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Calibration in the Pharmaceutical Laboratory

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tion in the Pharmaceutical Laboratory

Description

Calibration in the Pharmaceutical Laboratory Tony Kowalski Editor

c Taylor & Francis Taylor €U Francis Group

Boca Raton London New York

A CRC title,

part of the Taylor & Francis imprint,

a member of the Taylor & Francis Group,

the academic division of T&F lnforma plc

Published in 2001 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW,

Suite 300 Boca Raton,

FL 33487-2742 © 2001 by Taylor & Francis Group,

LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U

Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 International Standard Book Number-10: 1-57491-092-2 (Hardcover) International Standard Book Number-13: 978-1-57491-092-6 (Hardcover) Library of Congress catalog number: 00-054188 This book contains information obtained from authentic and highly regarded sources

Reprinted material is quoted with permission,

A wide variety of references are listed

Reasonable efforts have been made to publish reliable data and information,

but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use

No part of this book may be reprinted,

or utilized in any form by any electronic,

now known or hereafter invented,

or in any information storage or retrieval system,

without written permission from the publishers

Trademark Notice: Product or corporate names may be trademarks or registered trademarks,

and are used only for identification and explanation without intent to infringe

Library of Congress Cataloging-in-Publication Data Catalog record is available from the Library of Congress

Visit the Taylor & Francis Web site at http://www

com Taylor & Francis Group is the Academic Division of Informa plc

and the CRC Press Web site at http://www

CONTENTS

Preface

Contributors

Introduction Tony Kowalski T h e Laboratory Balance

Printed Results

Data Communications Via a Personal C o m p u t e r

S o f t w a r e I n t e g r a t e d'into Balances

Moisture Analysers

Calibration of Micropipettes in a Quality System Using a Balance a n d'P C

Intrinsically S a f e Weighing Equipment f o r Hazardous A r e a s

Commissioning of B a l'a n c'e s

Appendix 1

Contents

Control of Test a n d'Measuring Equipment in a Quality System: Balances a n d'Scales in GLP/GMP/IS09000

Stephan Weyhe Motivation

Selection of Suitable Test and Measuring Equipment

Determination of t h e U n c'e r t a i n t y of Measurement

Calibration and Adjustment

Traceability of a M e a s'u r e m e n t

Documentation

Defining the I n t e r v a l'of Confirmation

Summary

Bibliography

Expression of Uncertainty f o r Displayed Net Values

J u e r g e n Ober Quantities Influencing U n c'e r t a i n t y of Measurement

Determination of t h e Components

Calculation of t h e Uncertainty

Uncertainty in P r a c't i c'a l'U s'e

Summary

Reference

Contents

Software Validation

Wichmann Software Use

Risk F a c't o r s

I n t e g r i t y Assessment

S o f t w a r e Development P r a c't i c'e

Conclusions

Acknowledgements

Appendix 4

A: Check-Lists

Appendix 4

B: Some E x a m p l'e Problems

Appendix 4

C: Recommended Software Engineer in g Techniques

References

Errors Associated with Weighing

Chris Jenkins E r r o r s'Caused by Weighing I n s't r u m e n t s

E r r o r s'Caused b y E n v i r o n m e n t a l'E f f e c't s

E r r o r s'Caused by O t h e r E f f e c't s

References

Weights and Weighing Machines

Buckley Metrology and S t a n d'a r d's

Mass S t a n d'a r d's a n d'Weights

Weighing Machines

Contents

Weighing in the

Pharmaceutical Industry

Ted Scorer The Pharmaceutical Industry

Check-Weighing

T h e Regulatory Environment

Non-Automatic Weighing I n s't r u m e n t s'D'i r e c't i v e 246

Methods for Estimating the Uncertainty of Electronic Balance Measurements

J o h n P

Clark and A

Harper Shull Weight M e a s'u r e m e n t Terminology

Summary

References

To my wife,

Pauline Kowalski,

Katherine Louise Kowalski and Rachel Caroline Kowalski

PREFACE

As with many product developments and discoveries,

this book was written as a result of a series of coincidences and circumstances

I was asked to make a presentation to a major pharmaceutical company on calibration weightstheir use,

storage and which class should be used

From this and subsequent similar presentations,

I was able to deduce that,

although such companies were expert in their field of drug discovery,

manufacturing and quality control,

there was generally a huge gap in their knowledge of metrology and weighing technology

A s'I made more presentations,

mostly on demand from pharmaceutical companies,

I gradually expanded the content to include GLP/GMP,

understanding and determination of uncertainty,

choosing the correct balance and aspects of in-house maintenance and external service contracts

It was after completing a series of calibration seminars during the London Laboratory ix

Preface

I began to develop this book-as a series of relevant and related chapters by recognised international experts in their respective fields

This was not only very interesting,

exciting and informative but also incredibly frustrating since all of the authors hold demanding positions and required varying amounts of time to produce their chapters

Nevertheless,

with a lot of effort and help,

this book has been completed and will,

I hope,

offer answers to many questions as well as insight into better mass measurements,

increasing the reader’s understanding and appreciation of the associated errors

As with all modern technology,

technical and scientific books are almost certainly guaranteed to be out of date or suffer from changes in opinion and shifts in emphasis due to the everchanging world in the pharmaceutical industry

A good example of this was the U

Food and Drug Administration’s introduction of a directive whereby all mass measurements must be made with a maximum uncertainty of 0

