Paul L. Pluta
Case Study #3—Process Validation
Failure of a Liquid Product
Batch Size Increase—“Identical”
Manufacturing Tanks
Paul L. Pluta
“Validation Case Studies” discusses situations useful
to practitioners in validation. Each case presented
deals with a specific validation problem, elements of
which are described to demonstrate strategy to solve
the problem. We intend this column to be a useful
resource for daily work applications. The main objective of this column: Useful and practical information.
Reader comments, questions, and suggestions are
needed to help us fulfill our objective for this column.
Case studies illustrating validation issues submitted
by readers are most welcome. Please send your comments and suggestions to journal coordinating editor
Susan Haigney at [email protected].
KEY POINTS DISCUSSED
The following key points are discussed:
t"DBTFTUVEZJOWPMWJOHQSPDFTTWBMJEBUJPOPGB
CBUDITJ[FJODSFBTFGPSBMJRVJETPMVUJPOQSPE
VDUJTEFTDSJCFE
t5IFCBUDITJ[FJODSFBTFXBTDPOTJEFSFEUPCFB
SFMBUJWFMZTJNQMFDIBOHFCFDBVTFPUIFSTJNJMBS
QSPEVDUTBUUIFTJUFXFSFBMSFBEZNBOVGBD
UVSFEBUUIFTBNFJODSFBTFECBUDITJ[FBOEUIF
FRVJQNFOUUPCFVTFEXBTUIPVHIUUPCFJEFO
UJDBMUPPUIFSTJUFFRVJQNFOU
t.BOVGBDUVSJOHXBTTUBSUFEBOEUIFGPSNVMB
UJPOJOHSFEJFOUTEJEOPUEJTTPMWFJOUIFQSPE
For more Author
information,
go to
gxpandjvt.com/bios
[
VDUTPMVUJPO5IFWBMJEBUJPOQFSGPSNBODF
RVBMJGJDBUJPO12
XBTBGBJMVSF.JYJOHJOUIF
UBOLXBTOPUTVGGJDJFOUMZSJHPSPVTUPEJTTPMWF
UIFGPSNVMBUJPOJOHSFEJFOUT
t5IFTVQQPTFEMZJEFOUJDBMUBOLEJEOPUIBWFUIF
TBNFJNQFMMFSBSSBOHFNFOUBTUIFPUIFSMBSHF
NJYJOHUBOLTBUUIFTJUF"MUIPVHIUIFWPMVNF
PGBMMUBOLTXFSFUIFTBNFUIFNJYJOHJNQFMMFST
were different.
t"OFXNBOVGBDUVSJOHQSPDFTTXBTEFWFMPQFE
VTJOHBSFEVDFETPMVUJPOWPMVNFBUBOJOUFS
NFEJBUFQSPDFTTTUBHFUIBUFOBCMFETVDDFTTGVM
NBOVGBDUVSJOH
t$PSSFDUJWFBDUJPOBOEQSFWFOUJWFBDUJPO
$"1"
BDUJWJUJFTJODMVEFEBOFXNBOVGBDUVS
JOHQSPDFTTUSBJOJOHEPDVNFOUBUJPOQSPDFTT
WBMJEBUJPOQPTUWBMJEBUJPONPOJUPSJOHFRVJQ
NFOURVBMJGJDBUJPOBOEBQQMJDBUJPOPGMFTTPOT
learned to other site products.
t&RVJQNFOURVBMJGJDBUJPOBOEFRVJQNFOU
FRVJWBMFODFEPDVNFOUBUJPOXFSFSFWJFXFE
BOENPEJGJFE
t4FWFSBMPUIFSQSPEVDUTXFSFBMTPNBOVGBDUVSFE
VTJOHUIFOFXNBOVGBDUVSJOHQSPDFEVSF
t.JOPSFRVJQNFOUEJGGFSFODFTNBZIBWFBWFSZ
TJHOJGJDBOUFGGFDUJONBOVGBDUVSJOHi*EFOUJDBMw
NBZSFBMMZOPUCFTP
ABOUT THE AUTHORS
Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive technical and management experience in the pharmaceutical industry. Dr. Pluta is also adjunct associate professor at the University
of Illinois College of Pharmacy in Chicago. He edited and contributed chapters of Cleaning and
Cleaning Validation, published by PDA and Davis Healthcare International. He may be reached by email at [email protected].
