CONTINUED PROCESS VERIFICATION

MONITORING AND MAINTAINING

THE VALIDATED STATE
LIFECYCLE APPROACH TO PROCESS
VALIDATION FDA STAGE 3
GMP MonitoringWhat, Why, Where, and How .................................................................................................. 3
Rational Revalidation ........................................................................................................................................ 8
Dos and Donts of Control ChartingPart I ....................................................................................................... 17
The Dos and Donts of Control ChartingPart II ............................................................................................... 21
Understanding the Process Nonconformity ConceptThe Scientific Reason for Process Validation ................... 27
VariationPast, Present, and Future ............................................................................................................... 36
Having It All .................................................................................................................................................... 42
Substandard Data and Documentation PracticesCase Study #5 ..................................................................... 47
Using Probability Distributions to Make Decisions ............................................................................................ 54
Case Study #3Process Validation Failure of a Liquid Product Batch
Size IncreaseIdentical Manufacturing Tanks ............................................................................................. 67
Like-For-Like Changes: Is Validation Testing Needed? Validation Case Study #7 ............................................... 73
Understanding and Reducing Analytical ErrorWhy Good Science Requires Operational Excellence ................. 78
Meeting Specifications is Not Good EnoughThe Taguchi Loss Function .......................................................... 85
Process Modeling: A Powerful Weapon in the Fight to Reduce VariationPart 1 .............................................. 90
White Spots on TabletsCompliance Case Study #8........................................................................................ 97
Compliance Case Study #5Secondary Packages With Defective Glue Joints ................................................ 102
 Gamal Amer

GMP Monitoring
What, Why, Where, and How
Gamal Amer

Welcome to Maintaining Validation. KEY POINTS DISCUSSED

This column addresses topics associated with
maintaining the validated state of processes,
equipment, facilities, utilities, and analytical
methods (i.e., anything that has been validated or
qualified and must be continually maintained in
the validated state). We intend this column to be a

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useful resource for daily work applications.

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This column was suggested by attendees at the


14th International Validation Week Meeting held in

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Philadelphia in October of 2008. The general topic

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of maintaining validation was a subject of great
interest. An ongoing discussion addressing these
questions and associated topics is warranted and
will be useful to our readers.
Validation and compliance practitioners are

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well aware that the conformance lots of process
validation, or the IQ/OQ/PQ of equipment, are at
most snapshots in time. These events serve to
document standard performance when completed.
However, they do not guarantee continued
good performance. It is through monitoring,
data evaluation, statistical analysis, change
control, and other programs that ongoing good


performance is maintained. These topics, including

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relevant examples, are addressed in Maintaining

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Validation.
Reader comments, questions, and suggestions
are needed to help us fulfill our objective for this

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column. Case studies submitted by readers are most

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welcome. We need your help to make Maintaining
Validation a useful resource. Please send your
comments and suggestions to journal coordinating
editor Susan Haigney at shaigney@advanstar.com.
The following key points are discussed in this
article:
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draft guidance Process Validation: General
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ensure an ongoing state of control.

[
For more Author
ABOUT THE AUTHOR
information,
Gamal Amer, Ph.D., is principal at Premier Compliance Services, Inc., management consultants
go to
for compliance and manufacturing operations performance in the life sciences industry. He holds a
gxpandjvt.com/bios
Ph.D. in chemical engineering and has over 27 years of experience in the pharmaceutical and related
industries. He can be reached by e-mail at vpainc@aol.com or amerg@premierc.net.

PROCESS VALIDATION Continued Process Verification 3

Gamal Amer

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 Gamal Amer

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PROCESS VALIDATION Continued Process Verification 5

Gamal Amer

Table: Environmental sampling frequencies for DIBOHFT
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6 PROCESS VALIDATION Continued Process Verification

 Gamal Amer

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REFERENCES 

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Sterile Drug Products

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Process Validation: General Produced by Aseptic Processing
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Principles and Practices, Draft Guidance
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The Journal of Validation Technology

PROCESS VALIDATION Continued Process Verification 7

Hosam Aleem, Tim McCarthy, and Rodger Edwards

Rational Revalidation
Hosam Aleem, Tim McCarthy, and Rodger Edwards

ABSTRACT
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[
ABOUT THE AUTHORS
For more Author Hosam Aleem has spent several years in the pharmaceutical industry as a validation and cali-
information,
bration engineer at both IPR owners and contract manufacturers. He may be reached by email at
hosam.aleem@manchester.ac.uk. Dr. Tim McCarthy is a professor of engineering design at the
go to
University of Wollongong, NSW Australia. Dr. Rodger Edwards is a senior lecturer at the School
gxpandjvt.com/bios of Mechanical, Aerospace and Civil Engineering at the University of Manchester Institute of Science
& Technology and University of Manchester.

8 PROCESS VALIDATION Continued Process Verification

 Hosam Aleem, Tim McCarthy, and Rodger Edwards

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PROCESS VALIDATION Continued Process Verification 9

Hosam Aleem, Tim McCarthy, and Rodger Edwards

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10 PROCESS VALIDATION Continued Process Verification

 Hosam Aleem, Tim McCarthy, and Rodger Edwards

Figure 1: Prioritization for revalidation.

Table II: Temporary options for a process
awaiting revalidation. Requirements

Discontinue production until revalidation is ready

Transfer production to another site within the organization capable
of validating the process
Impose additional procedural controls (such as 100% inspection)
Outsource manufacturing
Business Regulatory

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PROCESS VALIDATION Continued Process Verification 11

Hosam Aleem, Tim McCarthy, and Rodger Edwards

Figure 2: When to revalidate. DIBOHF
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The essence of this section is that the choice
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priority than unplanned changes whose purpose is PQFSBUJOH
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JT
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12 PROCESS VALIDATION Continued Process Verification

 Hosam Aleem, Tim McCarthy, and Rodger Edwards

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Figure 3: Some means for detecting and reduc-

UIFN
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Change
HOW TO IDENTIFY AND REDUCE THE
NEED FOR REVALIDATION
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Detection Reduction
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SPC PQR PM Calibration
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SPC = Statistical Process Control PM = Planned Maintenance

PQR = Product Quality Review
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usefulness of this exercise in detecting the need
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PROCESS VALIDATION Continued Process Verification 13

Hosam Aleem, Tim McCarthy, and Rodger Edwards

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14 PROCESS VALIDATION Continued Process Verification

 Hosam Aleem, Tim McCarthy, and Rodger Edwards

THE BUSINESS MODEL PG
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PROCESS VALIDATION Continued Process Verification 15

Hosam Aleem, Tim McCarthy, and Rodger Edwards

Figure 4: Business issues related to revalidation. 
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The Journal of Validation Technology

16 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

Dos and Donts of Control

ChartingPart I
John McConnell, Brian K. Nunnally, and Bernard McGarvey

Analysis and Control of Variation is dedicated
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based on sound science, but that demonstrably work. WBSJBUJPO
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of variation submitted by readers are most welcome. XJUI
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Please send your comments and suggestions to column there are right ways and wrong ways to set up and
coordinator John McConnell at john@wysowl.com. use control charts. It is the purpose of this article
au or journal coordinating editor Susan Haigney at to explore the right and wrongs of control charting.
shaigney@advanstar.com. 5IJT
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INTRODUCTION historical occurrence of these production issues. They
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[
ABOUT THE AUTHORS
For more Author John McConnell is owner and director at Wysowl Pty Ltd. in Queensland, Australia. He may be
information, reached at john@wysowl.com.au. Brian K. Nunnally, Ph.D., is in charge of process validation at
go to
Pfizer in Sanford, NC. He may be reached at nunnalb@wyeth.com. Bernard McGarvey, Ph.D., is
Process Modeling Group Leader, Process Engineering Center at Eli Lilly and Company in Indianapolis,
gxpandjvt.com/bios
IN. He may be reached at mcgarvey_bernard@lilly.com.

PROCESS VALIDATION Continued Process Verification 17

John McConnell, Brian K. Nunnally, and Bernard McGarvey

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18 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

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PROCESS VALIDATION Continued Process Verification 19

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 6: Control charts for the daily delta Figure 7: Control chart for production rate.
metric.
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Daily production
Individual values

Date
Date

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Figure 8: Control chart for production rate

by shift.

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The Journal of Validation Technology

20 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian Nunnally, and Bernard McGarvey

The Dos and Donts of Control

ChartingPart II
John McConnell, Brian Nunnally, and Bernard McGarvey

Analysis and Control of Variation is dedicated INTRODUCTION

to revealing weaknesses in existing approaches

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to understanding, reducing, and controlling
variation and to recommend alternatives that
are not only based on sound science, but also
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.
Case studies illustrating the successful reduction
or control of variation submitted by readers are
most welcome. Please send your comments and
suggestions to column coordinator John McConnell
at john@wysowl.com.au or journal coordinating
editor Susan Haigney at shaigney@advanstar.com.

"
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[
ABOUT THE AUTHORS
For more Author John McConnell is owner and director at Wysowl Pty Ltd. in Queensland, Australia. He may be
information, reached at john@wysowl.com.au. Brian K. Nunnally, Ph.D., is in charge of process validation at
go to
Pfizer in Sanford, NC. He may be reached at nunnalb@wyeth.com. Bernard McGarvey, Ph.D., is
Process Modeling Group Leader, Process Engineering Center at Eli Lilly and Company in Indianapolis,
gxpandjvt.com/bios
IN. He may be reached at mcgarvey_bernard@lilly.com.

PROCESS VALIDATION Continued Process Verification 21

John McConnell, Brian Nunnally, and Bernard McGarvey

Figure 1: Conversion time monthly average.

X Chart for Conversion Time Monthly Average

80
Individual Values

70
60
50
40
30
20
10
0

Jul-01

sep-01

Jan-02
Jun-01

Oct-01
Feb-01

Feb-02
Apr-01

Dec-01
Nov-01
Mar-01

Aug-01
May-01

Date

mR Chart for Conversion Time Monthly Average

35
Moving Range Values

30
25
20
15
10
5
0
Jul-01

sep-01

Jan-02
Jun-01

Oct-01
Feb-01

Feb-02
Apr-01

Dec-01
Nov-01
Mar-01

Aug-01
May-01

Date

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22 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian Nunnally, and Bernard McGarvey

Figure 2: Product conversion time on a lot basis.

X Chart for Conversion Time by Lot

90
Individual Values

80
70
60
50
40
30
20
10
0
Lot 1
Lot 3
Lot 5
Lot 7
Lot 9
Lot 11
Lot 13
Lot 15
Lot 17
Lot 19
Lot 21
Lot 23
Lot 25
Lot 27
Lot 29
Lot 31
Lot 33
Lot 35
Lot 37
Lot 39
Date

mR Chart for Conversion Time by Lot

Moving Range Values

40
35
30
25
20
15
10
5
0
Lot 1
Lot 3
Lot 5
Lot 7
Lot 9
Lot 11
Lot 13
Lot 15
Lot 17
Lot 19
Lot 21
Lot 23
Lot 25
Lot 27
Lot 29
Lot 31
Lot 33
Lot 35
Lot 37
Date Lot 39

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the last three to four lots of these data are trending
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BSF
NJTTJOH
B
MBSHF
BNPVOU
PG
QSPDFTT

CFIBWJPS
CZ
POMZ
MPPLJOH
BU
NPOUIMZ
BWFSBHF
EBUB
5IF
MFTTPO
MFBSOFE
GSPN
FYBNQMF
GPVS
JT
UIBU


UIF
QVSQPTF
PG
B
iQFPQMF
QFSGPSNBODFw

BHHSFHBUFE
EBUB
TIPVME
OPU
CF
VTFE
XIFO
DPOTUSVDUJOH

B
DPOUSPM
DIBSU

5IF
NPTU
HSBOVMBS
EBUB
BWBJMBCMF

TIPVME
CF
VTFE
4PNFUJNFT
XF
DPOUSPM
DIBSU
NFBTVSFT
UIBU
EP
OPU

SFBMMZ
NFBTVSF
UIF
JOUFOEFE
QSPDFTT
QFSGPSNBODF

5IF

rational for this is typically a lack of understanding of
UIF
USVF
QVSQPTF
PG
UIF
QSPDFTT
PS
B
SFBMJ[BUJPO
UIBU

B
NFBTVSF
UIBU
USVMZ
SFQSFTFOUT
XIBU
XF
XBOU
XJMM
CF

EJGGJDVMU
UP
NFBTVSF

8F
UIFO
VTF
B
TJNQMFS
NFBTVSF


4PNF
FYBNQMFT
EFNPOTUSBUJOH
UIJT
BSF
BT
GPMMPXT
t
Percent completed training. The only
NFBTVSF
XF
IBWF
BSPVOE
QFPQMF
QFSGPSNBODF

JT

*51

*51
JT
UIF
QFSDFOU
PG
UIFJS
USBJOJOH

QMBO
UIBU
JOEJWJEVBMT
*51
5IJT
NFBTVSF
POMZ
SFGMFDUT
XIFUIFS
B
QFSTPO

IBT
PCUBJOFE
BMM
UIFJS
SFRVJSFE
USBJOJOH
DPVSTFT


)PXFWFS
QSPDFTT
JT
UP
FOTVSF
UIBU
UIF
QFPQMF
JNQBDU
PO

B
QSPDFTT
PS
QFPQMF
QFSGPSNBODF
JT
PQUJNBM


8F
TIPVME
MPPL
UP
TFF
XIBU
UIF
USVF
JNQBDU
PG

PROCESS VALIDATION Continued Process Verification 23

John McConnell, Brian Nunnally, and Bernard McGarvey

QFPQMF
NJHIU
CF
PO
UIF
QSPDFTT

0OF
XBZ
UP
*OWFTUJHBUPS

i8IZ w
BQQSPBDI
UIJT
JT
UP
MPPL
GPS
NFBTVSFT
UIBU
NPSF

5FDIOJDBM
TVQQPSU
QFSTPO

i"MM
UIF
SBX

EJSFDUMZ
TIPX
UIF
JNQBDU
PG
QFPQMF
WBSJBCJMJUZ
PO
NBUFSJBMT
BSF
JO
TQFD
TP
UIFZ
DBOOPU
CF
IBWJOH

UIF
QSPDFTT

*U
XPVME
CF
GBS
QSFGFSBCMF
UP
PCTFSWF
BO
JNQBDU
PO
UIF
QSPDFTTw
UIF
OVNCFS
PG
EFWJBUJPOT
XIPTF
SPPU
DBVTFT
BSF

EVF
UP
HBQT
JO
UIF
iQFPQMF
QFSGPSNBODFw
QSPDFTT


BTJDBMMZ
CFDBVTF
XF
IBWF
OPU
GVMMZ

#
4PNF
PG
UIFTF
NBZ
CF
EVF
UP
MBDL
PG
USBJOJOH
DIBSBDUFSJ[FE
UIF
JNQBDU
PG
UIF
SBX
NBUFSJBM

NJTVOEFSTUBOEJOH
PG
JOTUSVDUJPOT
BOE
PUIFS
PO
UIF
QSPDFTTOPU
BO
FBTZ
UBTLBOE
BMM
UIF

reasons. SBX
NBUFSJBM
NFBTVSFT
XF
EP
DPOUSPM
DIBSU
BSF

t
Percent analytical variation.

*O
B
RVBMJUZ
JO
TUBUJTUJDBM
DPOUSPM
JU
JT
BTTVNFE
UIBU
UIF
SBX

DPOUSPM
MBCPSBUPSZ
XF
NBZ
GBJM
UP
NFBTVSF
NBUFSJBM
JT
OPU
UIF
JTTVF

)PXFWFS
JU
NBZ
UVSO

POF
PG
UIF
NPTU
JNQPSUBOU
NFBTVSFT
GSPN
PVU
UIBU
XF
XFSF
TJNQMZ
OPU
MPPLJOH
BU
UIF
SJHIU

B
DVTUPNFST
QFSTQFDUJWF
UIBU
JT
UIF

PG
BTQFDU
PG
UIF
SBX
NBUFSJBM
RVBMJUZ
UPUBM
WBSJBUJPO
JO
BO
BTTBZ
UIBU
JT
EVF
UP
t
Asset management.

8IFO
NPOJUPSJOH
UIF

NFBTVSFNFOU
FSSPS
PS
VODFSUBJOUZ

5IJT
JT
TVDDFTT
PG
BO
BTTFU
NBOBHFNFOU
QSPDFTT
XF

BO
JNQPSUBOU
NFBTVSF
CFDBVTF
GPS
FYBNQMF
DBO
MPPL
BU
DPTU
PG
NBJOUBJOJOH
BTTFUT
TQBSFT

UPP
NVDI
NFBTVSFNFOU
FSSPS
EFHSBEFT
UIF
JOWFOUPSZ
MFWFMT
BOE
PUIFS
WBSJBCMFT

)PXFWFS

QFSGPSNBODF
PG
B
QSPEVDUJPO
DPOUSPM
DIBSU
UIBU
XF
NVTU
BMTP
CF
TVSF
UIBU
XF
NFBTVSF
UIF

is trying to detect changes in the production JNQBDU
PG
UIF
BTTFU
NBOBHFNFOU
TZTUFN
PO

QSPDFTT

1FSGPSNJOH
BTTBZT
TQFFEJMZ
BOE
UIF
QSPEVDUJPO
QSPDFTT

5IJT
DBO
CF
EPOF
CZ

FGGJDJFOUMZ
NBZ
OPU
CF
FOPVHI
JG
UIF
FSSPS
PG
MPPLJOH
BU
UIF
OVNCFS
PG
QSPEVDUJPO
JODJEFOUT

UIF
NFBTVSFNFOU
QSPDFTT
JT
MBSHF

*O
HFOFSBM
UIBU
XFSF
EVF
UP
FRVJQNFOU
JTTVFT
TVDI
BT

B
TUBOEBSE
GPS
UIF
NFBTVSFNFOU
FSSPS
JT
UIF
VOFYQFDUFE
FRVJQNFOU
GBJMVSF
XSPOH
NBUFSJBMT

GPMMPXJOH
FRVBUJPO PG
DPOTUSVDUJPO
BOE
PUIFS
JODJEFOUT

5IF
MFTTPO
MFBSOFE
GSPN
FYBNQMF
GJWF
JT
UIBU
XF

TIPVME
OPU
DPOUSPM
DIBSU
B
NFBTVSF
TJNQMZ
CFDBVTF

JU
JT
FBTZ

.FBTVSFT
UIBU
HJWF
JOTJHIU
JOUP
UIF
QSPDFTT

TIPVME
CF
TFMFDUFE
GPS
UIF
DPOUSPM
DIBSU
where .
JT
UIF
WBSJBUJPO
EVF
UP
NFBTVSFNFOU

and 1
JT
UIF
WBSJBUJPO
EVF
UP
UIF
QSPDFTT

EXAMPLE SIX
5IJT
JT
XIZ
DPOUSPM
DIBSUJOH
MBCPSBUPSZ
BTTBZ
.BOZ
ZFBST
BHP
POF
PG
UIF
BVUIPST
IBE
B

DPOUSPMT
BSF
TP
JNQPSUBOU

*G
UIF
DPOUSPMT
CFHJO
DPOWFSTBUJPO
XJUI
B
OFX
.#"
HSBEVBUF
XIP
IBE

to display a lack of statistical control on the KVTU
KPJOFE
UIFJS
DPNQBOZ
5IF
HSBEVBUF
IBE
CFFO

DPOUSPM
DIBSU
JU
NBZ
JOEJDBUF
UIBU
BTTVNFE
exposed to the use of control charts and was
NFBTVSFNFOU
VODFSUBJOUZ
PG
UIF
BTTBZ
JT
FBHFS
UP
VTF
UIFN
JO
UIF
QSPDFTT
GPS
XIJDI
IF
XBT

suspect. SFTQPOTJCMF

8F
EJTDVTTFE
XIBU
XF
DPVME
EP
BOE
*

t
Raw materials management.