1 percent

This directive,

Pharmacopeia regulations,

lay virtually undetected by pharmaceutical scientists for some three years

Today it not only has been discovered but is highly topical due to misunderstanding and misinterpretation of the document

As a result,

most calls from the pharmaceutical industry to balance manufacturers are for help in determining the smallest mass that can be measured on

Preface

particular balances and still comply with this directive

A short section,

has therefore been added to Chapter 1 as an appendix,

which outlines the requirements and details the procedures involved in determining the minimum weight that can be measured on individual balances

In my experience,

uncertainty of measurement has not previously been understood or taken into consideration by any balance operators outside mass calibration even though it can be a significant hidden influence on the accuracy of results

A full description and outline of the factors affecting the uncertainty of measurement is given in Chapter 8

Next year,

the flavor of enquiry will change as the FDA not only moves the goal posts farther apart but also may introduce new regulations

I am quite sure that one of the next hot topics will be validation of the software embedded within the microprocessor of measuring equipment such as balances

So far,

manufacturers have not needed to provide documentation since validation of the measuring accuracy (described in Chapter l'under hardware validation) and repeatability has satisfied the FDA

During my 16 years at Sartorius,

I have been grateful for knowledge imparted to me by my colleagues within product management,

product manager for moisture analysis and pipette calibration,

and Dirk Mueller and Thomas Pertsch,

Preface

of precision laboratory balances

In addition,

I am especially appreciative for the commitment from my co-authors who contributed chapters for this book

Tony Kowalski February 2001

CONTRIBUTORS

Tony Kowalski,

Editor Tony Kowalski is currently the product manager for laboratory balances and head of marketing for weighing equipment at Sartorius Limited at Epsom,

He was educated at the College of Science and Technology Newcastle upon Q n e and trained as a laboratory technician

Before joining Sartorius,

he worked in quality control and process development for Harcross,

and for the Cancer Research Unit at Newcastle upon Tyne

Buckley Mike Buckley joined the trading standards service of Leicestershire Council and Rutland County Council in 1972 and later became standards officer and general manager with the South Yorkshire County Council in 1976

Contributors

Buckley now heads the South Yorkshire Trading Standards Unit,

which is a UKAS accredited calibration laboratory that provides services to industry and trading standards services to the South Yorkshire Metropolitan District Council

Buckley has presented papers on mass calibration to conferences in Europe,

the United States and the Far East and was chairman of the Weighing 2000 Conference

Clark John P

Clark has over 20 years of experience at the Westinghouse Savannah River Company

A metrological engineer,

he has technical oversight for the mass and pressure calibration laboratories

Prior to working at the Savannah River site,

he set up and managed the chemical standards laboratory at the Barnwell Nuclear Fuels Plant and worked in the analytical laboratories at the Idaho National Engineering Laboratory

Clark is currently implementing a site-wide scale and balance calibration program and measurement control programs

He is a frequent presenter and session developer at national and international professional meetings

Chris Jenkins Trained in mathematics and statistics,

Chris Jenkins became a trading standards professional and has held legal metrology enforcement posts

Contributors

Since his appointment as Calibration Services Manager at Kent Scientific Services,

he has lead the development of a modern metrological laboratory,

which has become the Trading Standards calibration house in South East England

Jenkins is a member of the Institute of Trading Standards Administration and a licentiate member of the Institute of Measurement and Control

He is also a a n advisor on legal metrology

Juergen Ober Trained in electrical and control engineering,

Juergen Ober joined Sartorius AG in 1972 as a scientist in the development department for weighing technology,

primarily responsible for all linear circuits inside the balances

Since 1993,

he has been head of the DKD (German Calibration Services) accredited calibration laboratory for electronic balances and is product manager for mass comparators

Ted Scorer Ted Scorer joined Glaxo Wellcome in 1969 and since then has worked in both quality assurance and quality compliance

In 1982,

he joined the Central Analytical Services Department (now the Laboratory Support Group) based at Barnard Castle

This group is a multidisciplinary analytical science group providing worldwide support

Contributors

for Glaxo Wellcome in laboratories and the introduction of measurement science to production lines

He has developed manual and automated check-weighing applications and in-house software for controlling these applications

Scorer is also a founding member of the National Physical Mass,

Weighing and Density Club

Harper Shull A

Harper Shull was a statistical consultant for Eastman Kodak for 17 years before joining the Westinghouse Savannah River Company in 1990

He is currently a principal scientist in the Advanced Planning and Process Support Section of the Analytical Laboratories Department

He provides technical support and statistical oversight to the laboratory in the areas of standards,

measurement uncertainty estimation,

variance propagation and experimental design

Stephan Weyhe Trained in physics,

Stephan Weyhe was a product manager for medical devices in the therapy of cancer

He joined Sartorius AG as product manager for micro and analytical balances in 1989

Weyhe subsequently became the head of product management for laboratory and industrial products

Contributors

Brian Wichmann Dr

Brian Wichmann has over 30 years of experience on software quality issues

He was responsible for the PASCAL validation suite used to check compilers internationally

He also was part of the team that designed Ada and was project editor for the IS0 Technical Report on using Ada in high integrity system

Wichmann is a visiting professor at the Open University

Chapter 1

INTRODUCTION Tony Kowalski Sartorius Limited Epsom,

Surrey,

United Kingdom

As the regulation of test and measuring equipment used in pharmaceutical manufacturing and quality assurance is ever increasingly becoming an administrative nightmare with continually moving goalposts and where new regulations could be introduced from either government,

the Food and Drug Administration (FDA) or the Medicines Inspectorate,

external help is often required from publications that specifically detail plans to incorporate equipment into quality systems