PROCESS VALIDATION – Continued Process Verification
67
Paul L. Pluta
INTRODUCTION
5IJTDBTFTUVEZXBTQSPWJEFEUPUIFJournal of Validation TechnologyCZBSFBEFSXIPSFRVFTUFEBOPOZNJUZ
5IFFWFOUEFTDSJCFEJTBOBDUVBMPDDVSSFODF
"TNBMMNPMFDVMFQIBSNBDFVUJDBMDPNQBOZ
SFRVJSFEBCBUDITJ[FJODSFBTFGPSBMJRVJETPMVUJPO
QSPEVDUUPNFFUJODSFBTFEDPNNFSDJBMEFNBOET5IF
CBUDITJ[FJODSFBTFXBTDPOTJEFSFEUPCFBSFMBUJWFMZ
TJNQMFDIBOHFCFDBVTFPUIFSTJNJMBSQSPEVDUTBUUIF
TJUFXFSFBMSFBEZNBOVGBDUVSFEBUUIFTBNFJODSFBTFE
CBUDITJ[F5IFOFFEGPSWBMJEBUJPOXBTRVFTUJPOFE
CFDBVTFUIFQSPEVDUBOEQSPDFTTBQQFBSFEUPCF
JEFOUJDBMUPPUIFSQSPEVDUNBOVGBDUVSJOHBOEUIF
FRVJQNFOUUPCFVTFEXBTUIPVHIUUPCFJEFOUJDBMUP
BMMPUIFSNJYJOHUBOLT"HSFFNFOUPOBPOFMPUDPO
GJSNBUPSZQFSGPSNBODFRVBMJGJDBUJPO12
WBMJEBUJPO
CBUDIXBTVMUJNBUFMZEFDJEFECFDBVTFUIFDIBOHFXBT
DPOTJEFSFEUPCFPGNJOJNBMSJTL"OJOGSFRVFOUMZ
VTFENJYJOHUBOLPGUIFBQQSPQSJBUFTJ[FUPNBLFUIF
MBSHFCBUDITPMVUJPOXPVMECFVTFE.BOVGBDUVSJOH
XBTTUBSUFE5IFVOFYQFDUFEIBQQFOFE‰NBOV
GBDUVSJOHIBEUPCFBCPSUFEBGUFSTFWFSBMIPVSTPG
NJYJOHNVDIMPOHFSUIBOUIFQSPDFTTTIPVMEIBWF
SFRVJSFE*OHSFEJFOUTEJEOPUEJTTPMWFJOUIFQSPEVDU
TPMVUJPO5IFWBMJEBUJPOXBTBGBJMVSF
5IJTEJTDVTTJPOQSPWJEFTUIFGPMMPXJOH
tProcess description background5IFNBO
VGBDUVSJOHQSPDFTTGPSUIFJODSFBTFECBUDITJ[F
QSPEVDUJTCSJFGMZEFTDSJCFE
tCompliance event"EFTDSJQUJPOPGUIFFWFOU
UIFLFZJTTVFTUPCFBEESFTTFEBOEBQQMJDBCMF
DVSSFOUHPPENBOVGBDUVSJOHQSBDUJDF$(.1
SFRVJSFNFOUT
tInvestigation*OUFSWJFXTBOEBDUJPOTDPOEVDU
FEUPJOWFTUJHBUFUIFFWFOU
tDiscussion,FZJOGPSNBUJPOBDUJWJUJFTBOE
analysis.
tCorrective action and preventive action
(CAPA)"DUJPOTBOEJNQSPWFNFOUTJNQMF
NFOUFE5IFTFJODMVEFEEFWFMPQNFOUPGBOFX
NBOVGBDUVSJOHQSPDFTTUSBJOJOHEPDVNFOUB
UJPOQSPDFTTWBMJEBUJPOQPTUWBMJEBUJPONPOJUPS
JOHFRVJQNFOURVBMJGJDBUJPOBOEBQQMJDBUJPOUP
PUIFSTJNJMBSQSPEVDUTBUUIFTJUF
tPost CAPA .BJOUBJOJOHWBMJEBUJPOBOEQFSGPS
NBODF0UIFSBDUJPOTBOEJNQSPWFNFOUTJNQMF
NFOUFEBTBSFTVMUPGLOPXMFEHFHBJOFEBOE
BDUJWJUJFTBTTPDJBUFEXJUIUIFJODJEFOU
PROCESS DESCRIPTION BACKGROUND
5IFNBOVGBDUVSJOHQSPDFTTJOUIJTDBTFTUVEZ
JOWPMWFENBOVGBDUVSFPGBOBRVFPVTTPMVUJPOJOB
TUBOEBSENJYJOHUBOLXJUIDFOUSBMJNQFMMFS*OHSF
EJFOUTJOUIFGPSNVMBUJPOJODMVEFEUIFBDUJWFESVH
IZESPQIJMJDQPMZNFSUPJODSFBTFWJTDPTJUZCVGGFS
TBMUTUPNBJOUBJOQ)QSFTFSWBUJWFTGMBWPSDPMPS
68
PROCESS VALIDATION – Continued Process Verification
BOEIZESPDIMPSJDBDJEPSTPEJVNIZESPYJEF5IF
NBOVGBDUVSJOHQSPDFTTGPSUIFQSPEVDUDPNQSJTFE
the following steps:
t"QQSPYJNBUFMZPGQVSJGJFEXBUFSXBTBEEFE
UPUIFNJYJOHUBOL4PMVUJPOWPMVNFXBTNFB
sured with a dip stick.