8IFO
TVHHFTUFE
IF
TFOE
NF
TPNF
EBUB
TP
*
DPVME
TFU
VQ
UIF

NPOJUPSJOH
UIF
QFSGPSNBODF
PG
B
SBX
NBUFSJBMT
DIBSUT
BOE
IF
DPVME
UIFO
NBJOUBJO
UIFN

)PXFWFS

NBOBHFNFOU
QSPDFTT
XF
DPOUSPM
TVDI
WBSJBCMFT
he was enthusiastic to apply his learning and wanted
BT
RVBMJUZ
EFMJWFSZ
QSJDF
BOE
PUIFS
WBSJBCMFT

UP
TFU
VQ
UIF
DIBSUT
IJNTFMG

8F
BHSFFE
BOE
B
GFX

"HBJO
UIF
NPUJWBUJPO
GPS
UIJT
JT
UIBU
UIFTF
EBZT
MBUFS
IF
TFOU
NF
IJT
DPOUSPM
DIBSUT
BT
QJDUVSFT

NFBTVSFT
BSF
FBTZ
UP
HFU
BOE
TIPVME
CF
DPOUSPM
JO
B
EPDVNFOU
5IF
DIBSUT
XFSF
GPS
EBUB
TVDI
BT

DIBSUFE

)PXFWFS
XF
NBZ
GBJM
UP
NFBTVSF
CBUDI
ZJFMET
DZDMF
UJNFT
BOE
TP
PO
BOE
TP
XFSF

UIF
JNQBDU
UIBU
UIF
SBX
NBUFSJBM
IBT
PO
UIF
QMPUUFE
PO
BO
JOEJWJEVBMT
DPOUSPM
DIBSU

"T
TPPO
BT

NBOVGBDUVSJOH
QSPDFTT
XIFSF
JU
JT
VTFE

5IJT
DBO
*
TBX
UIF
DIBSUT
*
LOFX
UIFSF
XBT
TPNFUIJOH
TVTQFDU

MFBE
UP
MPDBM
PQUJNJ[BUJPO
PG
UIF
SBX
NBUFSJBMT
BCPVU
UIF
DIBSUT

*U
BQQFBSFE
UP
NF
UIBU
UIF
EBUB

NBOBHFNFOU
QSPDFTT
BU
UIF
FYQFOTF
PG
UIF
TIPVME
JOEJDBUF
PVUPGDPOUSPM
TJHOBMT

"MM
EBUB
GFMM

QFSGPSNBODF
PG
UIF
QSPEVDUJPO
QSPDFTT

*U
JT
XFMM
XJUIJO
UIF
DPOUSPM
MJNJUT
IF
KVEHFE
UIBU
BMM

BMTP
UIF
SFBTPO
XIZ
XF
NBZ
IFBS
UIF
GPMMPXJOH
NFBTVSFT
XFSF
JO
DPOUSPM

*
SFRVFTUFE
UIF
GJMFT
XJUI

DPOWFSTBUJPO
EVSJOH
B
SPPU
DBVTF
JOWFTUJHBUJPO UIF
DBMDVMBUJPOT

)F
IBE
VTFE
B
TQSFBETIFFU
UP
TFU

VQ
UIF
DPOUSPM
DIBSUT
XIJDI
JT
GJOF

CVU
JO
TFUUJOH

*
OWFTUJHBUPS

i)BWF
XF
MPPLFE
BU
UIF
SBX
VQ
UIF
DPOUSPM
DIBSU
MJNJUT
IF
IBE
DBMDVMBUFE
UIF

NBUFSJBMT
BT
UIF
TPVSDF
PG
UIF
QSPCMFN w DPOUSPM
DIBSU
MJNJUT
BT
GPMMPXT
5FDIOJDBM
TVQQPSU
QFSTPO

i/P
OFFEw

24 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian Nunnally, and Bernard McGarvey

Figure 3: The right and wrong way to control chart individuals data.
6 Individual Measurement of Metric
4 90

2
85 UCL=85.36
Signal

Metric
0

80 Avg=79.81
-2

-4 75 LCL=74.26

-6

4
8
12
16
20
24
28
32
36
40
44
48
0 10 20 30 40 50 60
Lot # Lot #

Signal Moving Range of Metric

90
8
7 UCL=6.82
85 Moving Range of Metric 6
5
4
80
Y

3
2 Avg=2.09
75 1
0 LCL=0.00
4
8
12
16
20
24
28
32
36
40
44
48
70
0 10 20 30 40 50 60 Lot #
Lot #
Y Metric Mean LCL UCL Correct Individuals / Moving
Range Control Chart
Incorrect Control Limits

-PXFS
$POUSPM
$IBSU
-JNJU

-$-

&

& BCTPMVUF
EJGGFSFODF
CFUXFFO
UIF
UXP
EBUB
QPJOUT

6QQFS
$POUSPM
$IBSU
-JNJU

6$-

&

&

JU
XJMM
IBWF
/

XIFSF
&
JT
UIF
FTUJNBUFE
NFBO
PG
UIF
EBUBTFU

and &
JT
UIF
FTUJNBUFE
TUBOEBSE
EFWJBUJPO
PG
UIF

dataset.
5IF
BCPWF
JT
B
DPSSFDU
BQQSPBDI
UP
DBMDVMBUJOH

DPOUSPM
DIBSU
MJNJUT

5IF
FTUJNBUFE
NFBO
JT
TJNQMZ

UIF
NFBO
PG
UIF
EBUBTFU

GPSNFE
CZ
TVNNJOH
UIF

EBUB
QPJOUT
JO
UIF
EBUBTFU
BOE
EJWJEJOH
CZ
UIF


8IFO
UIF
EBUB
XFSF
SFQMPUUFE
PO
DPOUSPM

OVNCFS
PG
EBUB
QPJOUT
JO
UIF
EBUBTFU

5IF
FTUJNBUFE


PVUPGDPOUSPM

TUBOEBSE
EFWJBUJPO
XBT
DBMDVMBUFE
CZ
VTJOH
UIF

TBNQMF
TUBOEBSE
EFWJBUJPO

*O
.JDSPTPGU
&YDFM

UIJT
JT
PCUBJOFE
CZ
VTJOH
UIF
TUEFW
GVODUJPO
BOE
JT

easily calculated. This is not the correct approach.
5IF
QSPCMFN
XJUI
UIF
VTF
PG
UIF
TBNQMF
TUBOEBSE


XBSOFE
BCPVU
NBOZ
ZFBST

EFWJBUJPO
JT
UIBU
JU
EPFT
OPU
BDDPVOU
GPS
UIF
UJNF

TFRVFODF
PG
UIF
EBUB

/P
NBUUFS
IPX
ZPV
NJY
B
TFU

PG
EBUB

JU
XJMM
TUJMM
IBWF
UIF
TBNF
TBNQMF
TUBOEBSE

EFWJBUJPO

4P
XIBU
JT
SFRVJSFE
JT
BO
FTUJNBUF
PG
UIF

TUBOEBSE
EFWJBUJPO
UIBU
UBLFT
UIF
UJNF
TFRVFODF


UIFZ
HFU
GVSUIFS
BOE
GVSUIFS
GSPN
UIF
PSJHJOBM


of the data into account. In practice this is done
CZ
VTJOH
UIF
NPWJOH
SBOHF
PG
UIF
EBUB

'PS
UXP

DPOTFDVUJWF
EBUB
QPJOUT

UIF
NPWJOH
SBOHF
JT
UIF

4P
JG
UIF
EBUBTFU
IBE
/
EBUB
QPJOUT
NPWJOH
SBOHF
WBMVFT

5IF
TUBOEBSE
EFWJBUJPO
PG
UIF

EBUBTFU
DBO
UIFO
CF
FTUJNBUFE
BT
&

.3 
XIFSF
.3
JT
UIF
BWFSBHF
PG
UIF
/
NPWJOH
SBOHF

WBMVFT

DIBSUT
XJUI
UIF
QSPQFS
DPOUSPM
MJNJUT
TJHOBMT
XFSF
DMFBS
5IF
.#"
HSBEVBUF
XIP
JOJUJBMMZ

DPOTUSVDUFE
UIF
DPOUSPM
DIBSU
MJNJUT
VTJOH
UIF

.JDSPTPGU
&YDFM
TUEFW
GVODUJPO
IBE
MFBSOFE
UIJT

BQQSPBDI
JO
UIF
.#"
DMBTTFT

5IJT
JMMVTUSBUFT
B

DPODFSO
UIBU
%FNJOH

BHP
XIFO
IF
DBVUJPOFE
BCPVU
TUBUJTUJDBM
NFUIPET

CFJOH
UBVHIU
CZ
QFPQMF
XIP
XFSF
OPU
GVMMZ
GBNJMJBS

XJUI
UIFN

8F
FOE
VQ
XJUI
UIF
QIPUPDPQZ
FGGFDU

XIFSF
FBDI
UJNF
UIF
NFUIPET
BOE
JEFBT
BSF
QBTTFE

EPXO
&YQFSUJTF
JO
DPOUSPM
DIBSUJOH
BOE
PUIFS
TUBUJTUJDBM

NFUIPET
POMZ
DPNFT
GSPN
B
TJHOJGJDBOU
JOWFTUNFOU
JO

learning and application.
PROCESS VALIDATION Continued Process Verification 25
John McConnell, Brian Nunnally, and Bernard McGarvey

"T
B
TJEF
OPUF
UIF
PUIFS
JTTVF
XJUI
UIF
.#"
PVS
QSPDFTT
UIFO
UIFSF
DBO
CF
HSFBU
BEWBOUBHFT
JO

HSBEVBUFT
BQQSPBDI
JT
UIBU
IF
OFWFS
DPOTUSVDUFE
UIF
QMPUUJOH
UIF
DPOUSPM
DIBSUT
JODPSSFDUMZ

.PSF
PGUFO

NPWJOH
SBOHF
DIBSU
XIJDI
JT
B
UJNF
TFSJFT
PG
UIF
UIBO
OPU
QMPUUJOH
UIF
DIBSUT
VTJOH
UIF
JODPSSFDU

NPWJOH
SBOHF
WBMVFT
XJUI
BO
BQQSPQSJBUF
DPOUSPM
NFUIPET
EFTFOTJUJTFT
UIF
DIBSUT
BOE
NBLFT
PVUPG
MJNJU

*U
JT
HFOFSBMMZ
BHSFFE


UIBU
UIFSF
JT
WBMVF
DPOUSPM
TJHOBMT
iGBEF
JOUP
UIF
CBDLHSPVOEw

)PXFWFS

JO
MPPLJOH
BU
UIJT
DIBSU
CFDBVTF
JU
QMPUT
UIF
TBNF
JG
PVS
PCKFDUJWF
JT
UP
HBJO
JOTJHIU
JOUP
UIF
CFIBWJPS
PG

EBUB
JO
B
EJGGFSFOU
XBZ
BOE
XJMM
HJWF
BOPUIFS
WJFX
UIF
QSPDFTT
TP
XF
DBO
JNQSPWF
UIF
QSPDFTT
UIFO
JU
JT

of what is happening in the process. It is easy to DMFBS
UIBU
VTJOH
UIF
DPSSFDU
DBMDVMBUJPOT
JT
JNQFSBUJWF
DPOTUSVDU
XJUI
NPEFSO
DPNQVUFS
TPGUXBSF
BMPOH
5IF
MFTTPO
MFBSOFE
GSPN
FYBNQMF
TJY
JT
UIBU
DPOUSPM

XJUI
UIF
JOEJWJEVBMT
DIBSU

3FGFSFODF

TIPXT
IPX
DIBSUT
NVTU
CF
DBMDVMBUFE
DPSSFDUMZ
UP
DPOTUSVDU
UIF
NPWJOH
SBOHF
DIBSU
*O
PSEFS
UP
JMMVTUSBUF
UIJT
QPJOU
B
TJNVMBUJPO
CONCLUSIONS
XBT
DPOTUSVDUFE
XIFSF
UIF
CBTF
EBUB
DPOTJTUFE
*O
UIJT
BSUJDMF
XF
IBWF
FYQMPSFE
TPNF
NPSF
EPT
BOE

PG
B
NFBTVSF
:
UIBU
WBSJFT
SBOEPNMZ
BDDPSEJOH
UP
EPOUT
PG
DPOUSPM
DIBSUJOH

5IF
JNQPSUBOU
MFTTPOT
BSF

B
OPSNBM
EJTUSJCVUJPO
XJUI
B
NFBO
PG

BOE
B
presented as follows:
TUBOEBSE
EFWJBUJPO
PG


"
EBUBTFU
DPOTJTUJOH
PG
t
%P
OPU
VTF
BHHSFHBUFE
EBUB
XIFO
DPOTUSVDUJOH
B


QPJOUT
XBT
DSFBUFE
VTJOH
UIJT
EJTUSJCVUJPO

"
TJOF
control chart
XBWF
JT
JOUSPEVDFE
POUP
UIJT
CBTF
TJHOBM
BT
TIPXO
JO
t
%P
OPU
DPOUSPM
DIBSU
B
NFBTVSF
TJNQMZ
CFDBVTF
JU

UIF
VQQFS
MFGU
QBSU
PG
'JHVSF


5IF
MPXFS
MFGU
DIBSU
JT
FBTZ
DPOUSPM
DIBSU
UIF
NFBTVSF
CFDBVTF
JU
HJWFT

TIPXT
UIF
DPOUSPM
DIBSU
VTJOH
UIF
TBNQMF
TUBOEBSE
insight into the process
EFWJBUJPO
BOE
UIF
SJHIUIBOE
TJEF
TIPXT
UIF
QSPQFS
t
%P
NBLF
TVSF
UIBU
UIF
DPOUSPM
DIBSU
MJNJUT
BSF

JOEJWJEVBMT
BOE
NPWJOH
SBOHF
DPOUSPM
DIBSUT calculated correctly.
*U
JT
DMFBS
GSPN
UIF
DIBSUT
UIBU
UIF
NFUIPE
VTJOH
"HBJO
GPS
DPOUSPM
DIBSUJOH
BT
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The Journal of Validation Technology

26 PROCESS VALIDATION Continued Process Verification

 Pramote Cholayudth

Understanding the Process

Nonconformity ConceptThe
Scientific Reason for Process
Validation
Pramote Cholayudth

INTRODUCTION Figure 1: A process model.

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Guidance for IndustryProcess Validation: General CBUDI
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[
ABOUT THE AUTHOR
For more Author Pramote Cholayudth is a validation consultant to Biolab, one of the top five leading pharmaceu-
information, tical manufacturers in Thailand, and executive director of Valitech, a GMP and validation service firm.
go to He is a guest speaker on process validation to the industry organized by local FDA. He was a lecturer
gxpandjvt.com/bios in a university from 1998-2001. Prior to entering the academic arena, he spent 23 years in the phar-
maceutical industry. He can be contacted by e-mail at cpramote2000@yahoo.com.

PROCESS VALIDATION Continued Process Verification 27

Pramote Cholayudth

Figure 2: Distribution curve for USP 29 content uniformity CZ
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Figure 3: Distribution curve for USP 30 content uniformity EBUB
FNCFEEFE
JO
UIF
CBUDI
PG
FWFO

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Figure 4: Distribution curve for USP 30 content unifor- /03.4%*45 2
 2





mity data (mean=100%; SD=6.4% LC). /03.4%*45 




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28 PROCESS VALIDATION Continued Process Verification

 Pramote Cholayudth

Figure 5: Distribution curve for USP 30 content uniformity 
JT
UIF
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TJ[F

data (mean=100% LC; SD=6.4% LC; red area=0.01%). 
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0.010%
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0 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00
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Figure 6: Distribution curve for USP 30 dissolution data UIBU
UIF
USVF
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(mean=Q+2.5% LC; SD=10% LC; green=95.99%; yellow=3.71%, XIJDI
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Figure 7: Distribution of nonconforming rates in samples
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(batch nonconforming rate:1.0%, sample size: 300 units).
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n = 300


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PROCESS VALIDATION Continued Process Verification 29

Pramote Cholayudth

Figure 8: Distribution of nonconforming rates in samples "T
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JO
'JHVSF

B
HSFBU

(batch nonconforming rate:1.0%, sample size:60 units). OVNCFS
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2$
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Figure 9: Distributions of contaminated units in media SBUFT
CBUDIXJTF
PS
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JU

fills (process contamination rate [PCR]: 0.1%). XPVME
CF
OFDFTTBSZ
UP
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JOGPSNBUJPO
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* 95% Condence that PCR 0.1%
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Contamination Rate = 2x100/6300 = 0.03% TBNQMJOH
5IFSFGPSF
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Figure 10: Distributions of batch nonconforming rates (1% PS
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average). Process NC rate (content uniformity): 1.0%. FYUFOEFESFMFBTF
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A PRACTICAL APPROACH FOR
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UIF

30 PROCESS VALIDATION Continued Process Verification

 Pramote Cholayudth

Figure 11: Distributions of batch nonconforming rates BDDFQUBODF
DSJUFSJB
GPS
UBCMFUT
BOE

(0.1% average). Process NC rate (dissolution): 0.1%. DBQTVMFT
EJGGFS
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0% 2% 4% 6% 8% 0% 2% 4% 6% 8% 0% 2% 4% 6% 8% 0% 2% 4% 6% 8% 0%
08 08 08 08 08 09 09 09 09 09 10 10 10 10 10 11 11 11 11 11 12 UIFSF
JT
OP
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0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.
Batch non-conforming rates UIBU
UIF
TBNQMF
JT
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Figure 12: Nonconformity distributions in batches and samples.

NC Rates in Samples
Sample 1 = 0.8%
AV =
Batch # 1 Sample 2 = 0.9%
0.9%
NC Rate = 0.9% Sample 3 = 1.0%

Sample 1 = 0.9%
Process Batch # 2 AV =
Sample 2 = 1.0%
1.0%
NC Rate = 1.0% Sample 3 = 1.1%
NC Rate = 1.0%
Sample 1 = 1.0%
Batch # 3 Sample 2 = 1.1% AV =
1.1%
NC Rate = 1.1% Sample 3 = 1.2%
NC Rate:
Nonconforming Rate Average = 1% Average = 1%

Figure 13: Batch evaluation using QC test results.