Today’s scientist is not only required to be a specialist in his or her own field but needs to become familiar with legislation that governs the 1

Calibration in the Pharmaceutical Laboratory

use of equipment in the pharmaceutical industry

Within Europe,

a new directive was introduced in 1993 (89/336/EEC) that radically changed the type of equipment used in quality control laboratories

This directive becomes final in January 2003 following a 10-year derogation period and is fully covered in the chapter covering the verification of balances (chapter 2)

Having decided on the correct balance,

which should be governed by the determination of required and actual accuracy of the weighing machine,

the end user must then follow a rigid process in order to validate the equipment prior to bringing it into use,

which is also covered later in this chapter

Scientists need to understand a great deal of physics in order to make decisions on pass and fail limits when testing laboratory balances with traceable mass standards and must also make informed decisions on which quality,

ultimately connected to accuracy,

of calibration mass should be used to test each type of balance

Taking into account the errors associated in measuring the mass of an object is also crucial in order that the uncertainty of measurement can be calculated

Without this knowledge,

a scientist cannot be sure that all measurements a r e made with the intended accuracy

As the requirements of the FDA are constantly tightening,

with the sole aim of reducing margins for error,

managers responsible for quality control and quality assurance require the best possible tools for the job and up-to-date

Introduction

accurate information in order to set out Standard Operating Procedures (SOPS) for balances and scales used throughout the manufacturing and testing process

Having been introduced some years earlier,

Pharmacopeia) covering the use of balances for quality control analysis of drugs destined for the U

market is currently the topic of discussion and in particular the determination of the minimum weight that can be measured on each balance

Details of how to comply with this directive can be found in Appendix 1

The goal of this book is to provide some general background information on laboratory balances and precision scales,

together with concise detailed information on key quality issues associated with weighing

THELABORATORY BALANCE The modern laboratory balance is taken for granted by many end users

it is the result of many years of development to both the mechanical weighing cell and the sophistication of the most recent microprocessor technology

Yet this is not the full picture,

since every balance requires complex software in order to produce even a simple weighing result because the weight readout is a dynamic average value of measurements integrated over a short time period

This readout is constantly updated at a rate

Calibration in the Pharmaceutical Laboratory

which means that the balance can react to the smallest changes in mass quickly

Depending on how well the digital filter algorithm is written,

the balance should stabilise quickly and be reasonably resistant to external influences

The first commercial microprocessorcontrolled electronic balances were introduced by Sartorius in 1973,

instigating a new revolution in weighing technology as other manufacturers followed suit

These first generation electronic balances gave the operator the ability to tare containers and weigh in components without having to make subtractions for the container weight

The weighing process was shortened even further: Since there is no requirement for preweighing with a mechanical system on partial release prior to the final measurement,

some estimates show that the total measuring time has been reduced by a factor of five

A further advantage of digital balances is the possibility of connection to a data printer for hard copies of all measurements,

which drastically reduces the risk of transcription errors,

and provides an easy means of storing measured values

PRINTED RESULTS Printouts from balances can offer far more than just simply the measured value

This is particularly useful since compliance to quality systems

Introduction

requires records that show the date,

equipment used and operator’s signature

Most balances today have the means to print this information,

and the top of the range models have the facility for additional alphanumeric header text that allows entry of the company and location of the balance

This type of printout is usually referred to as a GLP (Good Laboratory Practice) or IS0 (International Organisation for Standardisation) compliant printout

A typical example of a GLP/ISO printout is as follows: 28

Dat e/Time

S A RTORI US Model LP42OOS

Balance Model

030319914

Unique serial number

01-30-01

Software Version

I D'123456789ABCDE

Alpha I D'(user definable)

L I D'123456789ABCDE

Lot or Location ID

S-ID 123456789ABCDE

Weighed Value Weighed Value

Sample ID Weighed Value

D a t e/Ti me

Operator Signature

Calibration in the Pharmaceutical Laboratory

Information concerning the unique serial number should preferably be read directly from the main microprocessor in the balance rather than relying on a text entry in the memory of the data printer

This prevents the obvious from happening should the printer be connected to another balance

Time and date stamps are important and in most cases are taken from the clock in the data printer

In cases where balances are connected to other devices,

the top of the range models from some manufacturers have internal real-time clocks which allow date and time stamping of the results

Balances with internal adjustment weights also generate printouts just after the adjustment routine has finished to give records of all changes in the calibration of the balance

(Please refer to the terms for calibration and adjustment for detailed definitions

) Many manufacturers offer balances that can automatically activate the internal adjustment weight,

where a change in temperature is significant enough to cause a change in the calibration

if the manufacturer has taken into account that air density may change whilst the temperature remains constant (air conditioning),

the balance will automatically adjust every four hours irrespective of temperature

As always,

the top of the line models offer the feature of storing up to 50 adjustment routines for printing at a later or more convenient time

This helps to prevent loss of the smaller individual printouts from single routines

In order for the end user to be confident that there is no

Introduction

excessive inherent drift and that the automatic adjustment routine is only there masking this,

there should be some indication of drift expressed on the calibration routine printout