t5IFNJYFSXBTTUBSUFE
t"MMTPMJEJOHSFEJFOUTJODMVEJOHUIFBDUJWFESVH
XFSFBEEFEUPUIFNJYJOHUBOLUISPVHIBQPSUBU
UIFUPQPGUIFNJYJOHUBOL1PXEFSBEIFSJOHUP
the side of the tank was rinsed into the solution
XJUIBTNBMMBNPVOUPGQVSJGJFEXBUFS
t"GUFSBMMJOHSFEJFOUTXFSFBEEFEUIFTPMVUJPO
XBTNJYFEGPSNJOVUFT
t4PMVUJPOQ)XBTNFBTVSFE*GOFDFTTBSZQ)
XBTBEKVTUFEXJUIIZESPDIMPSJDBDJETPMVUJPOPS
TPEJVNIZESPYJEFTPMVUJPO
t"EEJUJPOBMQVSJGJFEXBUFSXBTBEEFEUPNBLF
UIFGJOBMTPMVUJPOWPMVNF'JOBMWPMVNFXBT
NFBTVSFEXJUIBEJQTUJDL
t5IFTPMVUJPOXBTNJYFEGPSNJOVUFT
t4PMVUJPOXBTGJMUFSFEBOEGJMMFEJOUPUIFDPN
NFSDJBMQBDLBHJOH
VALIDATION EVENT
"TNBMMNPMFDVMFQIBSNBDFVUJDBMDPNQBOZSFRVJSFE
BCBUDITJ[FJODSFBTFGPSBOPSBMMJRVJETPMVUJPO
QSPEVDU1MBOUNBOBHFNFOUBOETVQQMZDIBJO
QFSTPOOFMPSEFSFEBOJODSFBTFECBUDITJ[FGPS
DPNNFSDJBMTVQQMZBOEDPTUSFEVDUJPOQVSQPTFT
&RVJQNFOUUPBDDPNQMJTIUIFJODSFBTFECBUDITJ[F
XBTBWBJMBCMF‰BOJOGSFRVFOUMZVTFENJYJOHUBOL
PGUIFBQQSPQSJBUFTJ[FXPVMECFVTFEUPNBLFUIF
MBSHFCBUDI5IFNJYJOHUBOLXBTUIFTBNFTJ[FBT
TFWFSBMPUIFSUBOLTJOUIFGBDJMJUZBOEXBTUIPVHIU
UPCFJEFOUJDBMUPBMMPUIFSUBOLT)PXFWFSJUXBT
BCBDLVQUBOLUIBUIBEOPUCFFOVTFEGPSTFWFSBM
ZFBST5IFWBMJEBUJPOHSPVQQSFQBSFEBQSPDFTT
WBMJEBUJPOQSPUPDPMBTSFRVFTUFECZQMBOUNBOBHF
NFOU5IFQMBOUNBOVGBDUVSFETFWFSBMPUIFSPSBM
TPMVUJPOQSPEVDUTBUUIFTBNFJODSFBTFECBUDITJ[F
JOPUIFSUBOLT.BOBHFNFOUBTTVNFEUIBUUIFSF
XPVMECFOPQSPCMFNXJUIUIFJODSFBTFECBUDI
TJ[FBOEPSEFSFEBOJNNFEJBUFCBUDITJ[FJODSFBTF
5IFQSPEVDUIBEBHPPENBOVGBDUVSJOHBOERVBM
JUZIJTUPSZBUUIFTNBMMFSCBUDITJ[F0OFMPUXBT
SFRVFTUFEUPWBMJEBUFUIFJODSFBTFECBUDITJ[F
CFDBVTFTFWFSBMPUIFSTJNJMBSQSPEVDUTXFSFBMSFBEZ
NBOVGBDUVSFEBUUIJTTBNFMBSHFCBUDITJ[F5IF
FYJTUJOHCBUDISFDPSEEPDVNFOUBUJPOXBTNPEJGJFE
UPNBOVGBDUVSFUIFJODSFBTFECBUDITJ[F/PQSPC
MFNTXFSFFYQFDUFE
.BOVGBDUVSJOHPQFSBUPSTNBOVGBDUVSFEUIFMBSHFS
CBUDITJ[FBDDPSEJOHUPUIFTQFDJGJFEEJSFDUJPOT5IF
QSPDFEVSFVTFEXBTTDBMFEGSPNUIFTNBMMFSCBUDI
TJ[FQSPDFEVSF5IFQSPDFEVSFVTFEXBTBMTPUIF
Paul L. Pluta
TBNFBTVTFEGPSPUIFSQSPEVDUTBUBTJNJMBSCBUDI
TJ[F8IFODFSUBJOJOBDUJWFJOHSFEJFOUTXFSFBEEFE
UPUIFNJYJOHUBOLUIFTFNBUFSJBMTGMPBUFEPOUIF
UPQPGUIFXBUFSJOUIFUBOLCVUEJEOPUEJTTPMWF
.JYJOHDPOUJOVFEGPSTFWFSBMIPVST5IFJOBDUJWF
JOHSFEJFOUTTUJMMEJEOPUEJTTPMWF5IFNBOVGBDUVS
JOHQSPDFTTXBTUFSNJOBUFE5IFWBMJEBUJPO12DPO
GPSNBODFMPUIBEGBJMFE
Figure: Mixing tank with different impellers.
What are the Issues?
5IFSFXFSFTFWFSBMDSJUJDBMJTTVFTUPCFJOWFTUJHBUFE
as follows:
t%JENBOVGBDUVSJOHPQFSBUPSTGPMMPXCBUDI
SFDPSEEJSFDUJPOTQSPQFSMZ
t%JEBMMHSPVQTBQQSPWFUIFOFXCBUDISFDPSE
t%JEUIFUFDIOJDBMHSPVQSFWJFXUIFQSPDFTTBOE
BQQSPWFUIFOFXCBUDISFDPSE
t8IZEJEUIFQSPDFTTWBMJEBUJPOGBJM
t8BTTPNFUIJOHXSPOHXJUIUIFFRVJQNFOU
CGMP Requirements
3FMFWBOUHPPENBOVGBDUVSJOHQSBDUJDF(.1
SFRVJSFNFOUTBQQMJDBCMFUPUIFFWFOUBSFMJTUFEBT
follows:
t4VCQBSU%‰&RVJQNFOU
t&RVJQNFOU$MFBOJOHBOE.BJOUFOBODF
t4VCQBSU+‰3FDPSETBOE3FQPSUT
t(FOFSBM3FRVJSFNFOUT
t#BUDI1SPEVDUJPOBOE$POUSPM3FDPSET
t1SPEVDUJPO3FDPSE3FWJFX
INVESTIGATION
*OWFTUJHBUJPOBOEVMUJNBUFSFTPMVUJPOPGUIJTFWFOU
SFRVJSFEJOWPMWFNFOUPGTFWFSBMHSPVQT5IFTF
JODMVEFEQFSTPOOFMJOWPMWFEJOUIFJODJEFOUFH
NBOVGBDUVSJOHBOERVBMJUZBTTVSBODF<2">
BOE
UFDIOJDBMQFSTPOOFMSFTQPOTJCMFGPSUIFNBOVGBD
UVSJOHQSPDFTTBOEQSPDFTTWBMJEBUJPO5IFSFXFSF
NBOZEFUBJMTUIBUOFFEFEUPCFJOWFTUJHBUFEPSDPO
GJSNFE1FSTPOOFMGSPNBMMHSPVQTXFSFJOUFSWJFXFE
and interacted to address the issues.
