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36 PROCESS VALIDATION Continued Process Verification
John McConnell, Brian K. Nunnally, and Bernard McGarvey
[For more Author information, go to gxpandjvt.com/bios
Welcome to Analysis and Control of Variation.We have seen many
approaches to improving quality,
compliance, and productivity during the past 30 years. However,
from the approaches of Shewhart, Deming, and Juran to TQM, Kaizen,
Kanban, and Six Sigma there is a golden thread that runs through
all of these approaches: Understanding and reducing variation. It
is axiomatic that if there is no variation, there will be no
deviations and no out-of-specification results. Some degree of
variation is unavoidable; we can nearly always reduce variation,
but we can never eliminate it. Any successful approach to
validating a process and then ensuring that it remains compliant
must include elements that help us to reduce variation and then to
continually monitor and control it.
This column is dedicated to revealing weaknesses in existing
approaches to understanding, reducing, and controlling variation,
and to recommend alternatives based on sound science that
demonstrably work. Case studies will be used to illustrate both
problems and successful methodologies. The objective of the column
is to combine sound science with proven practical advice.
Reader comments, questions, and suggestions will help us fulfil
our objective for this column. Suggestions for future discussion
topics or questions to be addressed are welcome. Case studies
illustrating the successful reduction or control of variation
submitted by readers are also most welcome. Please send your
comments and suggestions to column coordinator John McConnell at
[email protected] or journal coordinating editor Susan Haigney at
[email protected].
KEY POINTS DISCUSSEDThe following key points are discussed in
this article:
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they are not
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VariationPast, Present, and FutureJohn McConnell, Brian K.
Nunnally, and Bernard McGarvey
ABOUT THE AUTHORSJohn McConnell is the coordinator of Analysis
and Control of Variation and is the owner and direc-tor of Wysowl
Pty Ltd. in Queensland, Australia. He may be reached at
[email protected]. Brian K. Nunnally, Ph.D., is associate
director, Validation, at Wyeth Research. He may be reached at
[email protected]. Bernard McGarvey, Ph.D., is process modeling
group leader, Process Engineering Cen-ter, Eli Lilly and Company.
He may be reached at [email protected].
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PROCESS VALIDATION Continued Process Verification 37
John McConnell, Brian K. Nunnally, and Bernard McGarvey
INTRODUCTION5IFJNQPSUBODFPGVOEFSTUBOEJOHSFEVDJOHBOEDPOUSPMMJOHWBSJBUJPODBOOPUCFPWFSTUBUFE*OUPPNBOZQMBDFTUIFQIBSNBDFVUJDBMJOEVTUSZIBTZFUto
apply approaches that are routinely successful in
NBOZPUIFSJOEVTUSJFT3FDFOUSFHVMBUPSZEPDVNFOUTBOEQSFTFOUBUJPOTBEESFTTJOHCPUIQIBSNBDFVUJDBMQSPEVDUTBOENFEJDBMEFWJDFTIBWFCFFODSJUJDBMPGUIFJOEVTUSZTBCJMJUZUPSFEVDFBOEDPOUSPMWBSJBUJPOBUJOQVUTBTXFMMBTJOQSPDFTTBOEKVTUJGJBCMZTP5IFQSJODJQMFTBOEQSBDUJDFTGPSCSJOHJOHBQSPDFTTJOUPBDPOUSPMMFEBOEDBQBCMFTUBUFBOEUIFONBJOUBJOJOHUIBUDPOEJUJPOPWFSUJNFBSFXFMMEFWFMPQFE)PXFWFSUIFQIBSNBDFVUJDBMJOEVTUSZIBTZFUUPXJEFMZBEPQUTPNFPGUIFTFQSJODJQMFTBOEpractices.
It is our intent to pursue these issues in
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their daily work.
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A BRIEF HISTORY OF
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were hundreds of years away. The
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38 PROCESS VALIDATION Continued Process Verification
John McConnell, Brian K. Nunnally, and Bernard McGarvey
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into tolerances or specifications.
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MORE RECENT
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statistically significant signals that ought to warn
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is poor science.
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specification (1).'SPN4IFXIBSUBOE%FNJOHUP5BHVDIJBOE4NJUI
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THE CHANGING FDA
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a state of control existed if all results fell within
specifications.
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PROCESS VALIDATION Continued Process Verification 39
John McConnell, Brian K. Nunnally, and Bernard McGarvey
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SHREWHART CONTROL
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is a signal to which the scientists should react.
#BUDISFQPSUFEBT004OPUCFDBVTFBOZUIJOHDIBOHFEEVSJOHUIFQSPEVDUJPOPGUIBUCBUDI*UJTBSBOEPNQPJOUJOBTZTUFNPGEBUBUIBUTIJGUFEBUCBUDIXIJDIJTXIFSFUIFSFBMSPPUDBVTFTPGUIFTFDPOE004FWFOUXJMMCFGPVOE/FWFSUIFMFTTJONPTUDPNQBOJFTXIFOTJNJMBSDJSDVNTUBODFTFYJTU
150
200
250
300
350
400
450
500
550
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80
Batch release data as a Shewhart control chart
Batch release results against specications
150
200
250
300
350
400
450
500
550
1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77
Figure 1: Two approaches to displaying variation.