The following is a typical example of a n adjustment routine printout: 28

Internal calibration Start: isoCAUtemp

00 g 28

Calibration Function Reason for isoCAL (automatic adjustment) Calibration result (drift since last adjustment) Adjustment function Adjustment result Datehime Operator signature

A question often asked in working to a quality system is,

“Can I have a certificate for the internal adjustment weight and is it traceable to a national standard

?” In short the answer is a resounding “NO” to both parts of the question

this does not render the internal weight obsolete

The internal weight is there only to

Calibration in the Pharmaceutical Laboratory

adjust the balance if during a calibration test using an external calibration weight the operator notices that the indicated value on the balance display deviates from the apparent mass value of the calibration weight by more than the tolerance set out in the SOP

This means that the balance is only adjusted using the internal weight and is then calibrated using an external certified and traceable calibration weight

Almost every balance with internal adjustment weights uses conveniently shaped pieces of stainless steel that can be easily raised and lowered and stored in a fixed position close to the weighing system

the weights a r e manufactured to a value close to the target value

It is therefore quite feasible that a weight with a target value of say 200

It is because of the non-OIML Organisation Internationale Metrology Legale compliant shape and odd mass value that the internal weight cannot be given a calibration certificate

However,

because its actual mass has been accurately determined,

a factor can be stored in the microprocessor so that the balance is always adjusted correctly

DATACOMMUNICATIONS VIA A PERSONAL COMPUTER Serial communications via RS232 have been the standard format for interface connections on laboratory balances since the earliest personal

Introduction

computers (PCs) adopted this standard

Because of the incredible processing power of the commercially available software packages,

the option to download data from the balance directly into a PC seems highly attractive

However,

anyone simply connecting a balance via the RS232 link and hoping to directly input data into a spreadsheet will be in for a rather rude awakening since software of this nature expects data entry via the keyboard and has no option for accepting data via the serial communications port

is at hand since most manufacturers can supply a solution in the form of a software wedge and connection cable

A software wedge is the description given to the utility written to allow the user to obtain full two-way serial communications between a [email protected] application and an external instrument,

in this case a laboratory balance,

although the device could be anything from a pH meter to a spectrophotometer (Figure 1

The software wedge operates on two levels: (1)by converting incoming serial data to keystrokes,

which means that the applications receive data as though they had been typed in or (2) the data can be downloaded using dynamic data exchange (DDE)

DDE is vastly more powerful than the keystrokes method,

as one would expect this superiority to require additional complexity in the set-up

These software packages are relatively low cost and as such are not available as fully validated for use in the quality control of tablets or medicines

Calibration in the Pharmaceutical Laboratory

Figure 1

Serial Communications from a Balance to a PC

Moreover,

there is no restriction preventing data from being entered manually or previous data being changed

SOFTWARE INTEGRATED INTO

BALANCES

Even the lowest cost laboratory balances a r e equipped with some applications software to perform calculations or routines that provide an instant solution,

saving valuable time and effort on behalf of the operator

With the advent of lower costing memory and faster microprocessors,

it is now common to have a large suite of applications software available in every balance,

although in most cases the balance would have

Introduction

been purchased with the intention to use only one of the programs available

When choosing a balance to solve problems,

be aware that (paradoxically) a lower cost balance with less sophisticated software is often more difficult to use than the top of the range model with more complex programs

The reason for this is that the more expensive top of the range models have more keys and usually have one key for each function

the better display on the more expensive balances will provide easy-to-follow prompts throughout setup and execution of programs

In particular,

look for a balance that utilises soft keys in combination with a dot matrix display and giving plain English prompts for easy operator instruction

The next few sections detail some of the most commonly used applications

Counting The counting program has two distinct areas of use for precision laboratory balances: (1) highcost,

small precision electronic components and (2) tablet counting in a pharmaceutical dispensary

Simply count out a small number of tablets,

place them on the balance and push a key to store the total weight

The balance automatically calculates the average tablet weight

The display of the balance now shows how many tablets a r e on the pan

all you need to do is add more tablets until the required total is reached

Calibration in the Pharmaceutical Laboratory

Percentage Weighing Where small recipes are written using a percentage rather than weight to define the amount of each component,

then this program offers an easy solution,

relieving the operator from the burden of calculating values in grams

Also be aware that for the printout generated,

it is usually possible to print the tare weight of the container as well as individual net weights and a gross or total weight

If the balance has a numeric keypad,

then it may be possible to define the weight of the first component as its percentage value in the recipe

This is particularly useful when one of the components is difficult to measure due to its nature

Simply dispense a convenient amount and define its percentage value in the recipe and weigh out the rest of the components in relation to this amount

Dynamic Weighing Dynamic weighing is used to give a close estimation of the weight of an object that causes extreme fluctuations in the displayed result

It is often used to weigh live animals

This program will take a series of measurements over a short time frame and give the value as a n average of these measurements

Often the facility of an automatic start helps,

as all the operator needs to do is load and unload the balance

In order to improve accuracy,

Introduction

that the balance will only start to record measurements when they fall within a predefined limit

For example,

when animals are initially placed on a balance,

their movements may cause fluctuations in the display of up to 75 percent

The window is set to start measurements when the fluctuations are no more than 25 percent,

the balance waits until the animal calms down,

leading to a final result that is much closer to the true value-a simple but effective method