QC Test Results
Test Result # 1/100
Test Result # 2/100
Test Result # 3/100

Test Result # 49/100

Test Result # 50/100 Production Batch
Test Result # 51/100

The high percentage (99%) of

Test Result # 97/100
successful QC test results
Test Result # 98/100
meeting the specication will
Test Result # 99/100
demonstrate the low non-
conforming rate.

PROCESS VALIDATION Continued Process Verification 31

Pramote Cholayudth

Figure 14: Batch validation using validation test results.

Validation Test Results

Test Result # 1

Test Result # 2 Validation Batch

The percentage of QC test results

meeting the specication is
Test Result # 3
predicted by computing the
probability of passing the spec. for a
sample using the validation data.

Figure 15: Process validation using validation test results.

Demonstrate at least three consecutive
Validation Test Results successful validation batches (i.e.,
demonstrate between-batch consistency).
Test Result 1
Test Result 2 PV Bat. # 1
Test Result 3 Low NC Rate

Test Result 1
PV Bat. # 2 Validated
Test Result 2
Process
Test Result 3 Low NC Rate
Low Process NC Rate
Test Result 1
Test Result 2 PV Bat. # 3
Test Result 3 Low NC Rate

Demonstrate the high probability of passing the specication by computation

using the validation data (i.e., demonstrate within-batch consistency).

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32 PROCESS VALIDATION Continued Process Verification

 Pramote Cholayudth

Figure 16: Probability of passing content uniformity tests (sample mean=100% LC, n=60, 95%
confidence level).
100%
Probability of passing CU test (%) USP 29: Capsule
90% USP 29: Tablet
USP 30
80%
70%
60%
50%
40%
30%
20%
10%
0%
0 5 0 5 0 5 0 5 0 5 0 5 0
2. 2. 3. 3. 4. 4. 5. 5. 6. 6. 7. 7. 8.
Sample RSD (%)

Figure 17: Probability of passing USP 30 content uniformity test (n=1x60=60, RSD=2.7-5.3%).

Approx. 98% Mean = 99.6, RSD = 4.5

100%
95% 2.7%
2.9%
90% 3.1%
3.3%
Probability (%)

85%
3.5%
80% 3.7%
3.9%
75%
4.1%
70% 4.3%
4.5%
65% 4.7%
60% 4.9%
5.1%
55% 5.3%

50%
.0 .4 .8 .2 .6 .0 .4 .8 .2 .6 .0 .4 .8 .2 .6 .0 .4 .8 .2 .6 .0 .4 .8 .2 .6 .0
95 95 95 96 96 97 97 97 98 98 99 99 99 100 100 101 101 101 102 102 103 103 103 104 104 105
CU sample mean (% LC)

PROCESS VALIDATION Continued Process Verification 33

Pramote Cholayudth

Figure 18: Probability of passing dissolution test (n=1x20=20, mean-Q=1.5-2.8).

100%

95% 1.5%
1.6%
90%
1.7%
85% 1.8%
Probability (%)

1.9%
80% 2.0%
2.1%
75%
2.2%
70% 2.3%
2.4%
65% 2.5%
2.6%
60%
2.7%
55% 2.8%

50%
0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4 6 8 0 2 4
0. 0. 0. 0. 0. 1. 1. 1. 1. 1. 2. 2. 2. 2. 2. 3. 3. 3. 3. 3. 4. 4. 4.
SD (% LC)

Figure 19: Probability of passing dissolution test (n=1x20=20, SD=1.4-4.0).

Approx. 99% Mean-Q = 3.8, SD = 2.8

100%

95% 1.4%
1.6%
90%
1.8%
85% 2.0%
Probability (%)

2.2%
80% 2.4%
2.6%
75%
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Dissolution sample mean-Q value (% LC)

34 PROCESS VALIDATION Continued Process Verification

 Pramote Cholayudth

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REFERENCES 6OJGPSNJUZ
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Draft Guidance for Industry: 7PMVNF

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Process Validation: General Principles and Practices

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The Journal of Validation Technology

PROCESS VALIDATION Continued Process Verification 35

John McConnell, Brian K. Nunnally, and Bernard McGarvey
VariationPast, Present, and
Future
John McConnell, Brian K. Nunnally, and Bernard McGarvey
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.

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It is axiomatic that if there is no variation, there will
be no deviations and no out-of-specification results.

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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

w
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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

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BOBMZTJT

john@wysowl.com.au or journal coordinating editor
Susan Haigney at shaigney@advanstar.com.
[
ABOUT THE AUTHORS
For more Author John McConnell is the coordinator of Analysis and Control of Variation and is the owner and direc-
information, tor of Wysowl Pty Ltd. in Queensland, Australia. He may be reached at john@wysowl.com.au. Brian K.
go to Nunnally, Ph.D., is associate director, Validation, at Wyeth Research. He may be reached at nunnalb@
gxpandjvt.com/bios wyeth.com. Bernard McGarvey, Ph.D., is process modeling group leader, Process Engineering Cen-
ter, Eli Lilly and Company. He may be reached at mcgarvey_bernard@lilly.com.
36 PROCESS VALIDATION Continued Process Verification
KEY POINTS DISCUSSED
The following key points are discussed in this article:
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INTRODUCTION TPNFUJNFT
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PROCESS VALIDATION Continued Process Verification 37

John McConnell, Brian K. Nunnally, and Bernard McGarvey

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38 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

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PROCESS VALIDATION Continued Process Verification 39

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 2: Two approaches to calculating limits.

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40 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 3: Trending laboratory controls.

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The Journal of Validation Technology

PROCESS VALIDATION Continued Process Verification 41

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Having It All
John McConnell, Brian K. Nunnally, and Bernard McGarvey

Analysis and Control of Variation is dedicated INTRODUCTION AND HYPOTHESIS

to revealing weaknesses in existing approaches to It is ironic that to this day we find people engaged
understanding, reducing, and controlling variation JO
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and to recommend alternatives that are not only BSF
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work. The objective of the column is to combine and higher unit costs.
sound science with proven practical advice. The central hypothesis of this article is that
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help us fulfill our objective for this column. Please SFEVDJOH
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send your comments and suggestions to column IJHIFS
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coordinator John McConnell at john@wysowl.com. JO
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KEY POINTS DISCUSSED
The following key points are discussed in this TYPES OF VARIATION
article: 'PS
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[
ABOUT THE AUTHORS
For more Author John McConnell is the coordinator of Analysis and Control of Variation and is the owner and
information, director of Wysowl Pty Ltd. in Queensland, Australia. He may be reached at john@wysowl.com.au.
go to Brian K. Nunnally, Ph.D., is associate director, Validation, at Wyeth Research. He may be reached
gxpandjvt.com/bios at nunnalb@wyeth.com. Bernard McGarvey, Ph.D., is process modeling group leader, Process
Engineering Center, Eli Lilly and Company. He may be reached at mcgarvey_bernard@lilly.com.

42 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

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PROCESS VALIDATION Continued Process Verification 43

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 1: Control chart for deviations.

60

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0
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44 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 2: Reduced variation in potency (1).

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PROCESS VALIDATION Continued Process Verification 45

John McConnell, Brian K. Nunnally, and Bernard McGarvey

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Pharmaceutical Industry
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The Journal of Validation Technology

46 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta and Timothy J. Fields

Substandard Data and

Documentation Practices
Case Study #5
Paul L. Pluta and Timothy J. Fields

Validation Case Studies discusses actual t
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validation situations useful to practitioners for


daily work applications. Each case presented deals

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with a specific validation problem. A strategy and
approach to solve the problem is proposed. 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 shaigney@
advanstar.com.
KEY POINTS DISCUSSED
The following key points are discussed:
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standards.
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INTRODUCTION
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[
ABOUT THE AUTHORS
For more Author Paul L. Pluta, Ph.D., has extensive pharmaceutical industry and university academic experience
information, and has been involved with the Journal of GXP Compliance and Journal of Validation Technology as
go to a writer and editor for several years. He may be reached at paul.pluta@comcast.net. Timothy J.
gxpandjvt.com/bios Fields is senior director of quality operations at Protein Sciences Corporation in Meriden, CT, with
responsibility for quality assurance and validation.

PROCESS VALIDATION Continued Process Verification 47

Paul L. Pluta and Timothy J. Fields

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EJTDVTTFE
QSPCMFNT
BOE
TUPSFE
JO
UIF
WBMJEBUJPO
MJCSBSZ
DPODFSOT
BU
UIF
*OTUJUVUF
PG
7BMJEBUJPO
5FDIOPMPHZT

Protocol.

"
QSPUPDPM
JT
XSJUUFO
TQFDJGZJOH

Validation Week
DPOGFSFODF
JO
1IJMBEFMQIJB
1"
JO
EFUBJMFE
TBNQMJOH
BOE
UFTUJOH
UP
DPOGJSN
UIF

0DUPCFS

5IF
NBOBHFST
FYQSFTTFE
DPODFSO
BDDFQUBCJMJUZ
PG
UIF
DIBOHF
5IF
7"$
BQQSPWFT
UIF

BCPVU
UFTUJOH
BOE
EBUB
HFOFSBUFE
GPS
UIF
WBMJEBUJPO
QSPUPDPM
5IF
BQQSPWFE
QSPUPDPM
JT
TUPSFE
JO
UIF

5IFTF
EBUB
BOE
EPDVNFOUT
BSF
QSPEVDFE
CZ
TDJFOUJTUT
WBMJEBUJPO
MJCSBSZ
FOHJOFFST
BOE
PUIFS
UFDIOJDBM
QFSTPOOFM
XIP
NBZ

Validation work.
7BMJEBUJPO
XPSL
JT

OPU
CF
JOWPMWFE
XJUI
HPPE
NBOVGBDUVSJOH
QSBDUJDF
QFSGPSNFE
BDDPSEJOH
UP
UIF
QSPUPDPM
4BNQMJOH
BOE

(.1

PO
B
EBJMZ
CBTJT
5IFJS
EBUB
SFDPSEJOH
NBZ
OPU
UFTUJOH
BSF
DPNQMFUFE
%BUB
BOE
PUIFS
SFTVMUT
BSF

NFFU
FYQFDUFE
RVBMJUZ
TUBOEBSET
8JUIPVU
QSPQFS
generated and recorded.
EPDVNFOUFE
EBUB
BDDFQUBCMF
WBMJEBUJPO
SFQPSUT

Validation report.
"
SFQPSU
DPOUBJOJOH

BSF
OPU
QPTTJCMF
'VSUIFS
TVCTUBOEBSE
EBUB
BOE
all test results with discussion and conclusions is
EPDVNFOUBUJPO
SFGMFDU
QPPSMZ
PO
UIF
PSHBOJ[BUJPO
QSFQBSFE
BOE
TVCNJUUFE
UP
UIF
7"$
GPS
BQQSPWBM
5IF

UIJT
JO
UVSO
NBZ
IBWF
TJHOJGJDBOU
SBNJGJDBUJPOT
JO
SFQPSU
JT
BQQSPWFE
BOE
UIF
QSPDFTT
PS
FRVJQNFOU

SFHVMBUPSZ
BVEJUT
"DDFQUBCMF
EBUB
BOE
BTTPDJBUFE
DIBOHF
JT
JNQMFNFOUFE
5IF
BQQSPWFE
WBMJEBUJPO

EPDVNFOUBUJPO
GPS
WBMJEBUJPO
BSF
DSJUJDBMMZ
JNQPSUBOU SFQPSU
JT
TUPSFE
JO
UIF
WBMJEBUJPO
MJCSBSZ
The discussion addresses situations in which 
Validation closure. If no other work is
PSJHJOBM
EBUB
BOE
EPDVNFOUBUJPO
HFOFSBUFE
GPS
OFFEFE
UIF
WBMJEBUJPO
QSPKFDU
JOJUJBUFE
CZ
UIF
DIBOHF

WBMJEBUJPO
SFQPSUT
XFSF
VOBDDFQUBCMF
"
WBSJFUZ
PG
SFRVFTU
JT
DMPTFE
QSPCMFNT
BSF
EFTDSJCFE
&YBNQMFT
EFNPOTUSBUF

Continued verification.
1PTUWBMJEBUJPO

UIF
CSPBE
TDPQF
BOE
NBHOJUVEF
PG
QPUFOUJBM
NPOJUPSJOH
DPOGJSNJOH
BDDFQUBCJMJUZ
PG
UIF
DIBOHF

QSPCMFNT
&YBNQMFT
EFTDSJCFE
BSF
BDUVBM
PDDVSSFODFT
continues throughout the lifecycle.
FYQFSJFODFE
CZ
UIF
QBSUJDJQBUJOH
NBOBHFST
This discussion will include the following: The issue addressed in this case study occurs
t
#BDLHSPVOE
5IF
UZQJDBM
WBMJEBUJPO
PS
JO
TUFQ
OVNCFS

5IF
BDUVBM
XPSL
DPOEVDUFE
UP

RVBMJGJDBUJPO
QSPDFTT
JT
EFTDSJCFE DPOGJSN
UIF
BDDFQUBCJMJUZ
PG
UIF
WBMJEBUJPO
QSPKFDU
JT

t
7BMJEBUJPO
FWFOUT
%FTDSJQUJPOT
PG
TFWFSBM
BDUVBM
EPDVNFOUFE
CZ
UFDIOJDBM
QFPQMF
%PDVNFOUBUJPO

WBMJEBUJPO
FWFOUT NBZ
CF
BDDPNQMJTIFE
JO
B
WBSJFUZ
PG
XBZT
JODMVEJOH

t
8IBU
BSF
UIF
JTTVFT
"
TVNNBSZ
PG
UIF
QSPCMFNT
SFTFBSDI
OPUFCPPLT
JOEJWJEVBM
EBUB
TIFFUT

EFTDSJCFE FMFDUSPOJD
TZTUFNT
BOE
PUIFS
BDDFQUBCMF
NFUIPET

t
$PSSFDUJWF
BDUJPOT
BOE
QSFWFOUJWF
BDUJPOT
$"1"

5IFTF
SFTVMUT
BOE
EBUB
BSF
BWBJMBCMF
JO
UIF
WBMJEBUJPO

3FDPNNFOEFE
BDUJPOT
BOE
JNQSPWFNFOUT
UP
SFQPSU
FJUIFS
BT
DPQJFT
PG
PSJHJOBM
EPDVNFOUBUJPO

QSFWFOU
UIFTF
QSPCMFNT PS
SFUZQFE
JOUP
UIF
SFQPSU
0GUFO
IPXFWFS

EPDVNFOUBUJPO
JT
TVCTUBOEBSE
PS
OPU
BDDFQUBCMF
GPS
B

4QFDJGJD
DPNNFOUT
PO
WBMJEBUJPO
SFWJFX
QSBDUJDFT
WBSJFUZ
PG
SFBTPOT
USBJOJOH
BOE
NBOBHFNFOU
TVQQPSU
BSF
BMTP
QSPWJEFE
VALIDATION EVENTS
BACKGROUND "
EJTDVTTJPO
XJUI
TFWFSBM
WBMJEBUJPO
NBOBHFST

5IF
QSPDFTT
PG
WBMJEBUJPO
UZQJDBMMZ
DPNQSJTFT
UIF
SFHBSEJOH
QSPCMFNT
XJUI
WBMJEBUJPO
BDUJWJUJFT

GPMMPXJOH
TFRVFODF
PG
BDUJWJUJFT JOEJDBUFE
UIBU
UIF
EPDVNFOUBUJPO
PG
PSJHJOBM

1. Change desired.
"O
FRVJQNFOU
PS
QSPDFTT
EBUB
TUFQ
OVNCFS


XBT
B
TJHOJGJDBOU
QSPCMFN

DIBOHF
JT
OFFEFE
PS
SFRVJSFE
5IJT
NBZ
CF
B
4FWFSBM
BDUVBM
FYBNQMFT
EFTDSJCFE
CZ
UIF
NBOBHFST

OFDFTTBSZ
DIBOHF
PS
B
EFTJSBCMF
JNQSPWFNFOU EFNPOTUSBUF
UIF
NBHOJUVEF
PG
UIF
QSPCMFN


Development work.
"QQSPQSJBUF
1FSTPOOFM
SFDPSEJOH
EBUB
EJE
OPU
VOEFSTUBOE
UIF

EFWFMPQNFOU
XPSL
JT
DPNQMFUFE
JO
TVQQPSU
PG
UIF
JNQPSUBODF
PG
UIF
PSJHJOBM
UFTU
EBUB
JO
UIF
WBMJEBUJPO

change. process.