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40 PROCESS VALIDATION Continued Process Verification
John McConnell, Brian K. Nunnally, and Bernard McGarvey
XFGJOETDJFOUJTUTTUVEZJOHUIFGBJMFECBUDISBUIFSUIBOUIFQPJOUJOUJNFXIFSFUIFQSPDFTTDIBOHFE
"TJNJMBSQSPCMFNDBOCFGPVOEXIFOTDJFOUJTUTBSFTUJMMVTJOHUIFPMEiNFBOPSwBQQSPBDIUPDBMDVMBUFMJNJUTXIJDIJTJMMVTUSBUFEJO'JHVSF"HBJOUXPDIBSUTBSFTIPXO#PUIDIBSUTTIPXB$52DIBSBDUFSJTUJDJOBDIFNJDBMDMFBWFQSPDFTTGPSBCJPMPHJD5IFUPQDIBSUVTFTUIFiNFBOwBQQSPBDI5IFMPXFSDIBSUJTB4IFXIBSUDPOUSPMDIBSUBHBJOUIF.PWJOH3BOHFDIBSUJTPNJUUFE
5PPNBOZTDJFOUJTUTDPODMVEFUIBUUIFDIBSUVTJOHUIFiNFBOwBQQSPBDITIPXTOPTJHOBMT*GGBDUUIFSFBSFTFWFOTJHOBMTJOUIJTEBUBTFUBMMPGXIJDIBSFFYQPTFEJOUIF4IFXIBSUDPOUSPMDIBSU5IJTJTXIBUUIF'%"HVJEFMJOFTBSFOPXEFNBOEJOHUIBUTDJFOUJTUTDBOCFUUFSUFMMUIFEJGGFSFODFCFUXFFOSBOEPNBOEOPOSBOEPNEBUBUIBUUIFZLOPXXIFOUPUBLFBDUJPOBOEXIFOOPUUP"DDPSEJOHUPUIF'%"HVJEFMJOFTUIFTJUVBUJPOJO'JHVSFJTVOBDDFQUBCMFFWFOUIPVHIBMMSFTVMUTUPEBUFSFNBJOFEXJUIJOTQFDJGJDBUJPOT#FDBVTFUIF'JHVSFQSPDFTTJTOPUTUBCMFPSDPOUSPMMFEJUIBTOPLOPXODBQBCJMJUZ4PPOFSPSMBUFSJUXJMMHFOFSBUFBO004SFTVMUCVUXIZXBJU
*GUIFNBOBHFSTBOETDJFOUJTUTXPSLJOHJOUIJTQSPDFTTEJEOPUIJOHNPSFUIBOUPTUBCJMJ[FUIFQSPDFTTUIFZXPVMEBMMCVUHVBSBOUFFJUTDBQBCJMJUZ/PDIBOHFTUPDVSSFOUHPPENBOVGBDUVSJOHQSBDUJDFTBSFSFRVJSFE*OUIJTDBTFBMMUIBUJTOFDFTTBSZUPFOTVSFHPPERVBMJUZBOEQSPEVDUJWJUZJTUPTUBCJMJ[FUIFQSPDFTTUPNBLFJUSFQFBUBCMFBOEQSFEJDUBCMF0ODFUIFWBSJBUJPOJTSFEVDFEUIFOJUXJMMCFFBTJFSUPTFFUIFDBVTBMSFMBUJPOTIJQTBOEVMUJNBUFMZJNQSPWFthe
process.
Analytical Processes
"OZTUBUJTUJDBMBQQSPBDIDBOCFOPCFUUFSUIBOUIFEBUBJUVTFT*NBHJOFBQSPEVDUJPOQSPDFTTUIBUJTJOTUBUJTUJDBMDPOUSPMCVUUIFBOBMZUJDBMQSPDFTTVTFEUPNFBTVSFJUJTVOTUBCMF*UJTQPTTJCMFUIBUUIFEBUBXJMMFYIJCJUJOTUBCJMJUZ5IJTJOUVSOXJMMDBVTFBOJOWFTUJHBUJPOGPSDBVTFTPGFYDFTTJWFWBSJBUJPOJOUIFQSPEVDUJPOBSFBBIVOUUIBUJTBMMXBTUFEFGGPSUBOEUIBUJTEPPNFEUPGBJMCFDBVTFUIFQSPCMFNTBSFJOUIFBOBMZUJDBMBSFB5IJTTVCKFDUBMPOFXPVMEGJMMTFWFSBMWPMVNFTBOEJUJTFBSNBSLFEBTUIFTVCKFDUGPSBGVUVSFUPQJDGPSUIJTDPMVNO'PSOPXJUXJMMTVGGJDFUPJMMVTUSBUFBTJNJMBSBOBMZUJDBMJTTVFXJUIUIFUXPDIBSUTJO'JHVSF5IFUPQDIBSUTIPXTUIFMBCPSBUPSZDPOUSPMTXJUIMJNJUTQMBDFEBUNFBO
and the lower DIBSUTIPXTUIFMBCPSBUPSZDPOUSPMTBTB4IFXIBSUcontrol
chart. The hunt for the trend factory people
TBXJOUIFQSPEVDUJPOEBUBXBTOFWFSHPJOHUPSFWFBMSPPUDBVTFTCFDBVTFUIFUSFOEXBTJOUIFMBCPSBUPSZTanalytical
processes.
