertainty

• Ensuring The validity Of Results

• The Comparison with results of other laboratories Is Not An Optional

Requirement

• Date of issue of the report Is add to the common requirements for reports

• Statement of conformity should consider false accept and false reject

• Identification of person authorizing the report no signature is required

• Metrological traceability (NMI/Accredited labs covered by ILAC MRA

• CRM From RMP comply with ISO 17034 7

 Metrology Laboratories

 Primary Laboratories N, NMI, NPL etc

 Reference Laboratories

 Calibration Laboratories

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 How Do We Get Traceability ?

Common point of reference

My laboratory Your laboratory Their laboratory

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NMI: The Link Organisation to the International Arena

International standards

National Metrology Institute

National community that is using

measurements

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 HIERACHY OF MEASUREMENT STANDARDS
HIERARCHY OF MEASUREMENTS

Primary Standards
Traceable to BIPM

Secondary
Standards

Working
Standards

Instruments
Used in Lab/
Industry

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 CALIBRATION HIERARCHY OF MASS STANDARDS

BIPM Kilogram

National Kilogram

Class E1, E2,F1, F2

Masses

OIML OIML R47

M1,M2,M3
Masses
Masses
Analytical &Top loading
Precision Platform & Top Weighing
TRADE
Balances loading balances
MASSES Bridges

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 Measurement Uncertainty
“ non-negative parameter characterizing the dispersion of the
quantity values being attributed to a measured, based on the
information used”
It arises due to the imperfections in the measurement system
No measurement system is perfect !!!!!

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 Uncertainty
An estimate of the possible error in a measurement

Type A evaluation
A series of repeated observations is obtained to determine
the standard deviation of the measurement result.

Type B evaluation
The evaluation is carried out using available information
found in calibration reports, certificates, specifications etc.

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 Expanded
Uncertainty

Calculate combined standard uncertainties

Exp. Unc. U = Combined Uncertainty X Coverage factor

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Type A Uncertainty
A normal distribution may represent a
random series of readings where the
majority of the readings occur near the
mean value. If these readings are
sufficient in number and graphed, a bell
shaped curve will result.

At lower levels of the calibration chain, where reference standards

are often assumed to be exactly known because they have been
calibrated by a national or primary standards laboratory, the
uncertainty of a calibration result may be a single Type A standard
uncertainty evaluated from the pooled experimental standard
deviation that characterizes the measurement.
JCGM 100: 2008

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 Some Sources of uncertainty
Type B
The uncertainty of measurements can come from various sources,
such as the
1.reference measurement device used for making the measurement
(imported uncertainty, resolution,
2.environmental conditions,
3.operator making the measurements
4.Resolution of unit under test

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 Ishikawa diagram

Reference T/C
Digital
Calibration (B) Thermometer
Resolution (B)

Scatter (A)
CJC (B)
Uncertainty
of an oven

Test oven

Resolution (B)

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 Confidence Level

Gaussian probability distribution

-kσ  +kσ
68% Within 1σ of mean
95% Within 2σ of mean
99% Within 3σ of mean

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 Uncertainty Decision Rule PASS/FAIL Criteria

Fail Area Limits of

possible results

Pass Area

Clear Pass Pass Likely Fail Likely Clear Fail

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 Calibration objectives

Calibration fulfills two objectives:

• It determines accuracy of the measured data
• It provides traceability to the measurement

From Calibration Definition

Calibration: Calibration is essentially the comparison, under specified

conditions, with a higher standard, which is traceable to a national or
international standard, or an acceptable alternative.

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 Test accuracy ratio
A higher standard means:
• A higher accuracy/uncertainty
(a ratio of 10:1 is preferable, but it should not normally be less than 3:1.)
• A better resolution
(the standard’s resolution should preferably be better by a 10:1 or 5:1 or 2:1
ratio.)
The ratio mentioned above refers to the test accuracy ratio. The ratio should be
as
large as economically viable since the higher this ratio, the lesser is the
measurement decision risk.
Test accuracy ratio:
Uncertainty of unit under calibration
TAR = ____________________________________
Uncertainty of standard

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 Test accuracy ratio
In accordance with ISO 10012:2003, the test accuracy ratio should be 3:1,
while
ANSI/NCSL Z540-1-1994 specifies this ratio as 4:1. The test accuracy ratio
today is
commonly known as the test uncertainty ratio, since accuracy is considered a
qualitative
measure and not a quantitative one. Thus, instead of quantifying the accuracy
of a measuring instrument, we use the term uncertainty to quantify this
parameter.
However, for ease and convenience of understanding, the term accuracy will
be used
in this publication.