48 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta and Timothy J. Fields

Data Recording on Loose Paper 1SJNBSZ
EBUB
TIPVME
CF
SFDPSEFE
EJSFDUMZ
JOUP

7BMJEBUJPO
NBOBHFST
EFTDSJCFE
TJUVBUJPOT
JO
XIJDI
UIF
MBCPSBUPSZ
OPUFCPPL
PS
FMFDUSPOJD
EBUB
SFUSJFWBM

PSJHJOBM
EBUB
XFSF
SFDPSEFE
PO
JOEJWJEVBM
QJFDFT
PG
TZTUFNUIJT
JT
UIF
QVSQPTF
PG
TVDI
TZTUFNT
8IFO

iTDSBQ
QBQFSw
JF
VOCPVOE
VOBUUBDIFE
JOEJWJEVBM
asked why data were not directly recorded into the
TIFFUT
PG
QBQFS

%BUB
FJUIFS
SFNBJOFE
PO
UIFTF
MBCPSBUPSZ
OPUFCPPL
IF
SFTQPOEFE
UIBU
IF
EJEOU

TIFFUT
PS
XBT
DPQJFE
JOUP
MBCPSBUPSZ
OPUFCPPLT
XBOU
UP
HFU
UIF
OPUFCPPL
XFU
PS
EVTUZ
BT
NJHIU

PS
PUIFS
EPDVNFOUBUJPO
TZTUFNT
*G
USBOTGFSSFE
UP
IBQQFO
JO
UIF
NBOVGBDUVSJOH
FOWJSPONFOU
XIFSF

PUIFS
TZTUFNT
UIF
PSJHJOBM
EBUB
TIFFUT
XFSF
VTVBMMZ
the testing was done.
EJTDBSEFE
1FPQMF
SFDPSEJOH
EBUB
EJE
OPU
VOEFSTUBOE

UIBU
XIFSF
UIFZ
PSJHJOBMMZ
SFDPSE
EBUB
JT
B
QSJNBSZ
Erroneous Transcribed Data
EPDVNFOU
UIBU
NVTU
CF
SFUBJOFE "GUFS
DISPOPMPHJDBMMZ
PSHBOJ[JOH
UIF
iQBQFS

Data on paper bags.
0OF
WBMJEBUJPO
NBOBHFS
UPXFM
EBUB
TIFFUTw
EJTDVTTFE
BCPWF
PSJHJOBM
EBUB

EFTDSJCFE
BO
FWFOU
JO
XIJDI
B
QBDLBHJOH
QSPDFTT
XFSF
DPNQBSFE
UP
SFTVMUT
MJTUFE
JO
UIF
WBMJEBUJPO

FOHJOFFS
TVCNJUUFE
BO
FYDFMMFOU
SFQPSU
EFTDSJCJOH
UIF
SFQPSU
.PSF
UIBO

FSSPST
XFSF
GPVOEOVNCFS

WBMJEBUJPO
DPOGPSNBODF
SVOT
GPS
B
CMJTUFS
QBDLBHJOH
USBOTQPTJUJPOT
XSPOH
OVNCFST
BOE
PUIFS
QSPCMFNT

QSPDFTT
5IF
MJNJUT
PG
UIF
QSPDFTT
XFSF
DPOGJSNFE
$BSFMFTTMZ
XSJUUFO
PSJHJOBM
OVNCFST
DPOUSJCVUFE

1SPDFTTJOH
BU
UIF
DFOUFS
QPJOU
XBT
SFQMJDBUFE
UP
UP
UIF
QSPCMFN
JF
JT
UIF
OVNCFS
B

PS
B


5IF

EFNPOTUSBUF
SFQFBUBCJMJUZ
5IF
SFQPSU
XBT
XFMM
XSJUUFO
NBHOJUVEF
PG
UIF
FSSPST
XBT
OPU
TVGGJDJFOU
UP
DIBOHF

BOE
DPOUBJOFE
TFWFSBM
SFMFWBOU
JMMVTUSBUJPOT
"MM
EBUB
UIF
JOUFSQSFUBUJPO
PG
SFTVMUT
4UJMM
IPXFWFS
UIF

XFSF
TVQQMJFE
JO
BO
&YDFM
TQSFBETIFFU
XJUI
TUBUJTUJDBM
GJOBM
WBMJEBUJPO
SFQPSU
EJE
OPU
BDDVSBUFMZ
SFGMFDU
UIF

BOBMZTJT
JO
UIF
GJOBM
WBMJEBUJPO
SFQPSU
5IF
SFTVMUT
BDUVBM
UFTU
EBUB
%BUB
USBOTGFSSFE
UP
UIF
WBMJEBUJPO

QSPWFE
UIF
QSPDFTT
XBT
WBMJEBUFE
5IF
7"$
XBT
QMFBTFE
report was not checked for accuracy. There were
XJUI
UIF
DPOUFOU
BOE
RVBMJUZ
PG
UIF
WBMJEBUJPO
SFQPSU OP
TJHOBUVSFT
CZ
QFSTPOOFM
SFTQPOTJCMF
GPS
EBUB

5IF
FOHJOFFS
XBT
UIFO
BTLFE
UP
QSPWJEF
UIF
BDUVBM
USBOTGFS
PS
WFSJGJDBUJPO
PG
UIF
EBUB
CZ
B
TFDPOE

UFTU
EBUB
UIBU
XFSF
MJTUFE
JO
UIF
SFQPSU
)F
SFUVSOFE
QFSTPO
$IFDLJOH
EBUB
USBOTGFS
JT
UFEJPVT
XPSL

UP
UIF
DPOGFSFODF
SPPN
XJUI
B
TFSJFT
PG
QBQFS
CBHT
OPU
TPNFUIJOH
UIBU
DBO
CF
EPOF
RVJDLMZ
PS
XJUI
B

DPOUBJOJOH
CMJTUFS
QBDLBHFT
XJUI
UFTU
SFTVMUT
XSJUUFO
PO
superficial approach.
UIF
QBQFS
CBHT
5IF
EBUB
PO
UIF
CBHT
IBE
CFFO
DPQJFE

JOUP
&YDFM
B
QSJOUPVU
PG
XIJDI
XBT
BWBJMBCMF
JO
UIF
Data Responsibility
WBMJEBUJPO
SFQPSU 7BMJEBUJPO
NBOBHFST
SFQPSUFE
UIBU
QBHFT
DPOUBJOJOH

5IF
FOHJOFFS
IBE
CFFO
USBJOFE
PO
QSPQFS
SFDPSEJOH
PSJHJOBM
WBMJEBUJPO
EBUB
XFSF
PGUFO
OPU
TJHOFE
PS

PG
EBUB
JO
B
QFSNBOFOU
CPVOE
OPUFCPPL

)PXFWFS
EBUFE
CZ
QFSTPOOFM
XIP
SFDPSEFE
UIF
EBUB
"MTP

UIF
QSPEVDUJPO
BSFB
OFFEFE
UIF
NBDIJOF
GPS
UIFSF
XBT
OP
WFSJGJDBUJPO
PG
EBUB
CZ
B
TFDPOE
QFSTPO


DPNNFSDJBM
QSPEVDU
BOE
UIF
FOHJOFFS
EJE
OPU
IBWF
&YBNQMFT
EFTDSJCFE
BCPWF
JF
TDSBQ
QBQFS
CBHT

UJNF
UP
QSFQBSF
IJT
OPUFCPPL
UP
QSPQFSMZ
SFDPSE
UIF
BOE
QBQFS
UPXFM
FYBNQMFT

XFSF
OPU
TJHOFE
PS
EBUFE

UFTU
SFTVMUT
)F
XSPUF
UIF
UFTU
EBUB
PO
UIF
CBHT
EVF
UP
CZ
UIF
FOHJOFFS
OPS
XFSF
QBHFT
WFSJGJFE
CZ
B
TFDPOE

UJNF
DPOTUSBJOUT QFSTPO
8JUIPVU
WFSJGJDBUJPO
CZ
B
TFDPOE
QFSTPO

Data on paper towels.

"
TJNJMBS
FWFOU
XBT
there is no assurance that the work was actually
EFTDSJCFE
JOWPMWJOH
UBCMFU
IBSEOFTT
UFTUJOH
"HBJO
B
done.
WFSZ
UIPSPVHI
SFQPSU
DPOUBJOJOH
IVOESFET
PG
UBCMFU

IBSEOFTT
UFTU
SFTVMUT
XBT
QSFTFOUFE
GPS
WBMJEBUJPO
Error Corrections
BQQSPWBM
#FDBVTF
UIFSF
XBT
TP
NVDI
EBUB
JO
UIF
4FWFSBM
WBMJEBUJPO
NBOBHFST
DPNNFOUFE
PO
FSSPS

SFQPSU
UIF
7"$
BTLFE
UP
TFF
UIF
PSJHJOBM
EBUB
UP
DIFDL
DPSSFDUJPOT
JO
PSJHJOBM
EBUB
$IBOHFT
BSF
NBEF

GPS
DPOTJTUFODZ
CFUXFFO
UIF
UZQFXSJUUFO
SFQPSU
BOE
UIF
CZ
iTDSBUDIPVUT w
iDSPTTPVUT w
VTJOH
iXIJUF
PVUw

original data. DPSSFDUJPO
GMVJE
BOE
PUIFS
NFBOT
8IFO
NJTUBLFT

5IF
GPSNVMBUJPO
TDJFOUJTU
UIFO
QSFTFOUFE
IJT
XFMM BSF
NBEF
UIFZ
TIPVME
CF
DPSSFDUFE
CZ
MJOJOH
PVU

PSHBOJ[FE
BOE
QFSGFDUMZ
DMFBO
MBCPSBUPSZ
OPUFCPPL
UIF
FSSPOFPVT
SFTVMU
XJUI
B
TJOHMF
MJOF
BOE
UIFO

UP
UIF
7"$
8IFO
BTLFE
IPX
IF
XBT
BCMF
UP
NBJOUBJO
BEEJOH
UIF
DPSSFDU
WBMVF
OFBS
UIF
FSSPOFPVT
WBMVF
"

TVDI
B
OFBU
OPUFCPPL
UIF
TDJFOUJTU
EFTDSJCFE
IJT
DMFBS
BOE
DPODJTF
FYQMBOBUJPO
PG
UIF
NJTUBLF
TIPVME

NFUIPE
PG
SFDPSEJOH
EBUB
PO
TFQBSBUF
TIFFUT
PG
QBQFS
CF
XSJUUFO
OFBS
UIF
DIBOHFT
7BMJEBUJPO
NBOBHFST

UIFO
USBOTGFSSJOH
UIF
EBUB
UP
IJT
OPUFCPPL

)F
XBT
DPNQMBJOFE
UIBU
FYQMBOBUJPOT
PG
NJTUBLFT
XFSF
PGUFO

UIFO
BTLFE
UP
TIPX
UIF
7"$
UIF
PSJHJOBM
EBUB
)F
DPNQMFUFMZ
BCTFOU
PS
XFSF
QPPSMZ
XSJUUFO
SFUVSOFE
XJUI
B
IBOEGVM
PG
XFU
BOE
DSVNQMFE
QBQFS

UPXFMT
UIBU
IF
XBT
BCMF
UP
SFDPWFS
GSPN
UIF
USBTI
5IFTF
Data Incomplete
QBQFS
UPXFMT
DPOUBJOFE
UIF
UBCMFU
IBSEOFTT
UFTU
data. "
WBMJEBUJPO
NBOBHFS
EFTDSJCFE
BO
JODJEFOU
JO
XIJDI

BO
FOHJOFFS
XBT
BTTJHOFE
B
QSPKFDU
UP
RVBMJGZ
GJWF

PROCESS VALIDATION Continued Process Verification 49

Paul L. Pluta and Timothy J. Fields

OFX
NFUBM
EFUFDUPST
UIBU
SFQMBDFE
PCTPMFUF
NFUBM
UFNQFSBUVSF
PG
$
"DUVBM
UFTUJOH
JOEJDBUFE
UIBU
B

EFUFDUPST
BU
UIF
TJUF
"
WBMJEBUJPO
QMBO
XBT
EFWFMPQFE
NBYJNVN
UFNQFSBUVSF
PG
POMZ
$
XBT
QPTTJCMF

BOE
BQQSPWFE
CZ
UIF
TJUF
7"$
'JWF
JOEJWJEVBM
5IF
FOHJOFFS
DIBOHFE
UIF
QSPUPDPM
GSPN
$
UP

JEFOUJDBM
QSPUPDPMT
XFSF
QSFQBSFE
BOE
BQQSPWFE
5IF
$
BOE
SFDPSEFE
i1BTTw
PO
UIF
EBUB
QBHF
$IBOHFT

GJSTU
VOJU
XBT
UFTUFE
BOE
UIF
WBMJEBUJPO
SFQPSU
XBT
XFSF
NBEF
XJUIPVU
DPOTVMUJOH
TVQFSWJTPST
PS

XSJUUFO
"MM
EBUB
XFSF
UZQFXSJUUFO
JOUP
UIF
SFQPSU
JOWFTUJHBUJOH
UIF
SFBTPO
GPS
UIF
QSPCMFN
5IF
7"$
BQQSPWFE
UIF
SFQPSU Missing equipment?
"OPUIFS
JODJEFOU
XBT

5IF
TFDPOE
VOJU
XBT
UFTUFE
BOE
UIF
WBMJEBUJPO
EFTDSJCFE
JO
XIJDI
UIF
QSPUPDPM
SFRVJSFE
UFTUJOH

SFQPSU
XBT
XSJUUFO
5IF
WBMJEBUJPO
QSPUPDPM
GPS
VOJU
UISFF
WJTJPO
TZTUFNT
JOTUBMMFE
PO
B
QBDLBHJOH

OVNCFS
UXP
XBT
JEFOUJDBM
UP
VOJU
OVNCFS
POF
CVU
MJOF
5IF
FOHJOFFS
DIBOHFE
UIF
SFRVJSFNFOU
UP

BMM
UFTUJOH
TIPVME
IBWF
CFFO
DPOEVDUFE
VTJOH
VOJU
iUXPw
TZTUFNT
FYQMBJOJOH
UIBU
UIF
MJOF
POMZ
IBE

OVNCFS
UXP
8IFO
UIF
7"$
SFWJFXFE
UIF
EBUB
UIFZ
UXP
TZTUFNT
JOTUBMMFE
BOE
UIBU
iUISFFw
XBT
B

OPUFE
UIBU
UIF
UFTU
EBUB
TIFFUT
XFSF
MBCFMFE
XJUI
UZQPHSBQIJDBM
FSSPS
*O
USVUI
UIF
UIJSE
TZTUFN
IBE

NFUBM
EFUFDUPS
OVNCFS
POF
BU
UIF
UPQ
PG
UIF
QBHF
CFFO
TFOU
UP
UIF
NBJOUFOBODF
TIPQ
GPS
SFQBJST
5IF

5IF
FOHJOFFS
TBJE
UIBU
CFDBVTF
UIF
VOJUT
XFSF
BMM
UIF
FOHJOFFS
XBT
HPJOH
PO
WBDBUJPO
BOE
DPVME
OPU
EFMBZ

TBNF
UIFSF
XBT
OP
OFFE
UP
SFQFBU
UIF
UFTUJOH
5IF
DPNQMFUJPO
PG
UIF
WBMJEBUJPO
XPSL
5IF
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50 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta and Timothy J. Fields

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PROCESS VALIDATION Continued Process Verification 51

Paul L. Pluta and Timothy J. Fields

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PSJHJOBM

FNQIBTJ[F
UIF
JNQPSUBODF
PG
HPPE
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TIPVME

UP
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BDUJWJUJFT
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package.
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TRAINING
and in the spoken word. 5IF
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NBZ

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PS
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PG

VALIDATION POLICY AND PRACTICE TFWFSBM
QSPDFEVSFT
JO
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7BMJEBUJPO
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PG
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BTTPDJBUFE
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XJUI
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PG
GVOEBNFOUBM

QSBDUJDFT
XFSF
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BOE
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OPODPNQMJBODF

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BOE
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BSF
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Review of Original Data by the VAC as Part OPU
BT
GBNJMJBS
XJUI
EBUBSFDPSEJOH
QSPDFEVSFT

of Validation Report Approval Processes BT
RVBMJUZ
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2"

PS
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MBC

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DPOUBJOJOH
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PO
NBZ
CF
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BMTP
CF
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this purpose.
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5IF
7"$
GVODUJPOT
BT
TVSSPHBUF

52 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta and Timothy J. Fields

BVEJUPST
PG
WBMJEBUJPO
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5IFZ
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PG
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when original data are reproduced in reports.
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CF
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PG
BOZ
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SFWJFX "QQSPWBM
PG
EPDVNFOUT
DPOUBJOJOH
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TIPVME
BMXBZT
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PG

SENIOR MANAGEMENT SUPPORT original data.
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BOZ
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QPMJDZ
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occurrences.
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CONCLUSIONS FMFDUSPOJD
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PG
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BOE

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PG
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GPS
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JO

NVMUJUVEF
PG
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BTTPDJBUFE
EPDVNFOUBUJPO
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JT
B
OFDFTTJUZ
5SBJOJOH

XJUI
PSJHJOBM
WBMJEBUJPO
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7BMJEBUJPO
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CF
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SFQFBUFE
UP
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EBUB
BSF
PGUFO
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CZ
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and encourage proper practice.
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BOE
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2"
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B
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expected standards. JVT
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BOE
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ARTICLE ACRONYM LISTING
BSF
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UP
WBMJEBUJPO
EPDVNFOUBUJPO
CAPA Corrective Action and Preventive Action
#FDBVTF
WBMJEBUJPO
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UP
GMP Good Manufacturing Practice
CF
SFWJFXFE
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BVEJUPST
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QA Quality Assurance
EPDVNFOUBUJPO
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SBNJGJDBUJPOT
VAC Validation Approval Committee
UP
UIF
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BOE
NBZ
HSFBUMZ
JOGMVFODF
UIF

PVUDPNF
PG
BO
BVEJU

0SJHJOBMMZ
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JO
UIF
8JOUFS

JTTVF
PG
The Journal of Validation Technology

PROCESS VALIDATION Continued Process Verification 53

David LeBlond

Using Probability Distributions

to Make Decisions
David LeBlond

8FMDPNF
+75
SFBEFST
UP
i4UBUJTUJDBM
7JFXQPJOUw
KEY POINTS

5IJT
DPMVNO
QSFTFOUT
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5IJT
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PG
i4UBUJTUJDBM
7JFXQPJOUw

VTFGVM
UP
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JO
DPNQMJBODF
BOE
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FYBNQMF
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JU
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CFDPNF
B
VTFGVM
EFNPOTUSBUF
IPX
B
QSPCBCJMJUZ
BQQSPBDI
DBO

resource. Barriers to the understanding and IFMQ
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BOE
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VTF
PG
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JO
B
NFBOJOHGVM
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TP
UIBU
including their corresponding applications is
PVS
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UPQJDT
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*
BOE
**
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UP
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DPODFQUT
UP
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PG
UIF
BQQSPQSJBUF
EJTUSJCVUJPO
NPEFM
GPS

situations. DBMDVMBUJPOT
JT
CBTFE
PO
UIF
NPEFMT
BQQMJDBUJPO

3FBEFS
DPNNFOUT
RVFTUJPOT
BOE
TVHHFTUJPOT
iTUPSZw

5IFTF
UPPMT
FOBCMF
RVBOUJGJBCMF

BSF
OFFEFE
UP
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VT
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UP
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BSF
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BSF
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UP
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INTRODUCTION
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GPS
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DPMVNO
5IF
GJSTU
JOTUBMMNFOU
PG
i4UBUJTUJDBM
7JFXQPJOUw

$BTF
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UIF
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JTTVF
PG
UIF

NPTU
XFMDPNF

8F
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Journal of GXP Compliance 

BOE
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CBTJD

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PG
BMM

[
For more Author ABOUT THE AUTHOR
information, David LeBlond, Ph.D., has 29 years experience in the pharmaceutical and medical diagnostics
go to ivthome.com/ fields. He is currently a principal research statistician supporting analytical and pharmaceutical
bios development at Abbott. David can be reached at David.LeBlond@abbott.com.

54 PROCESS VALIDATION Continued Process Verification

 David LeBlond

Table I: Some common discrete distributions.

Distribution Excel function Distribution Story
Binomial M or P =BINOMDIST(X,,,*) A jar contains a very large (i.e., infinite) number of tablets. A known
proportion, , of the tablets are defective. We randomly select
tablets from the jar and measure X, the number in this sample that
are defective.
Bernoulli M or P =BINOMDIST(X,1,,*) Same as binomial with the sample size, = 1.
Hypergeometric M=HYPGEOMDIST(X,,K,N) K of the N tablets in a jar are known to be defective. We randomly
select tablets and measure X, the number in this sample that are
defective.
Negative binomial M=NEGBINOMIST(X,,) A lot manufacturing process has a known probability of success,
on each run. We run the process until we make good lots and
measure X, the number of failed lots produced.
Poisson M or P = POISSON(X, , *) A batch of well blended, fine, white powder is contaminated with
tiny black specks. The true mean number of black specks per unit
volume is . We randomly sample a unit volume and measure X,
the number of black specks in the sample.
*FALSE produces the probability, M, of observing exactly X (probability mass function). TRUE produces the probability, P, of observing X or less (cu-
mulative probability mass function).