! A further use for dynamic weighing is where the location prevents reasonable stability from being achieved on the balance,

in fume cupboards or on oil rigs

Statistics Usually used in statistical process control (SPC) applications rather than tablet weighing since pharmacopoeial limits are set as limits of uniformity rather than as statistical limits fixed around a set target value,

a specific pharmacopoeial program exists in its own right and can be integrated into a standard balance for some manufacturers or is available in a PC program

However,

where statistics are required,

then these programs are usually configurable to print out and display the important parameters and set-up via the menu and will allow the user to select automatic data transfer and taring between additions of samples to speed up the process

Calibration in the Pharmaceutical Laboratory

Other typical programs available include density,

and the conversion of mass units,

none of which have typical applications that spring to mind within the pharmaceutical industry

MOISTURE ANALYSERS There are many different moisture analysers (Figure 1

all making different claims for temperature ranges,

maximum sample size and novel heating sources

All of the different types work on broadly the same principle: An integrated balance measures the starting weight of the sample,

and infrared energy emitted from a source causes the volatiles in the sample to evaporate

After an elapsed time or pre-set end-point determination,

the energy source is turned off,

and the results are displayed either as a percentage of moisture lost or solids remaining

Since the moisture unit simply measures all volatiles lost as moisture,

this value cannot be considered as an absolute value for water,

and care must be taken to avoid denaturing the sample due to excessive bombardment with infrared energy,

as this will cause weight loss that will erroneously be calculated as moisture

This method is ideal for providing rapid results for single samples,

where drying times can be as short as 5 min,

but typically 10 to 20 min based on a typical sample size of 3 to 6 g

Such moisture

Introduction

Figure 1

Samples Being Loaded into a Moisture Balance

analysers are used widely throughout the pharmaceutical industry,

often in production as a means of measuring the moisture of in-process material prior to compression into tablet form

There are a few misunderstood concepts of infrared moisture analysers that are well worth discussing at this point so as to dispel some of the myths and untruths that may be causing concern

Calibration in the Pharmaceutical Laboratory

when comparing one moisture analyser to another or to a different,

moisture determination process

all of these analysers dry the sample by means of infrared energy,

although there are many different energy sources,

including ceramic surface radiators,

Although infrared energy is invisible to the human eye,

this type of energy is classified as light energy and as such is governed by the laws of optical physics

Any visible red light emitted is only a by-product of when the radiator converts electrical energy into infrared energy

This red visible light is seen only on certain types of infrared radiators

The next topic of contention is that of the drying temperature that the analyser will raise the sample to during the drying process

One manufacturer quotes 40 to 160°C,

Wave Spectrum Infrared RadiolTV waves Microwaves

300 MHz

Ultraviolet Visible light

3x10'' MHz

Introduction

one unit quotes temperatures as high as 400°Cso which will dry the sample the quickest

? Since the sample is dried by absorbing infrared energy,

and energy is measured in watts or joules per second,

how could it be possible to quote temperatures in degrees Celsius

? The answer to this comes in two parts,

namely how the temperature of the sample is affected by its own character and how the output from the infrared source is measured and calibrated

Consider two similar samples: The first sample is a light-coloured powder,

and the second sample is almost black,

although both have the same temperature content

Once again,

the laws of optical physics once again play their part in the drying process

The dark-coloured sample readily absorbs infrared energy,

and the sample temperature will ultimately be higher than the light-coloured powder which in turn reflects more of the infrared energy and reaches a lower temperature

The drying process is also likely to take a little longer for the lighter sample

Common sense will tell you that if a temperature probe is located closer to the infrared radiator,

then it will register a different value than if it were placed at a distance

Furthermore,

the type of probe used will also cause slight differences in the measured temperature within the chamber to be recognised

A thermocouple in conjunction with a digital readout is the most common and reliable method for measuring the reproducibility of the infrared radiator within a moisture balance

If in doubt,

Calibration in the Pharmaceutical Laboratory

always best to consult the manufacturer and inquire how they would check and adjust their own moisture balances

If you are then able to utilise the same method,

this will give you the ability to calibrate the heating source of the moisture balances throughout your company to the same standard

Sartorius can supply as a n accessory the same type of thermocouple and digital readout as used in manufacture and servicing together with an SOP for testing the reproducibility of the heating source

In order to test the reproducibility of the instrument,

there is a method detailed in the Sartorius SOP for moisture balances that utilises a saturated saline solution with a specified criterion for the settings of the heat source and the anticipated results

Since all moisture balances calculate the moisture content of a sample as being the total weight of all components lost by evaporation during a rapid heating process,

the method cannot be considered as capable of providing an absolute value as would be given in the case of,

moisture standards that are used to calibrate such instruments cannot be used to calibrate infrared moisture balances

Multireweighing or Backweighing Software for Moisture Determination Where the volume of samples is too great to use a moisture balance (which can analyse only one

Introduction

most manufacturers have integrated software into their balances that will allow the storage of container weights and sample weights in a non-volatile memory

The samples can then be processed and reweighed to determine the moisture content as a percentage

As the name multireweigh suggests,

samples can be processed more than once in order to calculate the loss after different processes,

drying at 105°C and then after ashing in a muffle furnace at 800°C

Flexibility in the software should allow the operator to weigh the sample in any order,

since it would be unlikely that samples will be removed from a dessicator in the same sequence that they were originally weighed

Such a program can,

be used to calculate changes other than loss of moisture,

measuring the change in mass after time of inhalers or measurement of repeated single doses