CONCLUSIONS*OPSEFSUPDPNQMZXJUIUIF'%"HVJEFMJOFTBOEUPCFUUFSHVBSBOUFFRVBMJUZBOEQSPEVDUJWJUZDPNQBOJFTJOUIFQIBSNBDFVUJDBMJOEVTUSZIBWFOPDIPJDFPUIFSUIBOUPVTF41$UFDIOJRVFTUPCSJOHBMMUIFJSDMJOJDBMUSJBMTEFWFMPQNFOUBOBMZUJDBMand
production processes into a state of statistical
DPOUSPM5IFHVJEFMJOFTTFFNUPMFBWFMJUUMFSPPNGPSJOUFSQSFUBUJPOBOEVOEFSTUBOEBCMZTP#FDBVTFBOVOTUBCMFQSPDFTTIBTOPLOPXODBQBCJMJUZXFDBOOPUDBMDVMBUFUIFQSPCBCJMJUZPGFJUIFSQBTTJOHPSGBJMJOHTQFDJGJDBUJPOTJOBTUBUJTUJDBMMZWBMJEXBZ
0
5
10
15
20
25
30
35
40
1 6 11 16 21 26 31 36 41 46 51 56 61 66 71 76 81 86 91 96 106101
111
0
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40
101816141211
1-P
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Data with Shewhart control limits
Limits set at mean 3Figure 2: Two approaches to calculating
limits.
-
PROCESS VALIDATION Continued Process Verification 41
John McConnell, Brian K. Nunnally, and Bernard McGarvey
0SJHJOBMMZQVCMJTIFEJOUIF4QSJOHJTTVFPGThe Journal of Validation
Technology
VOUJMUIFQSPDFTTVOEFSFYBNJOBUJPOJTLOPXOUPCFTUBCMF0VSDPOTVNFSTIBWFBSJHIUUPFYQFDUUIBUUIFNFEJDJOFTUIFZUBLFDPNFGSPNDPOUSPMMFEBOEQSFEJDUBCMFQSPDFTTFT0VSTUPDLIPMEFSTIBWFBSJHIUUPFYQFDUUIBUXFXJMMOPUUISPXBXBZUIFJSJOWFTUNFOUXJUIVOOFDFTTBSZWBSJBUJPOBOEEFWJBUJPOT0VSFNQMPZFFTIBWFBSJHIUUPUBLFQSJEFBOEKPZJOUIFJSXPSL1SPEVDUJPOQFPQMFIBWFBSJHIUUPFYQFDUUIBUUIFBOBMZUJDBMTZTUFNTPOXIJDIUIFZBSFTPEFQFOEFOUBSFTUBCMF#SJOHJOHPVSprocesses
into statistical control will help us to satisfy all these
needs.
4QFDJGJDBUJPOTBSFBOFDFTTBSZQBSUPGUIFCVTJOFTTMBOETDBQFCVUUPVTFUIFNGPSQSPDFTTBOBMZTJTBOEDPOUSPMPSGPSQSPDFTTNPOJUPSJOHJTBSFDJQFGPSUSPVCMF5IF4IFXIBSUBQQSPBDIJTJEFBMGPSUIFTFpurposes.
It is a tried and true approach that has
TUPPEUIFUFTUPGUJNF"MMUIBUSFNBJOTJTGPSUIFQIBSNBDFVUJDBMJOEVTUSZUPVTFJUXJEFMZBOEXJTFMZ
REFERENCES#,/VOOBMMZBOE+4.D$POOFMMSix Sigma in the
Pharmaceutical
Industry$3$1SFTT#,/VOOBMMZ%'/VOOBMMZBOE+4.D$POOFMM
i"WPJEJOHUIF1BJOPG0VUPG4QFDJGJDBUJPO3FTVMUTwBioPharm
International+VOF
8"4IFXIBSUEconomic Control of Quality of Manufactured
Product7BO/PTUSBOE
8"4IFXIBSUStatistical Method from the Viewpoint of Quality
Control5IF(SBEVBUF4DIPPMPG"HSJDVMUVSF8BTIJOHUPO
884DIFSLFOCBDIThe Deming Route to Quality and
Productivity$&&1SFTT
8&%FNJOHOut of the Crisis.*5'%"(VJEBODFGPS*OEVTUSZProcess
Validation: General
Principles and PracticesDraft GuidanceJVT
ARTICLE ACRONYM LISTINGCTQ Critical to QualityFDA US Food and
Drug AdministrationOOS Out-Of-SpecificationSPC Statistical Process
Control
15
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Data with Shewhart control limits
Limits set at mean 3
Figure 3: Trending laboratory controls.