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STABILITY RISK USING NORMAL PRIOR
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opinions.
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JT
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UPPM
PG
DIPJDF
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UP
QSPCF
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UIF
QSJPS

QSPCBCJMJUZ
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PG
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UFBN

NBLFST
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UIF
GBDU
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QSPCBCJMJUZ
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NFNCFST
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GFFMT
B
CFUUFS
TUVEZ
QMBO
XJMM
SFTVMU

GVODUJPOT
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FJHIU
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TJUVBUJPOT
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UIF
GPMMPXJOH
BEWJDF
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,FMWJO

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UIF
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PG
B
QSPCBCJMJTUJD
BQQSPBDI


1MFBTF
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QSPCMFNT
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... when you can measure what you are speaking
professional help. It is always wise to consult a about and express it in numbers, you know
USBJOFE
TUBUJTUJDJBO
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something about it, but when you cannot ... express
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PG
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it in numbers, your knowledge is of a meager and
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VODMFBS

unsatisfactory kind ...

PROCESS VALIDATION Continued Process Verification 55

David LeBlond

Table II: Some common continuous distributions.

Distribution Excel function Distribution Story
Normal or D or P =NORMDIST(X,,,*) In the manufacture of a drug lot, an amount of API exactly needed
Gaussian to achieve the desired potency, , is added. However a large (i.e.,
X = NORMINV(P,,) infinite) number of subsequent processing steps (e.g., weighing and
= + *NORMINV(P,,1) adding various excipients) each produce small, random increases
or decreases in final lot potency. The net effect produces a stan-
dard deviation of about the mean of . Make a lot and measure
the observed potency X.
Lognormal P=LOGNORMDIST(X,,) The measured response, X, of an analytical test is the multiplicative
product of the effects of many small, independent factors (volumes,
X=LOGINV(P,,) path-length, etc). The natural log of X follows a normal distribution
with mean and standard deviation .
Exponential D or P=EXPONDIST(X,,*) An electrical supply system experiences occasional random black-
outs. The long term mean blackout frequency is known to be con-
X = -LN(1-P)/ stant, . Measure X, the time between blackouts.
Gamma D or P =GAMMADIST(X,,1/,*) Same as the Exponential above, except measure X, the time re-
quired for 1 blackouts to occur.
X=GAMMAINV(P,,1/)
Weibull D or P =WEIBULL(X,,1/,*) Same as the Exponential above except the long term mean black-
out frequency is not constant but increases or decreases over time
X = =(-LN(1-P)/)^(1/) according to the parameter >0. Measure X, the time between
blackouts.
Beta P = BETADIST(X,,+1,0,1) A very large lot of tablets is known to contain defects. Tablets are
sampled randomly from the lot until defective tablets have been
X = BETAINV(P,,+1,0,1) found. Measure X, the fraction of the lot tested.
Rectangular or P=X Same as the Beta, with = = 1.
Uniform D=1
Chi-squared P = 1-CHIDIST(X,1) A sample of size is taken from a normal random variable with
known standard deviation = . The sample variance (V=square of
D = GAMMADIST(X,(1)/2,2,TRUE) the standard deviation) is calculated. Measure X=(1)V/ 2.
X = CHIINV(1P,1)
Students-t if X<0 A sample of size is taken from a normal population with
P = TDIST(ABS(X),1,1) mean = 0. The sample average, X , and standard deviation, s, are
calculated. X
if X0 Measure X = s/ .
P = 1-TDIST(X,1,1)

if 0.5 P < 1
X = TINV(2*(1-P),1)

if 0 < P < 0.5

X = -TINV(2*P, 1)
F P = 1-FDIST(X,1, 1) A sample of size is taken from a normal population and the vari-
ance (V1) is calculated. A second sample of size is also taken
X = FINV(1 - P,1,1) from the same population and the variance (V2) is calculated. Mea-
sure X = V1/V2 .
*FALSE produces the probability of density, D, of observing exactly X. TRUE produces the probability, P, of observing x or less (cumulative probabil-
ity density function).

#PUI
DIFNJTUT
BHSFF
UIBU
UIF
BDUJWF
UIFSFGPSF
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FYQSFTT
UIFJS

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PG
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#PUI
PG


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PG
UIF
NFBO
QPUFODZ
MPTT

56 PROCESS VALIDATION Continued Process Verification

 David LeBlond

"GUFS
DBSFGVM
UIPVHIU
CPUI
DIFNJTUT
BHSFF
UIBU

Figure 1: Estimates of the mean and standard deviations
PO
BWFSBHF
QSPEVDU
MPUT
TIPVME
MPTF
BCPVU

VOJUT

using MS Excel function NORMDIST.
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) = +
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0.2

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0
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=

True potency loss on 24 month storage
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=

/03.*/7   




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and are known precisely.
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[POF
$

PROCESS VALIDATION Continued Process Verification 57

David LeBlond

Figure 2: Four common control chart rules. #*/0.%*45    '"-4&

=


*U
DBO
CF
TFFO
UIBU
UIF
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3
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the center line.
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UNIFORMITY FAILURE RISK USING THE

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also fail on the upper side of the chart and so the B
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 on the lower side NVTU
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o

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=
 PG

NH
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UIF

5IF
FSSPS
QSPCBCJMJUJFT
GPS
SVMFT

BOE

NBZ
CF

o

NH
SBOHF
DBO
CF
DBMDVMBUFE
BT
GPMMPXT
PCUBJOFE
TJNJMBSMZ
BT
GPMMPXT

3VMF

GBMTF
BMBSN
SBUF
=
/03.%*45    536&

+1

#*/0.%*45  
/03.%*45    536&

=

/03.%*45    536&
'"-4&

=

4JNJMBS
UP
UIF
DPOUSPM
DIBSU
FYBNQMF
HJWFO
BCPWF


3VMF

GBMTF
BMBSN
SBUF
= UIF
QSPCBCJMJUZ
PG
PCUBJOJOH

PS
NPSF
PVU
PG
SBOHF

58 PROCESS VALIDATION Continued Process Verification

 David LeBlond

UBCMFUT
JO
B
SBOEPN
TBNQMF
PG

XJMM
GPMMPX
B

Figure 3: Scaled probability density plots.
DBUFHPSJDBM
CJOPNJBM
EJTUSJCVUJPO
TFF
5BCMF
*


BOE

XF
DBO
PCUBJO
UIF
CBUDI
GBJMVSF
SBUF
BT
0.18

1
#*/0.%*45  
 536&

=
 0.16
True SD=0.5
0.14

Probability density
True SD=0.7
5IVT
GVUVSF
CBUDIFT
DBO
CF
FYQFDUFE
UP
GBJM
UIF
0.12
JOQSPDFTT
DPOUFOU
VOJGPSNJUZ
UFTU

PG
UIF

0.1
UJNF
0.08
ASSESSING THE SUITABILITY OF 0.06
ANALYTICAL METHODS USING THE CHI- 0.04
SQUARED DISTRIBUTION
0.02
*O
UIJT
TDFOBSJP
UXP
IJHIQSFTTVSF
MJRVJE

DISPNBUPHSBQIZ
)1-$

BOBMZUJDBM
NFUIPET
BSF
0
CFJOH
EFWFMPQFE
*U
JT
EFDJEFE
UIBU
TJY
DPOUSPM
0 0.5 1.0 1.5 2.0
TBNQMFT
XJMM
CF
SVO
XJUI
FBDI
BOBMZUJDBM
SVO
5P

Observed variance
NFFU
UIF
TZTUFN
TVJUBCJMJUZ
SFRVJSFNFOUT
JF
GPS

UIF
SFTVMUT
PG
VOLOPXO
TBNQMFT
JO
UIBU
SVO
UP
CF

SFQPSUBCMF

UIF
PCTFSWFE
TUBOEBSE
EFWJBUJPO
PG

UIFTF
O


SFQMJDBUF
UFTUT
NVTU
CF
OP
NPSF
UIBO
EPFT
OPU
TVQQMZ
B
$IJTRVBSFE
EFOTJUZ
GVODUJPO


PG
UIF
OPNJOBM
DPOUSPM
DPODFOUSBUJPO
"
TZTUFN
4VDI
GVODUJPOT
BSF
BWBJMBCMF
JO
TPGUXBSF
TVDI

TVJUBCJMJUZ
GBJMVSF
JT
DPTUMZ
JO
UFSNT
PG
BOBMZTU
BT
4"4
+.1
PS
3
%JSFDU
DBMDVMBUJPO
PG
UIF
$IJ
UJNF
BOE
SFBHFOUT
'VSUIFS
BOBMZUJDBM
FRVJQNFOU
TRVBSFE
EFOTJUZ
JT
QPTTJCMF
CVU
RVJUF
DPNQMJDBUFE

JT
MJNJUFE
$POTFRVFOUJBMMZ
QSPQFS
SFTPVSDF
'PSUVOBUFMZ
UIF
$IJTRVBSFE
EJTUSJCVUJPO
JT
B

NBOBHFNFOU
SFRVJSFT
UIF
BCJMJUZ
UP
BOUJDJQBUF
UIF
TQFDJBM
DBTF
PG
UIF
DPOUJOVPVT
(BNNB
EJTUSJCVUJPO

SBUF
PG
TZTUFN
TVJUBCJMJUZ
GBJMVSFT TFF
5BCMF
**

TVDI
UIBU

5IF
UXP
BOBMZUJDBM
NFUIPET
BSF
WFSZ
BDDVSBUF

CVU
IBWF
XJUIJO
SVO
TUBOEBSE
EFWJBUJPOT
) of
IJTRVBSFE
QSPCBCJMJUZ
EFOTJUZ

$

BOE

SFTQFDUJWFMZ
*O
CPUI
DBTFT
UIF
=
(".."%*45 
7

  536&

XJUIJO
SVO
EFWJBUJPOT
GSPN
UIF
FYQFDUFE
DPOUSPM

WBMVF
BSF
EJTUSJCVUFE
OPSNBMMZ
5IJT
TVHHFTUT
UIBU
5IJT
FRVBUJPO
XBT
VTFE
UP
HFOFSBUF
UIF
TDBMFE

B
DPOUJOVPVT
$IJTRVBSFE
EJTUSJCVUJPO
NJHIU
CF
QSPCBCJMJUZ
EFOTJUZ
QMPUT
TIPXO
JO
'JHVSF

XJUI
7

VTFE
UP
EFTDSJCF
UIF
EJTUSJCVUJPO
PG
UIF
XJUIJO
SVO
QMPUUFE
PO
UIF
IPSJ[POUBM
BYJT
5IF
FYDFTTJWF
GBJMVSF

WBSJBODF
JF
7
UIF
TRVBSF
PG
UIF
PCTFSWFE
TUBOEBSE
rate with the second assay is clearly due to the fact
EFWJBUJPO
 UIBU
UIF
$IJTRVBSFE
EFOTJUZ
UFOET
UP
IBWF
B
MPOH

5IF
$IJTRVBSFE
iTUPSZw
EFTDSJCFT
TBNQMJOH
GSPN
SJHIU
UBJM
JF
JT
SJHIU
TLFXFE

XIFO

JT
TNBMM
B
OPSNBM
QPQVMBUJPO
XIPTF
TUBOEBSE
EFWJBUJPO
JT


TFF
5BCMF
**

5IJT
QBSBNFUFS
DPSSFTQPOET
UP
UIF
SETTING A PRECISION SPECIFICATION
XJUIJO
TUBOEBSE
EFWJBUJPOT
PG

PS

5IVT
LIMIT FOR AN ANALYTICAL METHOD
UIF
QSPCBCJMJUZ
PG
FYDFFEJOH
UIF

MJNJU
DBO
CF
TRANSFER USING THE F DISTRIBUTION
DBMDVMBUFE
GPS
UIF
UXP
BOBMZUJDBM
NFUIPET
BT
GPMMPXT 8IFO
BO
BOBMZUJDBM
NFUIPE
JT
USBOTGFSSFE
GSPN


'BJMVSF
SBUF
GPS
GJSTU
NFUIPE
POF
MBCPSBUPSZ
UP
BOPUIFS
JUT
VTF
JO
UIF
TFDPOE

=$)*%*45 
??
1) =
 MBCPSBUPSZ
NVTU
GJSTU
CF
WBMJEBUFE
5IJT
JT
UP
BTTVSF

UIBU
EJGGFSFOU
BOBMZTUT
VTJOH
EJGGFSFOU
FRVJQNFOU

'
BJMVSF
SBUF
GPS
TFDPOE
NFUIPE BOE
SFBHFOUT
BOE
QPTTJCMZ
TMJHIUMZ
EJGGFSFOU

=$)*%*45 
??



 QSPDFEVSFT

DBO
BDIJFWF
UIF
TBNF
BOBMZUJDBM

QFSGPSNBODF
"
LFZ
FMFNFOU
PG
QFSGPSNBODF

4VSQSJTJOHMZ
UIF
TNBMM
JODSFBTF
JO
USVF
TUBOEBSE
GPS
RVBOUJUBUJWF
BTTBZT
JT
QSFDJTJPO
BT
NFBTVSFE

EFWJBUJPO
GSPN

UP

SFTVMUT
JO
OFBSMZ
B
CZ
NFUIPE
TUBOEBSE
EFWJBUJPO
0OF
HPBM
PG
B

GPME
JODSFBTF
JO
TZTUFN
TVJUBCJMJUZ
GBJMVSF
SBUF
NFUIPE
USBOTGFS
QSPUPDPM
JT
UIFSFGPSF
UP
NBLF
B

5IF
TFDPOE
BTTBZ
XPVME
GBJM
OFBSMZ

PVU
PG
FWFSZ
TUBUJTUJDBM
DPNQBSJTPO
PG
TUBOEBSE
EFWJBUJPOT
5IF


BOBMZUJDBM
SVOT QFSGPSNBODF
NFUSJD
NJHIU
CF
B
SBUJP
PG
UIF
UXP

*U
JT
PGUFO
JOTUSVDUJWF
UP
BDUVBMMZ
QMPU
UIF
PCTFSWFE
TUBOEBSE
EFWJBUJPOT
UFTUDPOUSPM


QSPCBCJMJUZ
EFOTJUZ
GVODUJPO
UP
TFF
UIF
TIBQF
PG
*G
UIJT
QFSGPSNBODF
NFUSJD
JT
TRVBSFE
UIF

UIF
TBNQMJOH
EJTUSJCVUJPO
6OGPSUVOBUFMZ
&YDFM
SFTVMUJOH
TUBUJTUJD
JT
B
SBUJP
PG
UXP
WBSJBODFT
5IJT

PROCESS VALIDATION Continued Process Verification 59

David LeBlond

Figure 4: Cumulative F distribution. XBOUT
UP
CF
BU
MFBTU

TVSF
UIBU
B
GBJMVSF
XPVME

OPU
PDDVS
CZ
TJNQMF
SBOEPN
DIBODF
POF
TIPVME

DPOTJEFS
BDDFQUBODF
MJNJUT
GPS
UIF
'
SBUJP
BCPWF


1
4QFDJGJDBMMZ
JU
DBO
CF
TIPXO
UIBU
0.9
Cumulative probability density

0.8 1'%*45   1) =


0.7
*G
POF
VTFT
BO
BDDFQUBODF
MJNJU
PG


0.6 DPSSFTQPOEJOH
UP
B
TUBOEBSE
EFWJBUJPO
SBUJP
PG

0.5 
UIF
QSPUPDPM
DSJUFSJPO
GPS
QSFDJTJPO
XJMM
IBWF
B

GBMTF
BMBSN
SBUF
PG
MFTT
UIBO

CFDBVTF
PG
SBOEPN

0.4
DIBODF
BMPOF
5IF
BDDFQUBODF
DSJUFSJPO
DBO
CF

0.3 SFEVDFE
CZ
JODSFBTJOH
UIF
OVNCFS
PG
SFQMJDBUFT
GPS

0.2 FBDI
MBCPSBUPSZ
SVO
5IVT
UIF
'
EJTUSJCVUJPO
DBO
CF

VTFE
UP
TFMFDU
CPUI
UIF
SFRVJSFE
TBNQMF
TJ[F
BOE
UIF

0.1
decision criterion.
0 /PUF
UIBU
UIF
'
UFTU
EFTDSJCFE
BCPWF
JT
B
POF
0 2 4 6 TJEFE
UFTU
8F
IBWF
DMFBSMZ
EFGJOFE
PVS
'
SBUJP

Observed variance ratio UFTUDPOUSPM

BOE
XF
POMZ
BSF
DPODFSOFE
BCPVU

(test/control) GBJMVSFT
PO
UIF
IJHI
TJEF
MBSHF
'
WBMVFT

*G
XF

XFSF
DPODFSOFE
BCPVU
UFTUJOH
GPS
FRVBMJUZ
PG
UIF

WBSJBODFT
XF
XPVME
BMTP
CF
DPODFSOFE
XJUI
GBJMVSFT

PO
UIF
MPX
TJEF
TNBMM
'
WBMVFT

*O
UIF
MBUUFS
DBTF

TUBUJTUJD
JT
EFOPUFE
'
BGUFS
UIF
&OHMJTI
TDJFOUJTU
4JS
XF
XPVME
OFFE
UP
DPOTUSVDU
B
UXPTJEFE
UFTU
UP

3POBME
'JTIFS
XIP
GJSTU
UBCVMBUFE
JUT
TBNQMJOH
detect significant differences of either kind.
EJTUSJCVUJPO
*G
UIF
WBSJBODFT
QSPEVDFE
CZ
UIF
UFTU

BOE
DPOUSPM
MBCPSBUPSJFT
BSF
JO
GBDU
USVMZ
FRVBM
BOE
SETTING A SPECIFICATION LIMIT FOR
JG
UIF
WBSJBUJPO
PG
NFBTVSFNFOUT
JT
EJTUSJCVUFE
A POWDER BLEND VALIDATION USING
OPSNBMMZ
UIFO
UIF
TJUVBUJPO
NBUDIFT
UIF
THE POISSON DISTRIBUTION
'EJTUSJCVUJPO
iTUPSZw
TFF
5BCMF
**

BOE
XF
NBZ
VTF
"
QPXEFS
CMFOEJOH
QSPDFTT
NVTU
CF
WBMJEBUFE
UP

UIF
'EJTUSJCVUJPO
UP
TFU
B
TUBUJTUJDBM
BDDFQUBODF
MJNJU
BTTVSF
UIBU
UIF
QSPDFTT
EJTUSJCVUFT
UIF
JOHSFEJFOUT

GPS
UIF
QSFDJTJPO
DSJUFSJPO
JO
UIF
NFUIPE
USBOTGFS
FWFOMZ
UISPVHIPVU
UIF
CBUDI
5IF
CMFOE
DPOTJTUT

protocol. of two white ingredients whose particles are of
$POTJEFS
B
WFSZ
TJNQMF
QSPUPDPM
GPS
BTTFTTNFOU
FRVBM
XFMMDPOUSPMMFE
TJ[F
BOE
IBWF
WFSZ
TJNJMBS