CALIBRATION OF MICROPIPETTES IN A QUALITY SYSTEM USING A BALANCE AND PC

Since according to any quality management system pipettes are classified as test and measuring equipment,

they too must have an SOP that includes a documented calibration log

Most companies have a contract with the manufacturer or a qualified service organisation to test,

Calibration in the Pharmaceutical Laboratory

and adjust their pipettes on a six-monthly basis

This usually involves sending them away,

although some companies offer a mobile calibration service

Both options offer a calibration and repair service,

although the latter may seem at first the more attractive option since your pipettes will be out of action for less time

Consider,

that in order to provide this service,

the agent has to transport the balance all over the country,

set it up and start calibration within a short time,

which is usually not enough time for the balance to fully equilibrate temperaturewise

Furthermore,

it is quite unlikely that in today’s well utilised (crowded) laboratory that the visiting technician will be given a perfect location with a solid stone weighing table and air-conditioning

Whichever route you decide upon to take care of six-monthly calibration testing,

there is still the question of how best to calibrate the pipettes in the interim in order to meet the requirements of the quality management system

Naturally,

a balance will feature somewhere in the plan but which balance,

what conditions and which international standard apply

? How can I be sure that I am reducing external influences such as evaporation,

all of which contribute to the accuracy and repeatability values for my pipette

? The main objective set out in any quality system must be to ensure that any measurements are made with the intended accuracy

Pipettes are judged by the following criteria: (in)accuracy and (im)precision,

Introduction

measured using an appropriate balance

According to IS0 10012,

this means that the balance should have an accuracy of one-tenth of the permissible error of the pipette to be tested

Additionally,

a documented system must be employed covering the measuring equipment and any measuring standards used in the calibration process,

together with all significant uncertainties identified,

including those contributed by personnel and the environment

For the gravimetric determination of the accuracy of a micropipette,

the volume of distilled water aspirated from the micropipette is calculated from the measured mass using the following equation: volume =

measured mass density of water

The corrected density of distilled water can be taken from tables published in reference booksThe density will be corrected for changes in both temperature and air pressure

The factor to correct for different combinations of air pressure and temperature is known as the Z factor

The first software packages appeared on the market in 1994,

and some incorporated a database facility to allow the entry of individual test plans for each type of pipette as well as longterm storage of results

The choice of testing in accordance with the current British,

American or European standard was given to the operator,

Calibration in the Pharmaceutical Laboratory

and all measured mass values are processed to give the correct result expressed as a volume,

correcting for the effects of temperature and air pressure

There are two schools of thought as regards to the optimum solution for counteracting the effect of evaporation-potentially the largest factor influencing the quality of your results

One approach is to measure the rate of evaporation of liquid from the vial on the balance pan and then to incorporate a factor in the calculation to correct for this phenomenon

At first,

this solution seems plausible,

I would ask you to consider that if liquid has been aspirated down the side of the container,

the rate of evaporation will be different to that of a vial containing liquid in the bottom,

and the settling time of a balance can easily double from one measurement to another,

therefore invalidating any correction factors applied

A better solution utilises a vapor or humidity trap where the vial is housed in a chamber where the humidity is between 60 percent and 90 percent,

thus removing the gradient between the vial and current ambient conditions,

therefore reducing evaporation to a negligible amount compared to the reproducibility of the pipette

As a further endorsement,

the latest international standard for the calibration of pipettes,

IS0 8655,

recommends the use of such a vapor trap

Introduction

The Humidity Trap The humidity trap (Figure 1

Water located in the trough provides the required humidity to prevent evaporation

Balances with an automated door can be controlled from the PC,

which means that the process of calibrating pipettes is totally automated,

releasing the operator to concentrate on his or Figure 1

The Humidity Trap

Calibration in the Pharmaceutical Laboratory

her technique of accurate and reproducible liquid aspiration and speeding up what in the past has been a laborious but essential procedure

Furthermore,

the requirement to reduce systematic errors (errors due to uncontrollable factors in the measurement process) means that all measurements should be of the same time order so that systemic errors are of the same magnitude and hence of lower influence to reproducibility (imprecision)

This is better achieved when all the operator has to do is dispense liquid and press a data transfer key

INTRINSICALLY SAFEWEIGHING EQUIPMENT FOR HAZARDOUS AREAS From country to country,

the regulations and regulating bodies are of course different,

the content of this section is general rather than in-depth or country specific

There are occasions in pharmaceutical manufacturing where an area is designated as a zoned area,

since there is a risk of fire or explosion from a spark or naked flame

As such,

any electrical equipment used in this location must be approved and certified by the relevant body

The hazard is due to the presence in the atmosphere of dust-flour,

Introduction

As a manufacturer,

you are governed by legislation to provide a safe working environment and,

to provide suitable equipment for the hazardous area

Depending on the material causing the hazard and the length of time it is present in the atmosphere,

the risk can be graded from extremely likely down to a mere possibility of fire or explosion,

and equipment is manufactured and certified with the relevant coding according to this hazard rating

Laboratory balances and scales fall into two categories

The first category is described as intrinsically safe,

which means that the components and printed circuit boards used in the equipment operate on very low voltage (less than 30 V and 50 mA current)

Therefore,

there is no possibility of sparking,

and the operating temperatures of the equipment a r e very low

Operating temperature is,

since some gases have very low flashpoints

Furthermore,

the equipment must remain safe even if a fault develops (a higher rating is awarded if the equipment remains safe when two faults develop)