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How often should we must recalibrate
 Calibration intervals – what do
standers requires
• Iso 17025 section 5.5.2 & 5.6.3.1 requires
– Calibration program to be established for
equipments and reference standers Reference
with procedures
• Iso 17025 section 5.5.8 requires
– Equipments shall be labeled to indicate date when
recalibration is due
 Factors to be considered

• What type of instrument is it

• What interval Does manufacturer recommend
• What is the environmental condition
• Does it have tendcy to wear or drift
• What is the risk of instrument exceeding the
maximum permissible error
• Are intermediate check performed
For how long measurement uncertainty is valid

• A calibration and the corresponding

measurement uncertainty, are just snapshot
in time
• Uncertainty growth (the loss of knowledge of
the values of attribute over time)
• When Does it exceed your out of tolerance
condition
Realability vs. Time
 Interval selection methods

• Interval
• A definite length of time marked of by two
instants
Establishing calibration interval
 No periodic calibration required

• No periodic calibration required or “NPCR”

• If the instrument does not make critical
measurements
– Pressure gauge at middle of transfer line
• If the instrument make measurements which
only provide an indication of the operational
statues
– Example existing of vacuum in line
 Calibration interval options

• Fixed interval
• General interval (single interval for every
thing)
• Automatic adjustment (aka staircase)
• In use time
• borrowed
• Control charts
• Calibration software
 Fixed Intervals
(every6,12 months…)
Pros Cons
Easy to implement “out-of-calibration equipment
may be in use
Easy to remember Test reports/products may
need to be recalled
Easy to schedule Equipment may be calibrated
too often = extra cost
Easy record keeping

Require little expertise for staff

How often?
 General interval
(single interval for everything)
Pros cons
Easy to implement “out-of-calibration” equipment
may be in use
Easy to remember Test reports/products may
need to be recalled
Easy to schedule Equipment may be calibrated
too often = extra cost
Easy record-keeping
Requires little expertise for
staff
 Automatic adjustment
(aka staircase)
• ILAC-G24 : Each time an instrument is
calibrated, the subsequent interval is
extended if its found to be within the
maximum permissible error required for
measurement, or reduced if found to be
outside this maximum permissible error
• (called “Simple Response Method” in NCSL
international RP-1)
 Automatic adjustment
(aka staircase)
Pros Cons
Intervals based on data Interval adjustments are
response to single calibration
event
Easy to implement Unbalanced workload-difficult
to track
Requires little expertise for staf “out-of-calibration” equipment
may be in use
Test reports/products may
need to be recalled
Equipment may be calibrated
too often = extra cost
 In-Use Time

• ILAC-g24
– calibration intervals are expressed in hours of use instead
of calendar time
 In-Use Time

Pros
Requires little expertise from staff
Track the equipment in use time
No. of calibrations varies directly with Unbalanced workload- difficult to
length of time in use
Some instruments drift over time
Cons
Can not be used with all instruments
Cost of timers can be high
track dead lines
“out-of-calibration” equipment may
be in use
Test reports/products may need to
be recalled
Equipment may be calibrated too
often = extra cost
 Borrowed intervals

Pros Cons
Easy to implement Depends on which method you borrow
Hard work is already done How do you know when intervals change
Possibly requires little expertise from stuff Must have similar risk tolerance
Control charts
 Control charts
• Baseline is the average from historical data
• The upper (UCL) and lower (LCL) control limits are:
• UCL = Accepted value + k*process standard deviation
• LCL = Accepted value - k*process standard deviation
• To achieve tight control of the measurement
process, set k = 2
• To flag only those measurements that are
egregiously out of control, set k = 3
 Control charts

Pros Cons
Calibration interval are flexible More work
Can help to predict out of control Unbalanced workload
situation= time of recalibrate
 Control chart Example

• Lab using 2000 gm standard weight to check

balance daily and takes five readings
• The measurements are recorded and then
collected in a spread sheet
• Each set of five readings is considered as a
subgroup
• Subgroup average and ranges are calculated
• The average of subgroup average and ranges are
calculated
Control Chart Data
Graph the data (average (X-bar)chart)

An out-of-control condition in the average (X) charts

indicates a shift in the population average and could due to
the measuring equipments going out of calibration or some
problem in the check standard
 Range (R) chart

An out-of-control condition in the range (R) chart indicate increase in the

dispersion of the repeat observations, which could be attributed to inadequate
control of the environment or incompetence of the operator involved in the
measurement
 WECO Rules

• In Statistical Process Control, the Western

Electric Rules are decision rules for detecting
"out-of-control“ on control charts.

• Locations of the observations relative to the

control chart control limits (typically at ±3
standard deviations) and centerline indicate
whether the process in
 What are the WECO rules for signaling "Out of Control"?