PG
QSFDJTJPO
&BDI
MBCPSBUPSZ
UFTUT

SFQMJDBUFT
QIZTJDBM
QSPQFSUJFT
"O
FOHJOFFS
IBT
EFDJEFE
UP

PG
B
DFSUBJO
DPOUSPM
BOE
EFUFSNJOFT
UIF
WBSJBODF
VTF
IJT
OFXGPVOE
VOEFSTUBOEJOH
PG
QSPCBCJMJUZ

PG
UIFTF

SFQMJDBUFT
5IFO
UIF
'WBSJBODF
SBUJP
JT
EJTUSJCVUJPOT
UP
TJNQMJGZ
UIF
WBMJEBUJPO
USJBMT
)F

DBMDVMBUFE
UFTUDPOUSPM

5IF
QSFDJTJPO
DSJUFSJB
QBTT
QMBOT
UP
JODMVEF
B
USBDF
BNPVOU
PG
B
UIJSE
JOFSU

BT
MPOH
BT
UIF
SBUJP
JT
BU
PS
CFMPX
TPNF
MJNJU
*G
UIF
JOHSFEJFOU
BMTP
PG
FRVBM
QBSUJDMF
TJ[F
BOE
QIZTJDBM

MJNJU
JT
TFU
UPP
MPX
UIF
DSJUFSJPO
XPVME
GBJM
UPP
QSPQFSUJFT
FYDFQU
UIBU
UIF
QBSUJDMFT
BSF
CMBDL
5IFZ

PGUFO
TJNQMZ
CZ
SBOEPN
DIBODF
5IF
MJNJU
TIPVME
DBO
CF
FBTJMZ
JEFOUJGJFE
BOE
DPVOUFE
JO
B
HSBN
PG

CF
TFU
IJHI
FOPVHI
CVU
OPU
UPP
IJHI

TVDI
UIBU
QPXEFS
CZ
FZF
VTJOH
B
NBHOJGZJOH
HMBTT
B
QSPUPDPM
GBJMVSF
HJWFT
B
CPOB
GJEF
JOEJDBUJPO
PG
5IF
FOHJOFFS
SFBTPOT
UIBU
JG
UIF
CMFOEJOH
JT

QSFDJTJPO
JOGFSJPSJUZ
JO
UIF
UFTU
MBCPSBUPSZ
8IBU
XF
FWFO
UIF
EJTUSJCVUJPO
PG
CMBDL
iTQFDLTw
JO
UIF

SFBMMZ
XBOU
UP
LOPX
JT
UIF
QSPCBCJMJUZ
PG
PCUBJOJOH
GJOBM
CMFOE
TIPVME
GPMMPX
B
DBUFHPSJDBM
1PJTTPO

BO
'SBUJP
CFMPX
TPNF
MJNJU
*O
PUIFS
XPSET
XF
EJTUSJCVUJPO
TFF
UIF
1PJTTPO
iTUPSZw
JO
5BCMF

XBOU
UP
LOPX
UIF
DVNVMBUJWF
'
EJTUSJCVUJPO
5IF
*

)F
QMBOT
UP
JOUSPEVDF
FOPVHI
PG
UIF
USBDF

DVNVMBUJWF
'
EJTUSJCVUJPO
GPS
B
SBUJP
PG
WBSJBODFT
JOHSFEJFOU
TP
UIBU
B
HSBN
PG
UIF
GJOBM
QPXEFS

FBDI
PCUBJOFE
GSPN
SFQMJDBUFT
PG

JT
HJWFO
BT
XJMM
DPOUBJO
PO
BWFSBHF

CMBDL
TQFDLT
5IF

follows: UFTU
GPS
FBDI
CBUDI
XJMM
DPOTJTU
PG
DBSFGVMMZ

SFNPWJOH
FYBDUMZ

HSBN
PG
QPXEFS
GSPN
B


SPCBCJMJUZ
UIBU
PCTFSWFE
'
SBUJP
JT

9


1 SBOEPN
MPDBUJPO
JO
UIF
CMFOEFE
CFE
VTJOH
B

1
'%*45 9  1) UIJFG
BOE
DPVOUJOH
UIF
OVNCFS
PG
CMBDL
TQFDLT

PCTFSWFE
JO
UIF
TBNQMF
*G
NVDI
GFXFS
PS
NVDI

5IJT
DVNVMBUJWF
EJTUSJCVUJPO
JT
TIPXO
JO
'JHVSF

HSFBUFS
UIBO

TQFDLT
BSF
TFFO
UIF
CBUDI
XJMM
CF

XJUI
UIF
SBUJP
'
HJWFO
PO
UIF
IPSJ[POUBM
BYJT
*G
POF
KVEHFE
UP
GBJM
UIF
CMFOE
VOJGPSNJUZ
WBMJEBUJPO

60 PROCESS VALIDATION Continued Process Verification

 David LeBlond

Figure 5: Probability mass function.

0.100

0.090

Probability mass
0.080

0.070

0.060

0.050

0.040

0.020
0.010

0.000
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Observed number of specs per sample

5IVT
UIF
UFTU
XJMM
CF
UXPTJEFE
5IF
RVFTUJPO
JT
Figure 6: Cumulative distribution function of t.

XIBU
MPXFS
BOE
VQQFS
MJNJUT
TIPVME
CF
QMBDFE

PO
UIF
CMBDL
TQFDL
DPVOU
5IF
MJNJU
TIPVME
CF
1
TFU
XJEF
FOPVHI
UP
BWPJE
GBJMJOH
UIF
DSJUFSJPO

CZ
SBOEPN
DIBODF
BMPOF
ZFU
OPU
TP
XJEF
UIBU
0.9
Cumulative probability density

JNQPSUBOU
MFWFMT
PG
TUSBUJGJDBUJPO
JO
UIF
CMFOE
BSF
0.8
NJTTFE
*O
DIPPTJOH
UIF
MJNJUT
JU
DBO
CF
IFMQGVM

UP
MPPL
BU
UIF
FYQFDUFE
1PJTTPO
EJTUSJCVUJPO
GPS
0.7
UIJT
TJUVBUJPO
'SPN
5BCMF
*
UIF
QSPCBCJMJUZ
NBTT
0.6
GVODUJPO
JT
PCUBJOFE
BT
GPMMPXT

1 SPCBCJMJUZ
PG
PCTFSWJOH
FYBDUMZ
9
CMBDL
TQFDLT
= 0.5
10*440/ 9  '"-4&
0.4

5IF
QSPCBCJMJUZ
NBTT
GVODUJPO
JT
TIPXO
JO
'JHVSF
0.3

XJUI
9
QMPUUFE
PO
UIF
IPSJ[POUBM
BYJT
*U
XPVME
0.2
BQQFBS
UIBU
OPSNBM
SBOEPN
WBSJBUJPO
DPVME
FBTJMZ

QSPEVDF
B
SBOHF
PG
9
WBMVFT
CFUXFFO

BOE

0.1
5IF
FOHJOFFS
GFFMT
UIBU
UIF
UFTU
TIPVME
OPU
GBJM
CZ
0
DIBODF
NPSF
UIBO

PG
UIF
UJNF
)F
DBMDVMBUFT
-4 -3 -2 -1 0 1 2 3 4
GBJMVSF
SBUFT
PO
UIF
MPX
BOE
IJHI
TJEFT
SFTQFDUJWFMZ

as follows: Observed t statistic

SPCBCJMJUZ
UIBU
9
<

=
10*440/ 




1 FYJTUJOH
DPOUSPM

CSBOE
5IF
USVF
QPQVMBUJPO


536&

=
 CBMBODF
UP
CBMBODF
TUBOEBSE
EFWJBUJPO
DBO
CF

BTTVNFE
FRVBM
GPS
CPUI
CSBOET
XJUI
OPSNBM
FSSPST


1 SPCBCJMJUZ
UIBU
9
>

=


10*440/ 



BMUIPVHI
UIF
USVF
NFBOT
BOE
TUBOEBSE
EFWJBUJPO

536&

=
 are unknown. Ten (=/

CBMBODFT
PG
FBDI
CSBOE

XJMM
CF
UFTUFE
CZ
XFJHIJOH
UIF
TBNF
TUBOEBSE

5IVT
BO
BDDFQUBODF
DSJUFSJPO
PG

UP

JODMVTJWF
PODF
PO
FBDI
CBMBODF
CZ
UIF
TBNF
PQFSBUPS
5IF

XPVME
TBUJTGZ
UIF
SFRVJSFE
GBMTF
BMBSN
SBUF
PG
 
CBMBODFT
XJMM
CF
UFTUFE
JO
SBOEPN
PSEFS
5IF

PCTFSWFE
TBNQMF

NFBO

X ) and standard
SETTING A PROCESS MEAN EFWJBUJPO
4

PG
FBDI
CSBOE
XJMM
CF
DBMDVMBUFE

SPECIFICATION IN A COMPARABILITY *O
UIF
QSFWJPVT
FYBNQMFT
B
TUBUJTUJD
XIPTF

STUDY USING THE T-DISTRIBUTION TBNQMJOH
EJTUSJCVUJPO
XBT
DPOTUSVDUFE
VOEFS
UIF

5IF
SFMBUJWF
BDDVSBDZ
PG
B
OFX
UFTU

CSBOE
PG
BTTVNQUJPO
UIBU
UIF
QSPDFTTFT
CFJOH
DPNQBSFE

MBCPSBUPSZ
CBMBODF
JT
CFJOH
DPNQBSFE
UP
UIF
XFSF
UIF
TBNF
XBT
LOPXO
UIFO
UIF
BDDFQUBODF

PROCESS VALIDATION Continued Process Verification 61

David LeBlond

Figure 7: Population as the area of a unit square. 5%*45 9 
+





GPS
9
>


5IF
DVNVMBUJWF
EJTUSJCVUJPO
GVODUJPO
PG
UIJT

TUBUJTUJD
JT
TIPXO
JO
'JHVSF

XJUI
9
HJWFO
PO
UIF

IPSJ[POUBM
BYJT
*U
XPVME
BQQFBS
UIBU
UIF
BDDFQUBODF

P(H&) P( H) SBOHF
GPS
UIJT
TUBUJTUJD
PG
o
UP

PVHIU
UP
CF

P( D) P(D&)
 DPOTJEFSFE
5IF
BDUVBM
SJTL
PG
GBJMJOH
UIF
UFTU
CZ

SBOEPN
DIBODF
DBO
CF
DBMDVMBUFE
BT
GPMMPXT
Test
result 1SPCBCJMJUZ
UIBU
U
< 
=
5%*45 "#4 
+ 

=

P(H&) P( H)

P(H&) 1SPCBCJMJUZ
UIBU
U
>

= 15%*45  + 


P( D)
=

4P
UIF
UPUBM
QSPCBCJMJUZ
PG
GBJMJOH
UIF
UFTU
CZ

P(D) P(H) SBOEPN
DIBODF
XJMM
CF

PS
VOEFS

D H
5IF
BCPWF
UUFTU
JT
DBMMFE
B
UFTU
PG
FRVBMJUZ
'PS

Disease state
TVDI
B
UFTU
UIF
POMZ
DPODFSOT
BSF
BCPVU
UIF
5ZQF

*
FSSPS
PS
GBMTF
BMBSN
SBUF
XIFO
EFTJHOJOH
UIF
UFTU

)PXFWFS
UIF
QSPCBCJMJUZ
PG
GBJMJOH
UP
EFUFDU
BO

DSJUFSJB
XBT
TFU
GPS
UIJT
TUBUJTUJD
UIBU
HBWF
B
MPX
SJTL
JNQPSUBOU
EJGGFSFODF
BMTP
DBMMFE
B
5ZQF
**
FSSPS

PG
GBJMVSF
CZ
SBOEPN
WBSJBUJPO
BMPOF
)PXFWFS
XF
PS
CSPLFO
BMBSN
SBUF

JT
B
DPOTJEFSBUJPO
XIFO
XF

EP
OPU
LOPX
UIF
EJTUSJCVUJPO
PG
FJUIFS
UIF
NFBOT
BSF
USZJOH
UP
HBUIFS
FWJEFODF
PG
FRVJWBMFODF
#PUI

PS
TUBOEBSE
EFWJBUJPOT
)PX
EP
XF
QSPDFFE
"
FRVBMJUZ
BOE
FRVJWBMFODF
UFTUT
XJMM
CF
EJTDVTTFE
JO

TPMVUJPO
UP
UIJT
QSPCMFN
XBT
OPU
LOPXO
CFGPSF
NPSF
EFUBJM
JO
GVUVSF
JOTUBMMNFOUT
PG
i4UBUJTUJDBM

UIF
UI
DFOUVSZ
5IFO
JO

8JMMJBN
(PTTFUU
B
7JFXQPJOUw

CSFXFS
XPSLJOH
BU
UIF
(VJOOFTT
CSFXFSZ
JO
%VCMJO

QVCMJTIFE
UIF
BQQSPQSJBUF
TUBUJTUJD
VOEFS
UIF
ASSESSING THE PREDICTIVE VALUE
QTFVEPOZN

i4UVEFOUw


)JT
JOHFOJPVT
TPMVUJPO
OF A SCREENING TEST USING THE
TVHHFTUT
UIBU
XF
GPSN
UIF
GPMMPXJOH
i4UVEFOUT
Uw
BERNOULLI DISTRIBUTION AND BAYES
statistic as a decision criterion. RULE
"
EJBHOPTUJD
TDSFFOJOH
UFTU
GPS
B
EJTFBTF
TVDI

BT
DBODFS
PS
IFQBUJUJT
JT
NFBOU
UP
CF
B
GBTU
TBGF

BOE
SFMBUJWFMZ
JOFYQFOTJWF
QSPDFEVSF
4VDI
UFTUT

Xtest  Xcontrol PGUFO
IBWF
BO
BQQSFDJBCMF
GBMTF
QPTJUJWF
SBUF

t $POTFRVFOUMZ
B
QPTJUJWF
SFTVMU
JT
VTVBMMZ
GPMMPXFE

(Ntest  1)S  (Ncontrol  1)S2control
( (
2
test 1 1 VQ
XJUI
B
NPSF
JOWBTJWF
BOE
DPTUMZ
CVU
NPSF


Ntest  Ncontrol  2 Ntest Ncontrol EJTDSJNJOBUJOH
DPOGJSNBUPSZ
UFTU
)PXFWFS

SFDFJWJOH
B
QPTJUJWF
SFTVMU
PO
TVDI
B
TDSFFOJOH
UFTU

DBO
CF
B
TUSFTTGVM
FYQFSJFODF
GPS
B
QBUJFOU
VOUJM

XIFSF
JO
PVS
DBTF
/test = Ncontrol


5IF
UIF
NPSF
EJTDSJNJOBUJOH
DPOGJSNBUPSZ
UFTU
JT
BCMF

OVNFSBUPS
PG
UIJT
TUBUJTUJD
JT
TJNQMZ
UIF
FTUJNBUFE
(hopefully) to discount the original screening
NFBO
EJGGFSFODF
BOE
UIF
EFOPNJOBUPS
JT
UIF
result.
FTUJNBUFE
QPPMFE
TUBOEBSE
EFWJBUJPO
PG
UIF
NFBO
+VTU
IPX
NVDI
OFX
JOGPSNBUJPO
EPFT
B
TDSFFOJOH

EJGGFSFODF
5IF
USJDL
PG
OPSNBMJ[JOH
B
TUBUJTUJD
UFTU
QSPWJEF
)PX
EPFT
SFDFJWJOH
B
QPTJUJWF

CZ
JUT
FTUJNBUFE
TUBOEBSE
EFWJBUJPO
JT
DBMMFE
TDSFFOJOH
SFTVMU
DIBOHF
UIF
QSPCBCJMJUZ
UIBU
B

i4UVEFOUJ[JOHw
5IF
SFTVMUJOH
U
TUBUJTUJD
GPMMPXT
B
QBUJFOU
IBT
UIF
EJTFBTF
*T
UIF
TDSFFOJOH
UFTU
DPTU
DPOUJOVPVT
4UVEFOUTU
EJTUSJCVUJPO
TFF
5BCMF
**

FGGFDUJWF
4VDI
RVFTUJPOT
BSF
OPU
POMZ
JNQPSUBOU

with 1 = Ntest + Ncontrol 
EFHSFFT
PG
GSFFEPN UP
QBUJFOUT
BOE
EPDUPST
CVU
BMTP
UP
NBOVGBDUVSFST

DPODFSOFE
XJUI
UIF
RVBMJUZ
BOE
BQQSPQSJBUFOFTT

5IF
DVNVMBUJWF
EJTUSJCVUJPO
GVODUJPO
PG
U
DBO
CF
PG
TVDI
QSPEVDUT
BOE
UP
UIF
SFHVMBUPST
XIP
BTTVSF

PCUBJOFE
BT
GPMMPXT UIF
TBGFUZ
BOE
FGGFDUJWFOFTT
PG
UIFTF
EFWJDFT
GPS
UIF

QVCMJD

1SPCBCJMJUZ
UIBU
U
XJMM
CF
MFTT
UIBO
9
= *O

UIF
XPSL
PG
3FWFSFOE
5IPNBT
#BZFT

5%*45 "#4 9

+





GPS
9


BOE
B
IVNCMF
&OHMJTI
1SFTCZUFSJBO
NJOJTUFS
XBT

62 PROCESS VALIDATION Continued Process Verification

 David LeBlond

QVCMJTIFE
QPTUIVNPVTMZ
CZ
IJT
GSJFOE
3JDIBSE
1SJDF

Figure 8: Population as the area of a unit square, subgroups.