The second category is described as flame-proof because the components that a r e likely to cause sparking have either been sealed in an enclosure or the equipment has been filled with granular quartz that will suppress any sparks generated

Flame-proof equipment is not considered as totally safe for use in zones with extreme hazard ratings

Depending on the type of equipment,

there are different notations used to describe the degree of protection inherent in a

Calibration in the Pharmaceutical Laboratory

As part of the regulation,

these markings must be clearly visible to the user

In the United Kingdom equipment may be labeled as follows: E E X ib I I B T6 where the markings indicate that the equipment is EEX

approved under European directive intrinsically safe b y design the types of gases present in the atmosphere for which the balance or scale is safe maximum surface temperature does not exceed 85°C

In countries other than Europe,

there are similar schemes for grading equipment deemed safe for use in a hazardous area,

although the markings and symbols will vary from country to country

Symbols a r e used in Europe,

the United States and Canada to indicate compliance to the required standard for those countries

These symbols must be clearly visible on the product to which they relate

Data acquisition from scales or balances in hazardous areas is by no means exempt from the requirement to download directly to a PC or

Introduction

the design of equipment has needed to keep pace with customers’ expectations,

and digital communication via a safe area network is possible

The most simple option is to equip the intrinsically safe scales with a 10 mV communication port

The data output can be transmitted to a converter in the safe area where conversion to RS232 takes place in a black box and a PC link established (Figure 1

Data generated by the weighing machine is recorded at the PC

communications are only possible in a simple format,

which means that the operator has no feedback from the PC terminal

The overall effect is to reduce the amount of data transfer to a few simple weighing results

Where the requirements are more demanding,

in a dispensary where a full recipe

Figure 1

Data Acquisition Processes

(A) Scale connected in hazardous area

RS232 including footswitches for printhare

(B) Signal converted to the safe area

Calibration in the Pharmaceutical Laboratory

PC terminals approved for use in hazardous areas are now available,

and these may well be integrated into the weighing scales

Communication will be on a network approved for use in the hazardous area,

fibre optic or in the past ArcNeT Novel would have been used

Ultimately,

all base data and software are stored in the safe area on a conventional PC and fileserver and downloaded to the terminals in the hazardous area when operators call up particular recipes for dispensing (Figure 1

Due to the potential consequence of installing non-appropriate equipment in a hazardous area,

it is imperative to involve not only the expert from the scale manufacturer but also the health and safety officer from your own company in order to properly categorise the zoned area and subsequently to specify the appropriate explosionproof rating for the weighing scales

COMMISSIONING OF

BALANCES

When manufacturing drugs and medicines for export or sale in the United States,

the FDA inspector will be a well-known person to you

In a constant effort to reduce as far as possible the risk of errors in manufacturing or quality control,

the FDA develops and improves protocols for qualifying the performance of new equipment being commissioned and for regular test-

Introduction

Figure 1

Intelligent Terminal That May Be Connected to a Scale in the Hazardous Area

No matter whether the new balance or scale has a readability of l'pg or l'kg,

there would be little value in any of the measurements made with such an instrument unless the equipment had been properly installed,

tested and passed as fit for its intended use

This has become known in the pharmaceutical industry as equipment qualification or EQ for short

As a function of GLP and GMP (Good Manufacturing Practice) quality systems,

which a r e covered later in greater detail,

equipment purchased must be appropriate for the purpose and function for which it will be used

This criterion

Calibration in the Pharmaceutical Laboratory

doubly crucial in circumstances where the quality of the product being manufactured or tested depends on the accuracy of measurements made on this equipment

There are three stages of (EQ),

installation qualification (IQ) and performance qualification (PQ)

Design Qualification In terms of weighing equipment,

DQ is least likely to require much input from the scientist,

since the fundamental principle of the modern electronic balance has changed little since 1975 and neither have the weighing techniques employed by chemists and technicians

most of the main manufacturers comply to the I S 0 9000 quality system covering manufacturing quality

DQ would become more relevant should a manufacturer introduce a totally new instrument or technique to make measurements,

when a microwave moisture analyser is purchased to replace a conventional convection oven,

qualification would be required to prove that the drying method used by this equipment is properly documented and that the manufacturer’s specification is appropriate to the application

Other important factors in DQ are the responsibility of the manufacturer to provide and include some or all of the following:

Introduction 0

Clear and well-documented development records,

which may often impinge on a manufacturer’s right to secrecy in order to maintain market superiority Certificates of conformance to specifications or a mutually agreed performance criterion Certificates of conformance to international or European legislation covering,

safety or conformity to electrical regulations

Clear and concise manuals of operation including advice on how to get started and some troubleshooting hints

This should include a version number or date of issue to avoid confusion when revisions are made

In the case where a weighing system has been supplied that includes PCs and complex control software,

a n agreement should be made with a third party to store source codes usually at a bank under the terms of an escrow agreement

Embedded software in microprocessors so far has not become subject to such agreements

it is becoming more of an issue in terms of validation

Chapter 4 covers this topic

Calibration in the Pharmaceutical Laboratory

Installation Qualification IQ is the responsibility of the end user (meaning the head of the laboratory) and may be performed by either the purchaser,

the manufacturer or a competent service agent

IQ covers the unpacking of the balance and completion of the first page in the EQ manual,

a completeness check for all items the serial number

the model number the asset or internal ID number the software version number its location and any environmental influences (drafts,

leveling and checking that functions are okay after power up

Operational Qualification In the case of laboratory balances,

OQ may be performed by a competent person within your own company,

although it is usually deferred to the manufacturer or a third-party service organisation