•          Any Point Above +3 Sigma 

 ---------------------------------------------    +3 σ LIMIT
       2 Out of the Last 3 Points Above +2 Sigma 
 ---------------------------------------------    +2 σ LIMIT
       4 Out of the Last 5 Points Above +1 Sigma 
 ---------------------------------------------    +1 σ LIMIT
       8 Consecutive Points on This Side of Control Line 
==============================   CENTER LINE 
       8 Consecutive Points on This Side of Control Line 
 ---------------------------------------------    -1 σ LIMIT
       4 Out of the Last 5 Points Below - 1 Sigma 
----------------------------------------------   -2 σ LIMIT
       2 Out of the Last 3 Points Below -2 Sigma 
 ---------------------------------------------    -3 σ LIMIT
       Any Point Below -3 Sigma 
• Trend Rules: 6 in a row trending up or down. 14 in a row alternating
up and down
What are the WECO rules for signaling "Out of Control"?

• if we observe a point outside the control

limits, we conclude the process has shifted
and is unstable. Similarly, we can identify
other events that are equally rare and use
them as flags for instability. The probability of
observing two points out of three in a row
between 2σ and 3σ and the probability of
observing four points out of five in a row
between 1σ and 2σ are also about 0.3 %.
What are the WECO rules for signaling "Out of Control"?
What are the WECO rules for signaling "Out of Control"?
What are the WECO rules for signaling "Out of Control"?
What are the WECO rules for signaling "Out of Control"?
 Calibration management software

Pros Cons
Reduce time in analyzing calibration Cost
results
Comply with regulations (part 11) Requires some expertise
Archive data
IECEE OD-5011:2015 © IEC 2015 - Annex A
Calibration Interval Extension Example (informative)
 RATING OF CALIBRATION RESULTS
Example
• For the rating of the sensor following points of
the calibration are important:
– Offset of the sensor (without tare) max. deviation
1%
– Characteristic value of the sensor (accuracy class
acc. manufacturer e.g. max. deviation 0.1%)
– Hysteresis determined from increasing series and
decreasing series (see indication in data sheet,
e.g. 0.1%)
 Example:

• If the result of a re-test shows that the measuring

instrument has changed less than 50% of
permissible error
• And the initial interval is defined for12months,
then the calibration interval can be increased to
• 12 months+50% of 12 months = 18 months
• If the measured values are within this 50 % mark
during the next calibration, it can be
• increased to 24 months (18 months + 50% of 12
months).
Examples of calibration interval UKAS
Lab 24
Examples of calibration interval
NIST GMP 11
 EXAMPLE
MASS COMPARATOR Traceable to

BIPM Prototype 1kg

USE

Transfer

Prototype 1kg

Traceable
Calibrate
to
SI Units

Analytical Balance Set of Classes E2, F1, F2, and M1 61

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 MASS

Reference and Auxiliary Equipment

 COMPARATOR BALANCES
 CLASS E1 1 kg
 CLASS E1 SET
 CLASS E2 SET
 CLASS F1 SET
 CLASS F2 SET
 CLASS M1 SET

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 Temperature measuring instruments calibration

• Some of Required reference instruments for filed

calibration
High precision Digital thermometer
Example :Range up to 350 C , resolution 0.01  C
Accuracy (instrument +Sensor ): ≤ 0.1 C
Usage : calibration of ovens, incubators , refrigerators , cold store

Dry block calibrator

Example :Range up to 350 C , resolution 0.1  C
Accuracy : ≤ 0.5 C
Usage: calibration of temperature sensors of autoclaves , tanks,….

Multifunction calibrator
Example :Range up to 1350 C , resolution 0.1  C
Accuracy : ≤ 0.5 C
Usage: calibration of temperature controllers , indicatores , transmitters.

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• Calibration of irregular shape measuring devices
Example :
1-HVAC temperature sensor s
Not suitable for regulated industries
Solution manufacturers offered :
replaceable digital sensing element with cal certificates
expensive solution
2-Temperature data loggers
Good solution in thermal
mapping of stores , refrigerators ,
• Using Temperature test Chamber

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 Pressure measuring instruments
calibration
• Some of Required reference instruments for
filed calibration
High resolution reference pressure gauge
Example :Range -1 to 30 bar , resolution 0.01 bar
Accuracy (instrument +Sensor ): ≤ 0.25 %
Usage : calibration of pressure and vacuum indicatores
in autoclave , process equipments , vacuum ovens , compressed air lines ,
water treatment plant
with hand pump to generate the required pressure

Accuracy classes for pressure gauges

(limits of permissible error)
Reference Devices : 0.1% , 0.25 % F.S.
Working devices : 0.6% , 1% , 1.6% , 2.5% , 4% F.S

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 Fine pressure measuring devices
calibration
• Example
HVAC room differential pressure measurement
HEA filter Differential pressure monitor