)JT
NFUIPE
JT
XPSUI
DPOTJEFSJOH
CFDBVTF
JU

JMMVTUSBUFT
UIF
WBMVF
PG
JODMVEJOH
QSJPS
LOPXMFEHF

FH

EJTFBTF
QSFWBMFODF
JO
B
QPQVMBUJPO
CFJOH

TDSFFOFE

XIFO
JOUFSQSFUJOH
OFX
EBUB
FH

SFTVMUT

P(D&) P(D )
of a recent screening test). P(D ) P(D&)
"
TDSFFOJOH
UFTU
HFOFSBMMZ
IBT
POMZ
UXP
PVUDPNFT
D

PS

5IF
TUBUF
PG
IFBMUI
PG
B
QFSTPO
IBT
POMZ
UXP

MFWFMT
)
PS
%
5IFTF
BSF
BOBMPHPVT
UP
B
DBUFHPSJDBM
Disease
state
CJOPNJBM
WBSJBCMF
XJUI
B
TBNQMF
TJ[F
PG

TFF
5BCMF

*

5IJT
TQFDJBM
DBTF
PG
UIF
CJOPNJBM
EJTUSJCVUJPO
P(H&) P(H )
JT
SFGFSSFE
UP
BT
UIF
#FSOPVMMJ
EJTUSJCVUJPO
BGUFS
H
UIF
UIDFOUVSZ
*UBMJBO
NBUIFNBUJDJBO
+BDPC
P(H&)
P(H )
#FSOPVMMJ
8PSLJOH
XJUI
UIF
#FSOPVMMJ
EJTUSJCVUJPO

JT
EFDFQUJWFMZ
TJNQMF
CFDBVTF
UIF
QSPCBCJMJUZ
NBTT

P() P()
PG
B

SFTVMU
JT
FRVBM
UP
UIF
QPQVMBUJPO
QSPQPSUJPO



TFF
UIF
#FSOPVMMJ
iTUPSZw
JO
5BCMF
*

"
TQFDJBM
 
&YDFM
GVODUJPO
JT
OPU
OFFEFE
5IF
QSPQPSUJPO
BT
B
Test result
QSPCBCJMJUZ
DBO
CF
XPSLFE
XJUI
EJSFDUMZ
'PS
FYBNQMF

+BNFT
JT
B
QBUJFOU
XIP
NBZ
IBWF
each depending on the proportion who would
B
EJTFBTF
+BNFT
IBT
OPU
ZFU
CFFO
TDSFFOFE
GPS
UIF


PS
o
MPXFS

TDSFFOJOH
UFTU
SFTVMU

EJTFBTF
8IBU
JT
UIF
QSPCBCJMJUZ
UIBU
IF
IBT
UIF

EJTFBTF
+BNFT
NJHIU
EP
BO
*OUFSOFU
TFBSDI
BOE

SFDFJWF
B

VQQFS
5IJT
HFOFSBUFT
GPVS
UPUBM
TVCTVCQPQVMBUJPOT
XIPTF

KPJOU
QSPQPSUJPOT
JO
UIF
PSJHJOBM
VOJU
TRVBSF
BSF

MFBSO
UIF
QSFWBMFODF
PG
UIF
EJTFBTF
JO
QFPQMF
MJLF
1 %


1 %


1 )


BOE
1 )

5IF

TZNCPM

IJNTFMG
1SFWBMFODF
JT
EFGJOFE
BT
UIF
QSPCBCJMJUZ
PG
SFBET
iBOEw
*U
JT
DPNNVUBUJWF
TP
UIBU
1 %



IBWJOH
UIF
EJTFBTF

1 %


GPS
NFNCFST
PG
B
XFMM 1 %

"MPOH
UIF
MFGU
BOE
SJHIU
WFSUJDBM
TJEFT
PG
UIF

EFGJOFE
QPQVMBUJPO
-FUT
QSFUFOE
UIBU
UIJT
FOUJSF
VOJU
TRVBSF
BSF
GPVS
OFX
WFSUJDBM
RVBOUJUJFT
XIPTF

QPQVMBUJPO
IBE
CFFO
TDSFFOFE
BOE
UIBU
UIF
USVF
MFOHUIT
DPSSFTQPOE
UP
UIF
DPOEJUJPOBM
QSPCBCJMJUJFT

EJTFBTF
TUBUF
JT
LOPXO
3FQSFTFOUJOH
UIF
QPQVMBUJPO
1 ]%


1 ]%


1 ])


BOE
1 ])

5IF
GJSTU
BOE

BT
UIF
BSFB
PG
B
VOJU
TRVBSF

BT
TIPXO
JO
'JHVSF


JT
TFDPOE
QSPCBCJMJUJFT
SFGFS
UP
QSPQPSUJPOT
PG
UIF

VTFGVM
CFDBVTF
QSPCBCJMJUZ
DBO
CF
NBOJQVMBUFE
BT
EJTFBTFE
TVCQPQVMBUJPO
BOE
UIF
UIJSE
BOE
GPVSUI

an area or a length. The area of any region within QSPCBCJMJUJFT
SFGFS
UP
QSPQPSUJPOT
PG
UIF
IFBMUIZ

UIF
TRVBSF
JT
UBLFO
BT
B
NFBTVSF
PG
UIF
GSBDUJPO
PG
TVCQPQVMBUJPO
UIF
QPQVMBUJPO
UIBU
NFFU
DFSUBJO
DSJUFSJB
5IJT
MFBET
5IJOL
PG
1 %

BT
UIF
QSPQPSUJPO
PG
UIF
BSFB

UP
B
HFPNFUSJDBM
TPMVUJPO
UP
+BNFT
RVFTUJPO
'SPN
PG
UIF
VOJU
TRVBSF
FRVBM
UP
UIF
QSPQPSUJPO
PG

UIF
CBTF
PG
UIF
VOJU
TRVBSF
XF
EJWJEF
UIF
QPQVMBUJPO
UIF
QPQVMBUJPO
UIBU
JT
CPUI
EJTFBTFE
BOE
IBT
B


XJUI
B
EBTIFE
WFSUJDBM
MJOF
TFQBSBUJOH
UIF
EJTFBTFE
screening result. Inspection of the upper left area
TVCQPQVMBUJPO
PO
UIF
MFGU

GSPN
UIF
IFBMUIZ
'JHVSF

TIPXT
UIBU
TVCQPQVMBUJPO
PO
UIF
SJHIU

5IF
QSPCBCJMJUZ
UIBU

+BNFT
JT
IFBMUIZ
JT
UIFO 1 %


1 ]%
1 %

<&RVBUJPO
>

1 )


1 %

<&RVBUJPO
> 4JNJMBSMZ
UIF
UPUBM
QSPQPSUJPO
PG

UFTU
SFTVMUT
JO

UIF
XIPMF
VOJU
TRVBSF
QPQVMBUJPO
JT
TFFO
BT
/PX
+BNFT
SFDFJWFT
IJT
TDSFFOJOH
SFTVMU

6OGPSUVOBUFMZ
UIF
SFTVMU
JT
QPTJUJWF


/PX
XIBU
1 


1 ]%
1 %


1 ])
1 )

<&RVBUJPO
>
JT
UIF
QSPCBCJMJUZ
UIBU
IF
IBT
UIF
EJTFBTF
HJWFO
$POTJEFSJOH
1 ])

BOE
1 ])

BT
QSPQPSUJPOT

UIJT
QPTJUJWF
SFTVMU
8F
EFOPUF
UIJT
QSPCBCJMJUZ
PG
B
VOJU
MJOF
UIBU
BEE
UP

XF
TFF
GSPN
UIF
SJHIU

1 %]

XIFSF
UIF
WFSUJDBM
CBS
SFBET
iDPOEJUJPOBM
WFSUJDBM
TJEF
PG
'JHVSF

UIBU
POw
PS
iHJWFO
UIBUw
8IBU
UIJT
NFBOT
JT
UIBU
XF
BSF

SFTUSJDUJOH
+BNFT
UP
B
TVCQPQVMBUJPO
XIP
XPVME
1 ])



o
1 ])

<&RVBUJPO
>
IBWF
B

TDSFFOJOH
SFTVMU
+BNFT
XBOUT
UP
LOPX

1 %]

BOE
UP
DPNQBSF
JU
UP
UIF
QSJPS
QSPCBCJMJUZ
5IF
TBNF
QPQVMBUJPO
NBZ
BMTP
CF
TVCEJWJEFE

1 %

EJGGFSFOUMZ
BT
TIPXO
JO
'JHVSF

JOUP
GPVS

5P
GJOE
1 %]

XF
NVTU
GVSUIFS
EJWJEF
UIF
TVCHSPVQT
IBWJOH
UIF
TBNF
QSPQPSUJPOT
BT
UIPTF

EJTFBTFE
%

BOE
IFBMUIZ
)

TVCQPQVMBUJPOT
JO
UIF
JO
'JHVSF

CVU
XJUI
EJGGFSFOU
RVBOUJUJFT
BMPOH
UIF

VOJU
TRVBSF
PG
'JHVSF

JOUP
UXP
TVCTVCQPQVMBUJPOT
IPSJ[POUBM
BOE
WFSUJDBM
BYFT
PG
UIF
VOJU
TRVBSF
*O

PROCESS VALIDATION Continued Process Verification 63

David LeBlond

'JHVSF

XF
GJSTU
EJWJEF
UIF
QPQVMBUJPO
BDDPSEJOH
GPME
JODSFBTF
4P
UIF
OFX
EBUB
EPFT
QSPWJEF

UP
TDSFFOJOH
UFTU
SFTVMU

PO
MFGU

PO
SJHIU

UIFO
TJHOJGJDBOU
JOGPSNBUJPO
)BE
+BNFT
SFDFJWFE
B
o

BDDPSEJOH
UP
EJTFBTF
TUBUF
%
BCPWF
BOE
)
CFMPX

TDSFFOJOH
UFTU
SFTVMU
XF
DPVME
TJNJMBSMZ
PCUBJO

"O
FYBNJOBUJPO
PG
'JHVSF

BSFBT
XJMM
TIPX
UIBU IJT
1 )]

UIF
QSFEJDUJWF
WBMVF
PG
B
OFHBUJWF

SFTVMU


0UIFS
BQQMJDBUJPOT
PG
#BZFT
3VMF
XJMM

1 %]


1 %


1 

<&RVBUJPO
> CF
BEESFTTFE
JO
GVUVSF
DPMVNOT
PG
i4UBUJTUJDBM

7JFXQPJOUw
/PUJDF
GSPN
FRVBUJPO

UIBU
XF
BSF
NBLJOH

QSPHSFTT
JO
PCUBJOJOH
UIF
RVBOUJUZ
1 %]

GPS
CONCLUSIONS
+BNFT
8JUIPVU
CPSJOH
UIF
SFBEFS
XJUI
UIF
BMHFCSB
%FDJTJPONBLJOH
JT
PGUFO
GBDJMJUBUFE
CZ

XF
TJNQMZ
TUBUF
UIBU
FRVBUJPOT

UISPVHI

NBZ
USBOTGPSNJOH
RVBMJUBUJWF
EFTDSJQUJPOT
BOE

CF
DPNCJOFE
UP
PCUBJO
UIF
GPMMPXJOH
TPMVUJPO
GPS
EJTDVTTJPOT
JOUP
RVBOUJUBUJWF
QSPCBCJMJUZ
NPEFMT

1 %]
5IF
QSFWJPVT
FJHIU
FYBNQMFT
XFSF
HJWFO
UP
JMMVTUSBUF

B
GSBNFXPSL
GPS
VTJOH
QSPCBCJMJUZ
DBMDVMBUJPOT
UP

NBLF
RVBOUJUBUJWF
QSFEJDUJPOT
QMBO
SFTPVSDFT
BOE

BTTFTT
SJTL
GSPN
EBUB
BOEPS
QSJPS
JOGPSNBUJPO
GPS

P( D)P(D) TPNF
DPNNPO
QIBSNBDFVUJDBM
EFDJTJPONBLJOH

P(D ) 
P( D)P(D)(1P( H))(1P(D)) TJUVBUJPOT
5IJT
BQQSPBDI
NBZ
CF
TVNNBSJ[FE
BT

follows:
t

, OPX
ZPVS
PCKFDUJWF
*G
UIJT
JOWPMWFT


<&RVBUJPO
> QSFEJDUJOH
UIF
WBMVFT
PG
SBOEPN
WBSJBCMFT

WBSJBCMF
EBUBTUBUJTUJDT
PS
VODFSUBJO

where QBSBNFUFST

UIFO
VTJOH
QSPCBCJMJUZ

EJTUSJCVUJPO
NFUIPET
XJMM
CF
VTFGVM

]%


TFOTJUJWJUZ
PG
UIF
TDSFFOJOH
UFTU

1 t

6OEFSTUBOE
UIF
TBNQMJOH
EJTUSJCVUJPO
PG
UIF

QSPCBCJMJUZ
PG
B

HJWFO
EJTFBTF
EBUBTUBUJTUJDT
ZPV
BSF
DPMMFDUJOH
*EFOUJGZ
UIF

type of data (discrete or continuous) and the

])


TQFDJGJDJUZ
PG
UIF
TDSFFOJOH
UFTU

1 EJTUSJCVUJPO
TUPSZ
BOE
BTTVNQUJPOT
UIBU
BQQMZ

QSPCBCJMJUZ
PG
B
o
HJWFO
IFBMUI
to your situation.
t

5SZ
JG
QPTTJCMF

UP
GJOE
B
NBUDI
CFUXFFO
ZPVS

&RVBUJPO

DBMMFE
i#BZFT
3VMFw
JO
IPOPS
PG
PXO
EBUB
HFOFSBUJPO
iTUPSZw
BOE
UIBU
PG
B

5IPNBT
#BZFT
JT
GJOEJOH
NPSF
BQQMJDBUJPOT
JO
DPNNPO
EJTUSJCVUJPO
TVDI
BT
UIPTF
JO
5BCMFT
*

UPEBZT
FSB
PG
GBTU
DPNQVUFST
1 %

JT
SFGFSSFE
or II.
UP
BT
UIF
QSJPS
QSPCBCJMJUZ
PG
EJTFBTF

CFGPSF
t

#FDPNF
GBNJMJBS
XJUI
QSPCBCJMJUZ
GVODUJPOT
JO

EBUB
JT
BWBJMBCMF
BOE
1 %]

JT
SFGFSSFE
UP
BT
UIF
SFBEJMZ
BWBJMBCMF
TPGUXBSF
TVDI
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64 PROCESS VALIDATION Continued Process Verification


GLOSSARY
Bayes rule: A process for combining the information
in a data set with relevant prior information
(theory, past data, expert opinion, and
knowledge) to obtain posterior information.
Prior and posterior information are
expressed in the form of prior and posterior
probability distributions, respectively, of the
underlying physical parameters.
Bernoulli distribution: A special case of the Binomial
distribution in which the sample size is equal to
1. A variable following the Bernoulli distribution
has only two possible levels: 0 or 1. The
probability mass associated with the 1 level is
equal to the proportion parameter, .
Broken alarm rate: The ability of a statistical test to
detect a difference that is large enough to
be practically important (e.g., the difference
between two means being greater than
is acceptable) is a consideration when
gathering evidence for equivalence of two
processes. The probability that a given test
will fail to detect such a difference is called
the broken alarm rate, the false negative
rate, a Type II error rate, or the beta error
rate.
Conditional probability: The probability of an event (say
A) occurring, given that some other relevant
event (say B) has occurred, symbolized P(A|B).
For example, let A = house is on fire and B =
smoke alarm is sounding.
False alarm rate: Because all statistical tests (e.g.,
control chart rules, comparison with
acceptance limits, t- or F-tests ) are based
on a comparison of a random variable (e.g.,
some categorical or continuous measure
calculated from data) to some fixed
decision limit, there is generally a non-zero
probability of exceeding the limit (i.e.,
failing the test) when, in fact, the process
is performing acceptably. This probability is
called the false alarm rate (also referred to
as the false positive, the Type I or alpha
error rate).
Multiplicity: When multiple statistical tests (e.g., control
chart rules) are applied to different aspects (e.g.,
trending patterns) of a data set, the overall false
alarm rate of any one test failing may be greater
than that of any single test when applied alone.
This statistical phenomenon is referred to as
multiplicity.
One-sided or two-sided test: Statistical tests often
involve the comparison of some random
statistic, calculated from data (such as
an F-ratio, a t value, a count, or other
David LeBlond
measurement) to some critical failure
range. In a one-sided test, the test can fail
on only one side (i.e., statistic > an upper limit
or statistic < a lower limit, but not both). In a
two-sided test, both an upper and lower limit
are used and thus the test can fail on either
side.
Pooled variance: An estimate of a population variance
obtained from two or more separate samples
obtained from the same population or at
least from populations having the same
population variance. The square root of the
pooled variance is called the pooled standard
deviation.
Posterior probability: An improved estimate of a
proportion that is obtained by using Bayes
rule to combine information from a subjective
prior probability with that available from
experimental data.
Predictive value of a failing test result: The
conditional probability that an object
under test (e.g., a person) is defective (e.g.,
diseased), given that the object failed the
test (e.g., a + result on a diagnostic test).
Prior probability: An estimate of a proportion
that is based on theory, past data, expert
opinion, and knowledge (e.g., prevalence
of disease in a population, false positive or
negative rates of a screening test). Often the
proportion is a parameter of a probability
distribution such as the binomial or Bernoulli
distribution.
Predictive value of a passing test result: The
conditional probability that an object under
test (e.g., a person) is acceptable (e.g.,
healthy), given that the object passed the test
(e.g., a - result on a diagnostic test).
Sensitivity of a test: The conditional probability of failing
a test (e.g., a + result on a diagnostic test),
given that the object under test (e.g., a person)
is truly defective (e.g., diseased).
Skewness: One characteristic of a continuous
probability distribution that indicates the
degree of symmetry of the distribution about
its center (i.e., mean, mode, or median).
Distributions showing longer tails at lower
or higher values are said to be left or right
skewed, respectively. The normal distribution
has no skewness and is perfectly symmetrical
about its mean. The lognormal distribution is
skewed to the right.
Specificity of a test: The conditional probability of
passing a test (e.g., a - result on a diagnostic
test), given that the object under test (e.g., a
person) is truly acceptable (e.g., healthy).
PROCESS VALIDATION Continued Process Verification 65
David LeBlond

Statistic: A numeric value calculated from data. Often



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probability distribution (e.g., the sample
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REFERENCES 



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The Journal of Validation Technology

66 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta

Case Study #3Process Validation

Failure of a Liquid Product
Batch Size IncreaseIdentical
Manufacturing Tanks
Paul L. Pluta

Validation Case Studies discusses situations useful VDU
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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 objec-
tive of this column: Useful and practical information.
Reader comments, questions, and suggestions are

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needed to help us fulfill our objective for this column.
Case studies illustrating validation issues submitted
by readers are most welcome. Please send your com-
ments and suggestions to journal coordinating editor
Susan Haigney at shaigney@advanstar.com.
KEY POINTS DISCUSSED

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[
ABOUT THE AUTHORS
For more Author Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive technical and management expe-
information, rience in the pharmaceutical industry. Dr. Pluta is also adjunct associate professor at the University
go to of Illinois College of Pharmacy in Chicago. He edited and contributed chapters of Cleaning and
gxpandjvt.com/bios Cleaning Validation, published by PDA and Davis Healthcare International. He may be reached by e-
mail at paul.pluta@comcast.net.