JODSFBTFECBUDITJ[F5IFDIBOHFIBECFFOFWBMV
BUFECZUIFWBMJEBUJPOBQQSPWBMDPNNJUUFFBOEPOF
12DPOGPSNBODFMPUXBTSFDPNNFOEFE5IFSFXBT
OPFYQFDUBUJPOUIBUUIFQSPDFTTXPVMEOPUCFDPN
pletely successful. Other products in the plant had
CFFOTVDDFTTGVMMZNBOVGBDUVSFEBUUIFTBNFCBUDI
TJ[F5IFTFMPUTIBECFFONBOVGBDUVSFEJOXIBU
XBTUIPVHIUUPCFFRVJWBMFOUNJYJOHUBOLT7BMJEB
UJPOEPDVNFOUBUJPOJOEJDBUFEUIBUBMMNJYJOHUBOLT
PGUIJTWPMVNFXFSFFRVJWBMFOU
Technical Personnel Evaluation
5FDIOJDBMQFSTPOOFMBGGJSNFEUIBUUIFSFTIPVME
IBWFCFFOOPQSPCMFNXJUINBOVGBDUVSJOHUIF
JODSFBTFECBUDITJ[FVOEFSOPSNBMDJSDVNTUBODFT
5IFNBOVGBDUVSJOHQSPDFTTXBTTUSBJHIUGPSXBSEBT
follows:
t"QQSPYJNBUFMZPGQVSJGJFEXBUFSXBTBEEFE
UPUIFNJYJOHUBOL
t4PMJEJOHSFEJFOUTXFSFBEEFEUPUIFNJYJOHUBOL
t5IFTPMVUJPOXBTNJYFEGPSNJOVUFT
"MMJOHSFEJFOUTXFSFFYQFDUFEUPEJTTPMWFXJUIJO
UIFNJOVUFNJYJOHUJNF
Key Information
Manufacturing Personnel Interviews
.BOVGBDUVSJOHQFSTPOOFMBGGJSNFEUIBUBMMCBUDI
SFDPSEEJSFDUJPOTXFSFQFSGPSNFEBTTQFDJGJFE
.BOVGBDUVSJOHPQFSBUPSTIBENBOVGBDUVSFEFRVJWB
MFOUQSPEVDUTBUMBSHFCBUDITJ[FVTJOHBOFRVJWBMFOU
QSPDFEVSFBUUIFTJUFNBOZUJNFT5IFZIBEBMTP
NBOVGBDUVSFEUIFTQFDJGJDQSPEVDUPGUIJTDBTFTUVEZ
BUTNBMMCBUDITJ[FNBOZUJNFT5IFSFXFSFOP
USBJOJOHJTTVFTPSWBSJBUJPOJOQFSGPSNBODFBTTPDJ
BUFEXJUIUIFNBOVGBDUVSJOHQSPDFEVSF
Batch Record Review and Approval
"MMSFMFWBOUQFSTPOOFMIBESFWJFXFEBOEBQQSPWFE
UIFOFXNBOVGBDUVSJOHCBUDISFDPSEXJUIUIF
5IFHFOFSBMNBOVGBDUVSJOHQSPDFTTXBTVTFEUP
NBOVGBDUVSFBTNBMMCBUDITJ[FNBOZUJNFT5IJT
TBNFQSPDFTTXBTBQQSPQSJBUFMZTDBMFEGPSVTFXJUI
UIFJODSFBTFECBUDITJ[F5IFFOHJOFFSJOHTUBGGXBT
SFRVFTUFEUPFWBMVBUFUIFNJYJOHUBOLVTFEGPSUIF
GBJMFE12DPOGPSNBODFSVO5IFNJYJOHUBOLUIBU
XBTVTFEUPNBOVGBDUVSFUIFJODSFBTFECBUDITJ[F
XBTBOJOGSFRVFOUMZVTFEUBOL5IJTUBOLEJEOPU
IBWFUIFTBNFJNQFMMFSBSSBOHFNFOUBTUIFPUIFS
MBSHFNJYJOHUBOLTBUUIFTJUF"MMNJYJOHUBOLT
FYDFQUUIFUBOLVTFEGPSUIFQSPDFTTWBMJEBUJPOIBE
UISFFQJUDIFECMBEFJNQFMMFSTMPDBUFEBUUIFUPQ
NJEEMFBOECPUUPNPGUIFNJYFSTIBGU5IFUBOL
VTFEGPSUIFGBJMJOHCBUDIIBEPOMZUXPQJUDIFE
PROCESS VALIDATION – Continued Process Verification
69
Paul L. Pluta
CMBEFJNQFMMFSTPOFMPDBUFEBUUIFCPUUPNBOEPOF
MPDBUFENJEMFWFMPOUIFNJYFSTIBGU5IFNJYJOH
UBOLXJUIUXPJNQFMMFSTEJEOPUQSPWJEFBEFRVBUF
BYJBMGMPXUPQVMMTPMJEJOHSFEJFOUTJOUPUIFCVML
MJRVJEUPFGGFDUEJTTPMVUJPO5IFNJYJOHUBOLVTFEJO
UIFGBJMFE12SVOXBTTJHOJGJDBOUMZEJGGFSFOUGSPN
BMMPUIFSNJYJOHUBOLTBUUIFTJUF)PXFWFSCFDBVTF
UIJTUBOLXBTBCBDLVQUBOLUIBUIBEOPUCFFOVTFE
GPSTFWFSBMZFBSTOPPOFXBTBXBSFPGUIFEJGGFS