In practice,

most companies use the manufacturer,

as OQ involves routine quality testing procedures very similar to regular service protocols

A qualified service technician is usually better placed than an in-house operative

Introduction

is a small overlap between what may be considered part of IQ or OQ

powering up and checking the basic functionality of the balance could become part of OQ instead

OQ is essentially confirmation of the performance of the new balance against a predetermined criterion and is concluded by the technician signing a ticked list of acceptable test results,

recorded modifications and calibration results

(There is a crucial difference between calibration and adjustment

discussions of these two different but easily confused terms are included in this book

) There are two schools of thought governing the setting of the criterion for acceptance

You could simply take the manufacturer’s specification as the pasdfail limits for repeatability,

While there is nothing fundamentally wrong with this approach,

there are other factors that may influence you toward choosing the second and perhaps more practical approach

The specifications set by manufacturers should be achievable in most laboratories and production areas where care has been taken to properly site the unit

what is the ultimate in performance that you are likely to expect from your balance or scale

? Why not determine the pasdfail criterion after establishing the maximum permissible error that you can tolerate in the measurement process

? State the error as a percentage and then according to IS0 10012 set your limits to ideally one-tenth of this value or at worst one-third in the case where there are

Calibration in the Pharmaceutical Laboratory

severe cost implications in achieving the former

To further illustrate this scenario,

consider the case of using a microbalance with a resolution of 1 pg and the same reproducibility which provides an uncertainty of measurement equivalent to one-tenth of the maximum error

Using a semimicrobalance costing only half the price,

meets the requirement by having a total uncertainty within one-third of the limit

In this instance the semi-microbalance would seem to be an acceptable alternative

Having decided on which method to determine your pass/fail limits,

then the process of qualification begins

As an example of the components in the testing procedure,

consider including the following (taken from the balance manual): Capacity Readability

Linearity

Reproducibility

Details of the weights used for the test: U K A S or equivalent certificate details

Serial numbers Date calibrated Recal ibration Date

Introduction

Before any testing commences,

ensure that the balance has been “warmed up” by connecting to a power supply for the minimum time indicated in the manual and that a calibration (adjustment) routine has been performed where there is in internal adjustment weight inside the balance

external adjustment will be required

(Adjustment corrects for differences in regional gravity that will affect the accuracy of the balance

the balance must be leveled prior to adjustment and calibration testing

Reproducibility Test A reproducibility test can be performed using a single calibration weight that is closest to the maximum capacity of the balance under test,

Never use two weights in order to be able to test closer to the maximum capacity of the balance,

as this will introduce eccentric loading errors,

whereas a single weight can be placed close to the centre of the pan for each measurement

Tare the balance,

then make a minimum of 6 and a maximum of 10 repeat measurements,

in each case removing the weight and replacing it as close as possible to the centre of the pan

Value 1

Value 6 (or 10)

Calibration in the Pharmaceutical Laboratory

Calculate the standard deviation using the formula

where S is the standard deviation,

V is the mean value,

and n is the number of measurements Test the linearity of the balance after taring at a minimum of 4 and a maximum of 10 (quite often 6 ) equally spaced points throughout the weighing range 25% Load Measured Value _ _ xx

Acceptflail 50% Load Measured Value ___ xx

Acceptflail Adjustments Required

Observations or Comments:

Introduction

Any adjustments,

repairs or routine servicing should be recorded in an appropriate section at the back of the balance manual

Eccentricity errors,

sometimes referred to as corner load errors,

must also be checked because these are subject to deterioration due to shocks and vibration that may well have occurred in transport from the manufacturer

Generally,

there are no values for this error given in the normal specifications tables in the balance manual,

although if you contact the service department of the manufacturer,

they should be able to offer you some assistance

As a general rule of thumb,

one should expect between two to three digits error at a maximum of half the capacity of the balance

Therefore,

a balance with a capacity of 4,000 g and a readability of 0

Rectangular Pan

Round Pan

Calibration in the Pharmaceutical Laboratory

Indicate the tolerance

Record measurement values a t positions A,

and D'in a similar manner as with the linearity

Record any observations or comments

If an adjustment is required,

ensure that details are recorded in the log

APPENDIX 1

It is the result of the U

ASTM and ANSI quality standards

Because of the international ramifications in the pharmaceutical industry,

more and more German pharmaceutical companies are introducing the USP

It is mandatory to apply the USP particularly in the pharmaceutical sectors that are audited by the FDA (Food and Drug Administration)

Section 41 of the USP specifies the use of weights and balances

It requires that the measurement uncertainty must be known for all balances that are used for pharmacopeia1 tests and assays

According to the USP,

the measurement uncertainty is calculated as three times the standard deviation

As the USP only states the measurement uncertainty for a minimum quantity,

this calculation is a good approximation

Moreover,

Section 41 stipulates that the minimum amounts weighed may not be less than Source: Dick Albrecht

Marketing Sales Communications News of Sartorius Weighing Technology,

September 2000,

Calibration in the Pharmaceutical Laboratory

the measurement uncertainty may not exceed 0

Tare weights,

such as vessels used for weighing samples,

may not be added to the minimum sample weight

Original text quoted from the USP 23,

Section 41 “Weights and Balances”

Pharmacopeia1 tests and assays require bal-

Unless otherwise specified,

when substances a r e 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