• Required reference instrument

Range : 0-1000 Pa
Resolution : 0.1 Pa
Accuracy : ± 0.1% F.S.
With integrated pump to generate low pressure

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 Relative humidity measuring devices
• Example
BMS : Building Management System
Stability test chamber humidity controller
Hand held humidity measuring devieses
Required Reference instrument
Calibrated hygrometer – reference humidity
cell
Dew point Gerator

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 Calibration of process equipment
Tablet Coating Machine
Critical parameters
1-Inlet air temperature
2-Inlet air moisture content
3-Outlet air temperature
4-Pan rotational speed
5-Pan Differential pressure
6-Spraying interval
7-Spraying volume
8-Spraying air pressure
9-Process time

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 Example of critical parameters for tablet coater

Equipment Requirement Instrument type Reference Calibration or Minimum

instrument verification frequency
procedure
Tablet Coating Inlet air Inlet air temperature Dry block calibrator Direct comparison Annually
machine Temperature sensor with accuracy ±0.5 with reference according to
Outlet air C or better instrument located process criticality
Temperature beside control
Inlet air moisture Dew point sensor Dew point calibrator sensor
content Or reference dew NLT 3 points to
point meter cover working range
Accuracy : accuracy
±2 C or better

Pan rotational tachometer tachometer

speed
Pan differential Differential pressure Calibrated
pressure controller manometer
Accuracy : ±0.25 %
F.S. Or better
Inlet air volume Anemometer Calibrated
anemomer
Accuracy : ± 2%
F.S. Or better
Spraying volume Flow meter Calibrated balance

Spraying air Pressure indicator Calibrated

pressure manometer
Accuracy : ±0.25 % 70
F.S. Or better
 CALBRATION INTERVALS

What is Calibration interval ???

Period of time of use to ensure the equipment remains reliable

Interval is too short : Calibration $$$$$

Interval too long : Risk of bad measurements

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 CALBRATION INTERVALS

ISO 17025 Requirements:

Capable of achieving required accuracy

Comply with specifications relevant to test/calibration method
Use under established calibration programme

Therefore need to :

Define required accuracy

Identify the equipment that can affect it
Manage all equipment under a calibration programme

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 RECOMMENDED CALBRATION INTERVALS

N No single correct answer Calibration represents an

instantaneous snapshot of
actual condition

Depend upon

Level of stress - subjected

Stability of past calibration
Allowable tolerance range
Required accuracy
Quality Assurance Requirements

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 RECOMMENDED CALBRATION INTERVALS

Final Analysis Period between two calibrations

Determined & Monitored

USER HIMSELF

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 HOW TO ESTABLISH CALIBRATION INTERVAL

Consider influencing factors and existing knowledge : eg

Accuracy sought & consequences of error
Manufacture’s recommendations
Accommodation & environment
Purpose and usage
Maintenance & servicing
Trends from previous calibration
Frequency of checks
Etc. etc. etc. ….

Ref. - ILAC – G 24 : Guidelines for determination of calibration interval of

measuring instruments
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 RECOMMENDED PRACTICES
 Calibration at (planned) periodic intervals to
ensure acceptable accuracy & reliability
 Shorten the intervals when results of previous
calibration suggest it
 May lengthen intervals on basis of demonstrated
performance
 Documented procedure for assigning and adjusting
calibration intervals
 Fully documented re-calibration system 76
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CALIBRATION OF VOLUMETRIC GLASSWARE

 FLASKS

 CYLINDERS

 BURETTES

 PIPETTES
ACCURACY CLASSES

CLASS A – Higher grade

CLASS B – Lower grade

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 IN-HOUSE PERFORMANCE CHECKS
(During Calibration Interval)

 ANALYTICAL BALANCES – Using a Calibrated

Weight

 INCUBATORS - Using a Calibrated

Thermocouple

 GLASS THERMOMETERS- Ice Point

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 Importance of Calibration
 Assurance of accurate of measurements
 Ability to trace measurements to International
standards
 International acceptance of test/calibration reports
 Correct diagnosis of illness (medical reports)
 Consumer protection (legal metrology)
 Meeting the requirements of ISO 9000 and 17025

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 How we ensure

Technical Competence of
Calibration Laboratories
&
Measurements are
traceable to SI Units

ACCREDITATION

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CONTENTS OF CALIBRATION CERTIFICATE
 NAME AND ADDRESS : CUSTOMER/ LABORATORY
 METHOD
 CONDITION RECEIVED
 IDENTIFICATION
 DATE OF CALIBRATION
 DATE OF RECALIBRATION ?
 CALIBRATION RESULTS
 UNCERTAINTY OF MEASUREMENT
 TRACEABILITY
 ENVIRONMENTAL CONDITION

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“Calibration of
equipment is
important to obtain
reliable results”

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