FODF"MUIPVHIUIFWPMVNFTPGBMMUBOLTXFSFUIF
TBNFUIFNJYJOHJNQFMMFSTXFSFWFSZEJGGFSFOUTFF
'JHVSF
/PPOFIBEMPPLFEJOTJEFUIFUBOL
DISCUSSION
*OGPSNBUJPOPCUBJOFEUISPVHIJOUFSWJFXTBOE
TVCTFRVFOUFYQFSJNFOUBMXPSLFOBCMFEHPPE
VOEFSTUBOEJOHPGUIFQSPCMFNBOEVMUJNBUFTPMV
tion. Technical personnel conducted experi
NFOUBMSVOTBOEQSPQPTFEQSPDFTTJOHDIBOHFTUP
FOBCMFNBOVGBDUVSJOHJOBMMNJYJOHUBOLT5XP
FYQFSJNFOUBMSVOTXFSFDPOEVDUFE
EPDVNFOUBUJPOXBTBMTPEFWFMPQFE5ISFF12SVOT
XFSFSFDPNNFOEFECFDBVTFUIFNBOVGBDUVSJOHQSP
DFTTXBTDPNQMFUFMZOFXUPUIFTJUF.BOVGBDUVS
JOH2"FOHJOFFSJOHBOEUFDIOJDBMTVQQPSUNBO
BHFNFOUBQQSPWFEUIFDIBOHFBOEBMMBTTPDJBUFE
EPDVNFOUBUJPO
CORRECTIVE AND PREVENTIVE
ACTIONS
5IFGPMMPXJOH$"1"BOEBTTPDJBUFEBDUJWJUJFTXFSF
conducted:
t/FXNBOVGBDUVSJOHQSPDFTT
tTraining
t%PDVNFOUBUJPO
t1SPDFTTWBMJEBUJPO
t1PTUWBMJEBUJPONPOJUPSJOH
t&RVJQNFOURVBMJGJDBUJPOBOEFRVJQNFOU
FRVJWBMFODF
t0UIFSTJNJMBSQSPEVDUTNBOVGBDUVSFEBUUIF
site.
New Manufacturing Process
Run Number One
5IFGJSTUSVODPNQSJTFEBEEJUJPOPGQVSJGJFEXBUFS
UPUIFNJYJOHUBOL5IFBNPVOUPGXBUFSBEEFEXBT
NFBTVSFEUPCFKVTUBCPWFUIFNJEEMFJNQFMMFS5IJT
XBUFSMFWFMQSPWJEFEHPPENJYJOHBTFWJEFODFECZB
TUSPOHWPSUFYBOEEJEOPUDBVTFFYDFTTJWFTQMBTIJOH
"QQSPYJNBUFMZPGUIFGJOBMTPMVUJPOWPMVNF
XBTSFRVJSFEUPDPWFSUIFJNQFMMFS.JYJOHXBTJOJUJ
BUFEBOEPCTFSWFEUPQSPWJEFBWPSUFYUIBUXPVME
EJTTPMWFUIFJOHSFEJFOUT5IFIZESPQIJMJDQPMZNFS
XBTLOPXOUPCFUIFTMPXFTUEJTTPMWJOHPGBMMJOHSF
EJFOUT5IFSFRVJSFEBNPVOUPGIZESPQIJMJDQPMZNFS
was added to the purified water in the tank. The
QPMZNFSXBTRVJDLMZESBXOJOUPUIFMJRVJEBOEFBT
JMZEJTTPMWFE
Run Number Two
"TFDPOEUSJBMSVOXBTDPOEVDUFEVTJOHBMMJOHSFEJFOUT
FYDFQUUIFBDUJWFQIBSNBDFVUJDBMJOHSFEJFOU/PU
JODMVEJOHUIFBDUJWFJOHSFEJFOUDPOTJEFSBCMZSFEVDFE
UIFDPTUPGUIFUSJBMSVO1VSJGJFEXBUFSXBTBEEFE
UPUIFNJYJOHUBOLBUPGUIFGJOBMWPMVNF.JY
JOHXBTJOJUJBUFE"MMJOBDUJWFJOHSFEJFOUTXFSFUIFO
BEEFEUPUIFQVSJGJFEXBUFS"MMJOHSFEJFOUTRVJDLMZ
EJTTPMWFE5IJTTFDPOESVODPOGJSNFEUIBUBMMGPSNVMB
UJPOJOHSFEJFOUTXPVMECFEJTTPMWFEJOUIFTPMV
UJPOWPMVNFEVSJOHUIFNJYJOHQSPDFTT5IFUSJBMSVO
HSFBUMZJODSFBTFEUIFDPOGJEFODFPGBMMJOWPMWFEUIBU
UIFQSPDFTTWBMJEBUJPOXPVMECFTVDDFTTGVM#FDBVTF
UIFBDUJWFJOHSFEJFOUXBTSFBEJMZTPMVCMFJOXBUFSJU
XBTOPUFYQFDUFEUPJNQBDUUIFTPMVUJPOQSPDFTT
"OFXCBUDISFDPSEXBTEFWFMPQFEVTJOHUIF
OFXMZEFWFMPQFENJYJOHQSPDFTT/FXWBMJEBUJPO
70 PROCESS VALIDATION – Continued Process Verification
"OFXNBOVGBDUVSJOHQSPDFTTDPNQSJTJOHUIFGPM
MPXJOHXBTJNQMFNFOUFEXIFOUIFCBDLVQUBOLXBT
used:
t"QQSPYJNBUFMZPGQVSJGJFEXBUFSXBTBEEFE
UPUIFNJYJOHUBOL
t.JYJOHXBTTUBSUFE
t"MMTPMJEJOHSFEJFOUTXFSFBEEFEUPUIFNJYJOH
tank
t"GUFSBMMJOHSFEJFOUTXFSFBEEFEUIFTPMVUJPO
XBTNJYFEGPSNJOVUFT
t1VSJGJFEXBUFSXBTBEEFEUPUIFNJYJOHUBOLUP
PGUIFGJOBMWPMVNF
t4PMVUJPOQ)XBTBEKVTUFEXJUIIZESPDIMPSJD
BDJETPMVUJPOPSTPEJVNIZESPYJEFTPMVUJPOJG
necessary
t1VSJGJFEXBUFSXBTBEEFETVGGJDJFOUUPNBLFUIF
GJOBMTPMVUJPOWPMVNF
t5IFTPMVUJPOXBTNJYFEGPSNJOVUFT
t4PMVUJPOXBTGJMUFSFEBOEGJMMFEJOUPUIFDPN
NFSDJBMQBDLBHJOH
Training
"MMQFSTPOOFMXFSFUSBJOFEPOUIFOFXNBOVGBDUVS
JOHQSPDFEVSF5IFJNQPSUBODFPGBEEJOHPOMZ
PGUIFGJOBMTPMVUJPOWPMVNFUPUIFNJYJOHUBOLXBT
stressed in the training. This procedure was used
POMZXIFOVTJOHUIFUXPJNQFMMFSNJYJOHUBOL
Documentation
"MMXPSLBTTPDJBUFEXJUIUIFPSJHJOBMWBMJEBUJPOXBT
DPNQMFUFE"MMJOWFTUJHBUJPOTBOBMZTFTBOEDPODMV
TJPOTXFSFEPDVNFOUFEUPDMPTFUIFPSJHJOBMGBJMFE
WBMJEBUJPO%FWFMPQNFOUPGUIFOFXNBOVGBDUVSJOH
Paul L. Pluta
QSPDFTTJODMVEJOHUSJBMSVOTXBTEPDVNFOUFEBOE
GJMFEJOUIFWBMJEBUJPOMJCSBSZBTTVQQPSUJOHJOGPS
NBUJPOGPSUIFOFXWBMJEBUJPO12SVOT
Process Validation
5IFJODSFBTFECBUDITJ[FNBOVGBDUVSJOHQSPDFTT
GPSQSPEVDUJOUIFCBDLVQUXPJNQFMMFSNBOVGBD
UVSJOHUBOLXBTWBMJEBUFE5ISFFMPUTXFSFUFTUFE
"MMUFTUEBUBQBTTFEBDDFQUBODFDSJUFSJB5IFOFX
NBOVGBDUVSJOHQSPDFTTXBTTVDDFTTGVMBOEUIF
QSPDFTTXBTWBMJEBUFE
Post-Validation Monitoring
"EEJUJPOBMNPOJUPSJOHPGNBOVGBDUVSJOHUIF
JODSFBTFECBUDITJ[FQSPEVDUXBTDPOEVDUFEUPDPO
GJSNTVDDFTTGVMQSPDFTTWBMJEBUJPO7JTVBMPCTFS
WBUJPOPGUIFNJYJOHBOEEJTTPMVUJPOQSPDFTTXBT
SFRVJSFEGPSTVCTFRVFOUMPUTNBOVGBDUVSFEEVSJOH
UIFOFYUUISFFNPOUIT0OFMPUXBTNBOVGBDUVSFE
FBDINPOUI5IFNBOVGBDUVSJOHQSPDFTTVTJOHUIF
OFXQSPDFTTXBTTVDDFTTGVMJOBMMCBUDIFT7JTVBM
PCTFSWBUJPOPGUIFNBOVGBDUVSJOHQSPDFTTXBTEPD
VNFOUFEBOEGJMFEJOUIFWBMJEBUJPOMJCSBSZ
Equipment Qualification and Equivalence
5IFJOTUBMMBUJPORVBMJGJDBUJPO*2
GPSUIFNBOV
GBDUVSJOHUBOLXJUIUIFUXPJNQFMMFSTXBTSFWJFXFE
UPCFTVSFUIBUJUTEPDVNFOUBUJPODPSSFDUMZTUBUFE
JUTJNQFMMFSBSSBOHFNFOU5IF*2EPDVNFOUBUJPO
GPSBMMPUIFSUBOLTXBTBMTPSFWJFXFE8IJMFUIF
SFTQFDUJWF*2EPDVNFOUTXFSFBDDVSBUFFRVJQNFOU
FRVJWBMFODFEPDVNFOUTJODPSSFDUMZJOEJDBUFEUIBU
BMMUBOLTXFSFJOUFSDIBOHFBCMFCFDBVTFUIFZBMMXFSF
UIFTBNFTJ[FBOEWPMVNF&RVJQNFOUFRVJWBMFODF
EPDVNFOUTXFSFDIBOHFEUPJOEJDBUFUIBUUIFUXP
JNQFMMFSUBOLXBTOPUMJTUFEBTFRVJWBMFOUUPUIF
PUIFSUISFFJNQFMMFSUBOLTGPSBMMQSPEVDUT8IJMF
UIFNBOVGBDUVSJOHWPMVNFTPGBMMUBOLTXFSFJEFOUJ
DBMUIFNJYJOHDBQBCJMJUJFTPGUIFUBOLTXFSFTJHOJGJ
DBOUMZEJGGFSFOUCFDBVTFUIFJNQFMMFSTPOUIFUBOLT
were different.
5IFUXPJNQFMMFSBOEUISFFJNQFMMFSUBOLTJO
UIJTFYBNQMFXFSFPSJHJOBMMZEFTJHOBUFEBTFRVJWB
MFOUNBOZZFBSTBHPXIFOUIFTJUFNBOVGBDUVSFE
SFMBUJWFMZTJNQMFGPSNVMBUJPOT5IFTFGPSNVMBUJPOT
DPOUBJOFEWFSZTPMVCMFJOHSFEJFOUTUIBUEJTTPMWFE
RVJDLMZJOBMMUBOLT"MMUBOLTQSPWJEFEFRVJWBMFOU
QFSGPSNBODFXIFOUIFTFTJNQMFGPSNVMBUJPOTOP
TMPXEJTTPMWJOHQPMZNFST
XFSFNBOVGBDUVSFEBOE
UIFZXFSFUIVTEFFNFEUPCFFRVJWBMFOUBUUIBUUJNF
&RVJQNFOUFRVJWBMFODFEPDVNFOUBUJPOXBT
NPEJGJFEUPJOEJDBUFUIBUBMMUBOLTDPVMECFVTFE
JOUFSDIBOHFBCMZGPSDFSUBJOGPSNVMBUJPOTCVU
XFSFOPUFRVJWBMFOUGPSPUIFSGPSNVMBUJPOT5IJT
BQQSPBDIHBWFNBOVGBDUVSJOHNBYJNVNGMFYJCJMJUZ
BOEQSFWFOUFEGVUVSFQPUFOUJBMNJYJOHQSPCMFNT
GSPNPDDVSSJOHXIFONPSFDPNQMFYGPSNVMBUJPOT
DPOUBJOJOHDFSUBJOJOHSFEJFOUTXFSFNBOVGBDUVSFE
Other Similar Products Manufactured at
the Site
.BOVGBDUVSJOHCBUDISFDPSETGPSPUIFSQSPEVDUT
XJUIMBSHFCBUDITJ[FTXFSFSFWJFXFE.BTUFSCBUDI
records for certain products were noted to exclude
UIFUXPJNQFMMFSUBOLGSPNPQUJPOBMVTFJONBOV
GBDUVSJOH"MMQSPEVDUTTQFDJGJFEJOJUJBMBEEJUJPO
PGPGQVSJGJFEXBUFSUPUIFNJYJOHUBOL5IJT
WPMVNFXPVMEIBWFSFTVMUFEJOJOBEFRVBUFNJYJOHJG
UIFUXPJNQFMMFSUBOLXBTVTFEGPSNBOVGBDUVSJOH
PGQSPEVDUTDPOUBJOJOHDFSUBJOGPSNVMBUJPOJOHSFEJ
FOUT*GUIFUXPJNQFMMFSUBOLXPVMECFOFFEFEGPS
NBOVGBDUVSJOHGMFYJCJMJUZPGDFSUBJOQSPEVDUTUIF
NBTUFSCBUDISFDPSETPGUIFPUIFSQSPEVDUTXPVMECF
DIBOHFEUPBEEPGQVSJGJFEXBUFSUPUIFNJYJOH
UBOLJOUIFGJSTUTUFQPGUIFNBOVGBDUVSJOHQSPDFTT
POST CAPA
4FWFSBMPUIFSQSPEVDUTXFSFMBUFSSFRVJSFEUPCF
NBOVGBDUVSFEJOUIFUXPJNQFMMFSUBOLJOUIFGPM
MPXJOHNPOUIT.BOVGBDUVSJOHFYQFSJFODFXJUI
the product of this case study including trial runs
XFSFVTFEBTTVQQPSUJOHKVTUJGJDBUJPOUPNPEJGZUIF
SFTQFDUJWFNBTUFSCBUDISFDPSETPGUIFBEEJUJPOBM
QSPEVDUT5IFGPSNVMBUJPOTGPSBMMQSPEVDUTXFSF
FTTFOUJBMMZJEFOUJDBMFYDFQUJOHUIFBDUJWFJOHSFEJ
FOU*OBMMDBTFTUIFBDUJWFJOHSFEJFOUXBTSFBEJMZ
TPMVCMFJOQVSJGJFEXBUFS.BOVGBDUVSJOHQSPDFTT
FTXFSFNPEJGJFEBOE12SVOTXFSFDPOEVDUFEUP
WFSJGZUIFTVDDFTTPGUIFOFXNBOVGBDUVSJOHQSP
DFTT0OF12SVOXBTDPOEVDUFEGPSWBMJEBUJPO
CONCLUSIONS
"DBTFTUVEZJOWPMWJOHUIFQSPDFTTWBMJEBUJPOPGBO
JODSFBTFECBUDITJ[FPGBOBRVFPVTMJRVJETPMVUJPO
QSPEVDUXBTEFTDSJCFE5IFCBUDITJ[FJODSFBTFXBT
DPOTJEFSFEUPCFBSFMBUJWFMZTJNQMFDIBOHFTJODF
PUIFSTJNJMBSQSPEVDUTBUUIFTJUFXFSFBMSFBEZNBOV
GBDUVSFEBUUIFTBNFJODSFBTFECBUDITJ[F5IFOFFE
UPBDUVBMMZEFNPOTUSBUFTVDDFTTGVMQSPDFTTJOHJO
WBMJEBUJPOXBTFWFORVFTUJPOFECFDBVTFUIFQSPEVDU
BOEQSPDFTTXFSFJEFOUJDBMUPPUIFSNBOVGBDUVSJOH
BOEUIFNJYJOHUBOLXBTUIPVHIUUPCFJEFOUJDBMUP
BMMPUIFSUBOLT5IFSFXBTUIPVHIUUPCFOPQPTTJCJM
JUZPGBOZQSPCMFNTPDDVSSJOH.BOVGBDUVSJOHXBT
TUBSUFEBOEUIFVOFYQFDUFEIBQQFOFE‰JOHSFEJFOUT
EJEOPUEJTTPMWFJOUIFQSPEVDUTPMVUJPOBOEUIF
NBOVGBDUVSJOHCBUDIXBTBDPNQMFUFGBJMVSF
5IFDBVTFPGUIFGBJMVSFXBTFBTJMZEFUFSNJOFE
5IFJNQFMMFSTPOUIFNJYFSJOUIFTQFDJGJDNJYJOH
UBOLVTFEGPSUIFJODSFBTFECBUDITJ[FXFSFEJGGFSFOU
UIBOBMMPUIFSTJUFNJYJOHUBOLT.JYJOHJOUIJTUBOL
XBTJOBEFRVBUF"OFXNBOVGBDUVSJOHQSPDFTTXBT
PROCESS VALIDATION – Continued Process Verification
71
Paul L. Pluta
VMUJNBUFMZEFWFMPQFEUIBUFOBCMFEBEFRVBUFNJY
JOHBOETVDDFTTGVMNBOVGBDUVSJOH"MMBTTPDJBUFE
EPDVNFOUBUJPOBGGJSNJOHUIBUBMMNJYJOHUBOLTXFSF
FRVJWBMFOUXBTDPSSFDUFE
5IJTJODJEFOUSFNJOEFEBMMHSPVQTBUUIFTJUFUIBU
UIFZNVTUCFTFOTJUJWFUPQFSDFJWFENJOPSEJGGFS
FODFTJOFRVJQNFOU5IFUXPJNQFMMFSBOEUISFF
JNQFMMFSUBOLTJOUIJTFYBNQMFXFSFPSJHJOBMMZEFT
JHOBUFEBTFRVJWBMFOUNBOZZFBSTBHPXIFOUIFTJUF
NBOVGBDUVSFESFMBUJWFMZTJNQMFGPSNVMBUJPOT5IFTF
GPSNVMBUJPOTDPOUBJOFEWFSZTPMVCMFJOHSFEJFOUT
UIBUEJTTPMWFERVJDLMZJOBMMUBOLT"MMUBOLTQSP
WJEFEFRVJWBMFOUQFSGPSNBODFXIFOUIFTFTJNQMF
GPSNVMBUJPOTXFSFNBOVGBDUVSFE)PXFWFSXIFO
NPSFDPNQMFYGPSNVMBUJPOTSFRVJSJOHFOIBODFE
NJYJOHXFSFNBOVGBDUVSFEEJGGFSFODFTCFUXFFO
NJYJOHUBOLTJFUXPJNQFMMFSTWTUISFFJNQFMMFST
CFDBNFBQQBSFOU
5IJTDBTFTUVEZEFNPOTUSBUFTUIFOFFEGPSDPNQMJ
BODFQSPGFTTJPOBMTUPCFWJHJMBOUFWFOXIFOBQQBS
FOUMZNVOEBOFDIBOHFTBSFJOJUJBUFEi*EFOUJDBMw
NBZSFBMMZOPUCFTPTFF3FGFSFODF
"OPUIFSMFT
TPO-PPLJOTJEFUIFFRVJQNFOU
REFERENCE
'%"i7BMJEBUJPOBOE&RVJQNFOU2VBMJGJDBUJPOo8IFO
A*EFOUJDBM3FBMMZ*TOUwHuman Drug CGMP Notes7PM
VNF/VNCFS4FQUFNCFSJVT
ARTICLE ACRONYM LISTING
CAPA
CGMP
GMP
IQ
PQ
QA
Corrective Action and Preventive Action
Current Good Manufacturing Practice
Good Manufacturing Practice
Installation Qualification
Performance Qualification
Quality Assurance
0SJHJOBMMZQVCMJTIFEJOUIF4VNNFSJTTVFPGThe Journal of Validation Technology
72
PROCESS VALIDATION – Continued Process Verification