PROCESS VALIDATION Continued Process Verification 67

Paul L. Pluta

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SFRVFTUFE
UP
WBMJEBUF
UIF
JODSFBTFE
CBUDI
TJ[F

BDUJWJUJFT
BTTPDJBUFE
XJUI
UIF
JODJEFOU CFDBVTF
TFWFSBM
PUIFS
TJNJMBS
QSPEVDUT
XFSF
BMSFBEZ

NBOVGBDUVSFE
BU
UIJT
TBNF
MBSHF
CBUDI
TJ[F

5IF

PROCESS DESCRIPTION BACKGROUND FYJTUJOH
CBUDI
SFDPSE
EPDVNFOUBUJPO
XBT
NPEJGJFE

5IF
NBOVGBDUVSJOH
QSPDFTT
JO
UIJT
DBTF
TUVEZ
UP
NBOVGBDUVSF
UIF
JODSFBTFE
CBUDI
TJ[F

/P
QSPC
JOWPMWFE
NBOVGBDUVSF
PG
BO
BRVFPVT
TPMVUJPO
JO
B
MFNT
XFSF
FYQFDUFE
TUBOEBSE
NJYJOH
UBOL
XJUI
DFOUSBM
JNQFMMFS

*OHSF .BOVGBDUVSJOH
PQFSBUPST
NBOVGBDUVSFE
UIF
MBSHFS

EJFOUT
JO
UIF
GPSNVMBUJPO
JODMVEFE
UIF
BDUJWF
ESVH
CBUDI
TJ[F
BDDPSEJOH
UP
UIF
TQFDJGJFE
EJSFDUJPOT

5IF

IZESPQIJMJD
QPMZNFS
UP
JODSFBTF
WJTDPTJUZ
CVGGFS
QSPDFEVSF
VTFE
XBT
TDBMFE
GSPN
UIF
TNBMMFS
CBUDI

TBMUT
UP
NBJOUBJO
Q)
QSFTFSWBUJWFT
GMBWPS
DPMPS
TJ[F
QSPDFEVSF

5IF
QSPDFEVSF
VTFE
XBT
BMTP
UIF

68 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta

TBNF
BT
VTFE
GPS
PUIFS
QSPEVDUT
BU
B
TJNJMBS
CBUDI
Figure: Mixing tank with different impellers.

TJ[F

8IFO
DFSUBJO
JOBDUJWF
JOHSFEJFOUT
XFSF
BEEFE

UP
UIF
NJYJOH
UBOL
UIFTF
NBUFSJBMT
GMPBUFE
PO
UIF

UPQ
PG
UIF
XBUFS
JO
UIF
UBOL
CVU
EJE
OPU
EJTTPMWF


.JYJOH
DPOUJOVFE
GPS
TFWFSBM
IPVST

5IF
JOBDUJWF

JOHSFEJFOUT
TUJMM
EJE
OPU
EJTTPMWF

5IF
NBOVGBDUVS
JOH
QSPDFTT
XBT
UFSNJOBUFE

5IF
WBMJEBUJPO
12
DPO
GPSNBODF
MPU
IBE
GBJMFE

What are the Issues?

5IFSF
XFSF
TFWFSBM
DSJUJDBM
JTTVFT
UP
CF
JOWFTUJHBUFE

as follows:
t
%JE
NBOVGBDUVSJOH
PQFSBUPST
GPMMPX
CBUDI

SFDPSE
EJSFDUJPOT
QSPQFSMZ
t
%JE
BMM
HSPVQT
BQQSPWF
UIF
OFX
CBUDI
SFDPSE
t
%JE
UIF
UFDIOJDBM
HSPVQ
SFWJFX
UIF
QSPDFTT
BOE

BQQSPWF
UIF
OFX
CBUDI
SFDPSE
t
8IZ
EJE
UIF
QSPDFTT
WBMJEBUJPO
GBJM
t
8BT
TPNFUIJOH
XSPOH
XJUI
UIF
FRVJQNFOU
CGMP Requirements
3FMFWBOU
HPPE
NBOVGBDUVSJOH
QSBDUJDF
(.1

pletely successful. Other products in the plant had
SFRVJSFNFOUT
BQQMJDBCMF
UP
UIF
FWFOU
BSF
MJTUFE
BT

follows:
t
4VCQBSU
%&RVJQNFOU

t

&RVJQNFOU
$MFBOJOH
BOE
.BJOUFOBODF
t
4VCQBSU
+3FDPSET
BOE
3FQPSUT
t


(FOFSBM
3FRVJSFNFOUT
t

#BUDI
1SPEVDUJPO
BOE
$POUSPM
3FDPSET
t


1SPEVDUJPO
3FDPSE
3FWJFX
INVESTIGATION
*OWFTUJHBUJPO
BOE
VMUJNBUF
SFTPMVUJPO
PG
UIJT
FWFOU

SFRVJSFE
JOWPMWFNFOU
PG
TFWFSBM
HSPVQT

5IFTF

JODMVEFE
QFSTPOOFM
JOWPMWFE
JO
UIF
JODJEFOU
FH

t
"QQSPYJNBUFMZ

PG
QVSJGJFE
XBUFS
XBT
BEEFE

NBOVGBDUVSJOH
BOE
RVBMJUZ
BTTVSBODF
<2">

BOE
UP
UIF
NJYJOH
UBOL
UFDIOJDBM
QFSTPOOFM
SFTQPOTJCMF
GPS
UIF
NBOVGBD
UVSJOH
QSPDFTT
BOE
QSPDFTT
WBMJEBUJPO

5IFSF
XFSF

NBOZ
EFUBJMT
UIBU
OFFEFE
UP
CF
JOWFTUJHBUFE
PS
DPO
GJSNFE

1FSTPOOFM
GSPN
BMM
HSPVQT
XFSF
JOUFSWJFXFE

and interacted to address the issues.
Manufacturing Personnel Interviews
.BOVGBDUVSJOH
QFSTPOOFM
BGGJSNFE
UIBU
BMM
CBUDI

SFDPSE
EJSFDUJPOT
XFSF
QFSGPSNFE
BT
TQFDJGJFE


.BOVGBDUVSJOH
PQFSBUPST
IBE
NBOVGBDUVSFE
FRVJWB
MFOU
QSPEVDUT
BU
MBSHF
CBUDI
TJ[F
VTJOH
BO
FRVJWBMFOU

QSPDFEVSF
BU
UIF
TJUF
NBOZ
UJNFT

5IFZ
IBE
BMTP

NBOVGBDUVSFE
UIF
TQFDJGJD
QSPEVDU
PG
UIJT
DBTF
TUVEZ

BU
TNBMM
CBUDI
TJ[F
NBOZ
UJNFT

5IFSF
XFSF
OP

USBJOJOH
JTTVFT
PS
WBSJBUJPO
JO
QFSGPSNBODF
BTTPDJ
BUFE
XJUI
UIF
NBOVGBDUVSJOH
QSPDFEVSF



IBE

Batch Record Review and Approval


"MM
SFMFWBOU
QFSTPOOFM
IBE
SFWJFXFE
BOE
BQQSPWFE


BOE
CPUUPN
PG
UIF
NJYFS
TIBGU
5IF
UBOL

UIF
OFX
NBOVGBDUVSJOH
CBUDI
SFDPSE
XJUI
UIF

JODSFBTFE
CBUDI
TJ[F

5IF
DIBOHF
IBE
CFFO
FWBMV
BUFE
CZ
UIF
WBMJEBUJPO
BQQSPWBM
DPNNJUUFF
BOE
POF

12
DPOGPSNBODF
MPU
XBT
SFDPNNFOEFE

5IFSF
XBT

OP
FYQFDUBUJPO
UIBU
UIF
QSPDFTT
XPVME
OPU
CF
DPN
CFFO
TVDDFTTGVMMZ
NBOVGBDUVSFE
BU
UIF
TBNF
CBUDI

TJ[F

5IFTF
MPUT
IBE
CFFO
NBOVGBDUVSFE
JO
XIBU

XBT
UIPVHIU
UP
CF
FRVJWBMFOU
NJYJOH
UBOLT

7BMJEB
UJPO
EPDVNFOUBUJPO
JOEJDBUFE
UIBU
BMM
NJYJOH
UBOLT

PG
UIJT
WPMVNF
XFSF
FRVJWBMFOU
Technical Personnel Evaluation
5FDIOJDBM
QFSTPOOFM
BGGJSNFE
UIBU
UIFSF
TIPVME

IBWF
CFFO
OP
QSPCMFN
XJUI
NBOVGBDUVSJOH
UIF

JODSFBTFE
CBUDI
TJ[F
VOEFS
OPSNBM
DJSDVNTUBODFT


5IF
NBOVGBDUVSJOH
QSPDFTT
XBT
TUSBJHIUGPSXBSE
BT

follows:
t
4PMJE
JOHSFEJFOUT
XFSF
BEEFE
UP
UIF
NJYJOH
UBOL
t
5IF
TPMVUJPO
XBT
NJYFE
GPS

NJOVUFT
"MM
JOHSFEJFOUT
XFSF
FYQFDUFE
UP
EJTTPMWF
XJUIJO

UIF
NJOVUF
NJYJOH
UJNF
Key Information
5IF
HFOFSBM
NBOVGBDUVSJOH
QSPDFTT
XBT
VTFE
UP

NBOVGBDUVSF
B
TNBMM
CBUDI
TJ[F
NBOZ
UJNFT
5IJT

TBNF
QSPDFTT
XBT
BQQSPQSJBUFMZ
TDBMFE
GPS
VTF
XJUI

UIF
JODSFBTFE
CBUDI
TJ[F
5IF
FOHJOFFSJOH
TUBGG
XBT

SFRVFTUFE
UP
FWBMVBUF
UIF
NJYJOH
UBOL
VTFE
GPS
UIF

GBJMFE
12
DPOGPSNBODF
SVO
5IF
NJYJOH
UBOL
UIBU

XBT
VTFE
UP
NBOVGBDUVSF
UIF
JODSFBTFE
CBUDI
TJ[F

XBT
BO
JOGSFRVFOUMZ
VTFE
UBOL
5IJT
UBOL
EJE
OPU

IBWF
UIF
TBNF
JNQFMMFS
BSSBOHFNFOU
BT
UIF
PUIFS

MBSHF
NJYJOH
UBOLT
BU
UIF
TJUF
"MM
NJYJOH
UBOLT
FYDFQU
UIF
UBOL
VTFE
GPS
UIF
QSPDFTT
WBMJEBUJPO
UISFF
QJUDIFECMBEF
JNQFMMFST
MPDBUFE
BU
UIF
UPQ
NJEEMF
VTFE
GPS
UIF
GBJMJOH
CBUDI
IBE
POMZ
UXP
QJUDIFE

PROCESS VALIDATION Continued Process Verification 69

Paul L. Pluta
CMBEF
JNQFMMFST
POF
MPDBUFE
BU
UIF
CPUUPN
BOE
POF

MPDBUFE
NJEMFWFM
PO
UIF
NJYFS
TIBGU
5IF
NJYJOH

UBOL
XJUI
UXP
JNQFMMFST
EJE
OPU
QSPWJEF
BEFRVBUF

BYJBM
GMPX
UP
QVMM
TPMJE
JOHSFEJFOUT
JOUP
UIF
CVML


2"

FOHJOFFSJOH

BOE
UFDIOJDBM
TVQQPSU
NBO
MJRVJE
UP
FGGFDU
EJTTPMVUJPO
5IF
NJYJOH
UBOL
VTFE
JO

UIF
GBJMFE
12
SVO
XBT
TJHOJGJDBOUMZ
EJGGFSFOU
GSPN

BMM
PUIFS
NJYJOH
UBOLT
BU
UIF
TJUF
)PXFWFS

CFDBVTF

UIJT
UBOL
XBT
B
CBDLVQ
UBOL
UIBU
IBE
OPU
CFFO
VTFE

GPS
TFWFSBM
ZFBST

OP
POF
XBT
BXBSF
PG
UIF
EJGGFS ACTIONS
FODF
"MUIPVHI
UIF
WPMVNFT
PG
BMM
UBOLT
XFSF
UIF

TBNF

UIF
NJYJOH
JNQFMMFST
XFSF
WFSZ
EJGGFSFOU
TFF
conducted:
'JHVSF

/P
POF
IBE
MPPLFE
JOTJEF
UIF
UBOL t
/FX
NBOVGBDUVSJOH
QSPDFTT
DISCUSSION
*OGPSNBUJPO
PCUBJOFE
UISPVHI
JOUFSWJFXT
BOE

TVCTFRVFOU
FYQFSJNFOUBM
XPSL
FOBCMFE
HPPE

VOEFSTUBOEJOH
PG
UIF
QSPCMFN
BOE
VMUJNBUF
TPMV
tion. Technical personnel conducted experi
NFOUBM
SVOT
BOE
QSPQPTFE
QSPDFTTJOH
DIBOHFT
UP

FOBCMF
NBOVGBDUVSJOH
JO
BMM
NJYJOH
UBOLT

5XP

FYQFSJNFOUBM
SVOT
XFSF
DPOEVDUFE
Run Number One
5IF
GJSTU
SVO
DPNQSJTFE
BEEJUJPO
PG
QVSJGJFE
XBUFS

UP
UIF
NJYJOH
UBOL
5IF
BNPVOU
PG
XBUFS
BEEFE
XBT

NFBTVSFE
UP
CF
KVTU
BCPWF
UIF
NJEEMF
JNQFMMFS
5IJT

XBUFS
MFWFM
QSPWJEFE
HPPE
NJYJOH
BT
FWJEFODFE
CZ
B

TUSPOH
WPSUFY
BOE
EJE
OPU
DBVTF
FYDFTTJWF
TQMBTIJOH


"QQSPYJNBUFMZ

PG
UIF
GJOBM
TPMVUJPO
WPMVNF

XBT
SFRVJSFE
UP
DPWFS
UIF
JNQFMMFS
.JYJOH
XBT
JOJUJ
BUFE
BOE
PCTFSWFE
UP
QSPWJEF
B
WPSUFY
UIBU
XPVME


UIF
TPMVUJPO

EJTTPMWF
UIF
JOHSFEJFOUT
5IF
IZESPQIJMJD
QPMZNFS

XBT
LOPXO
UP
CF
UIF
TMPXFTU
EJTTPMWJOH
PG
BMM
JOHSF
EJFOUT
5IF
SFRVJSFE
BNPVOU
PG
IZESPQIJMJD
QPMZNFS

was added to the purified water in the tank. The
QPMZNFS
XBT
RVJDLMZ
ESBXO
JOUP
UIF
MJRVJE
BOE
FBT

JG

JMZ
EJTTPMWFE
Run Number Two
"
TFDPOE
USJBM
SVO
XBT
DPOEVDUFE
VTJOH
BMM
JOHSFEJFOUT

FYDFQU
UIF
BDUJWF
QIBSNBDFVUJDBM
JOHSFEJFOU

/PU

JODMVEJOH
UIF
BDUJWF
JOHSFEJFOU
DPOTJEFSBCMZ
SFEVDFE

UIF
DPTU
PG
UIF
USJBM
SVO

1VSJGJFE
XBUFS
XBT
BEEFE

UP
UIF
NJYJOH
UBOL
BU

PG
UIF
GJOBM
WPMVNF
.JY
JOH
XBT
JOJUJBUFE
"MM
JOBDUJWF
JOHSFEJFOUT
XFSF
UIFO

BEEFE
UP
UIF
QVSJGJFE
XBUFS

"MM
JOHSFEJFOUT
RVJDLMZ

EJTTPMWFE
5IJT
TFDPOE
SVO
DPOGJSNFE
UIBU
BMM
GPSNVMB
UJPO
JOHSFEJFOUT
XPVME
CF
EJTTPMWFE
JO
UIF

TPMV
UJPO
WPMVNF
EVSJOH
UIF
NJYJOH
QSPDFTT
5IF
USJBM
SVO

HSFBUMZ
JODSFBTFE
UIF
DPOGJEFODF
PG
BMM
JOWPMWFE
UIBU

UIF
QSPDFTT
WBMJEBUJPO
XPVME
CF
TVDDFTTGVM
#FDBVTF

UIF
BDUJWF
JOHSFEJFOU
XBT
SFBEJMZ
TPMVCMF
JO
XBUFS

JU
"MM
XPSL
BTTPDJBUFE
XJUI
UIF
PSJHJOBM
WBMJEBUJPO
XBT

XBT
OPU
FYQFDUFE
UP
JNQBDU
UIF
TPMVUJPO
QSPDFTT

BOBMZTFT

BOE
DPODMV
"
OFX
CBUDI
SFDPSE
XBT
EFWFMPQFE
VTJOH
UIF

OFXMZ
EFWFMPQFE
NJYJOH
QSPDFTT

/FX
WBMJEBUJPO

70 PROCESS VALIDATION Continued Process Verification
EPDVNFOUBUJPO
XBT
BMTP
EFWFMPQFE

5ISFF
12
SVOT

XFSF
SFDPNNFOEFE
CFDBVTF
UIF
NBOVGBDUVSJOH
QSP
DFTT
XBT
DPNQMFUFMZ
OFX
UP
UIF
TJUF

.BOVGBDUVS
JOH
BHFNFOU
BQQSPWFE
UIF
DIBOHF
BOE
BMM
BTTPDJBUFE

EPDVNFOUBUJPO
CORRECTIVE AND PREVENTIVE
5IF
GPMMPXJOH
$"1"
BOE
BTTPDJBUFE
BDUJWJUJFT
XFSF

t
Training
t
%PDVNFOUBUJPO
t
1SPDFTT
WBMJEBUJPO
t
1PTUWBMJEBUJPO
NPOJUPSJOH
t
&RVJQNFOU
RVBMJGJDBUJPO
BOE
FRVJQNFOU

FRVJWBMFODF
t
0UIFS
TJNJMBS
QSPEVDUT
NBOVGBDUVSFE
BU
UIF

site.
New Manufacturing Process
"
OFX
NBOVGBDUVSJOH
QSPDFTT
DPNQSJTJOH
UIF
GPM
MPXJOH
XBT
JNQMFNFOUFE
XIFO
UIF
CBDLVQ
UBOL
XBT

used:
t
"QQSPYJNBUFMZ

PG
QVSJGJFE
XBUFS
XBT
BEEFE

UP
UIF
NJYJOH
UBOL
t
.JYJOH
XBT
TUBSUFE
t
"MM
TPMJE
JOHSFEJFOUT
XFSF
BEEFE
UP
UIF
NJYJOH

tank
t
"GUFS
BMM
JOHSFEJFOUT
XFSF
BEEFE
XBT
NJYFE
GPS

NJOVUFT
t
1VSJGJFE
XBUFS
XBT
BEEFE
UP
UIF
NJYJOH
UBOL
UP


PG
UIF
GJOBM
WPMVNF
t
4PMVUJPO
Q)
XBT
BEKVTUFE
XJUI
IZESPDIMPSJD

BDJE
TPMVUJPO
PS
TPEJVN
IZESPYJEF
TPMVUJPO
necessary
t
1VSJGJFE
XBUFS
XBT
BEEFE
TVGGJDJFOU
UP
NBLF
UIF

GJOBM
TPMVUJPO
WPMVNF
t
5IF
TPMVUJPO
XBT
NJYFE
GPS

NJOVUFT
t
4PMVUJPO
XBT
GJMUFSFE
BOE
GJMMFE
JOUP
UIF
DPN
NFSDJBM
QBDLBHJOH
Training
"MM
QFSTPOOFM
XFSF
USBJOFE
PO
UIF
OFX
NBOVGBDUVS
JOH
QSPDFEVSF

5IF
JNQPSUBODF
PG
BEEJOH
POMZ


PG
UIF
GJOBM
TPMVUJPO
WPMVNF
UP
UIF
NJYJOH
UBOL
XBT

stressed in the training. This procedure was used
POMZ
XIFO
VTJOH
UIF
UXPJNQFMMFS
NJYJOH
UBOL
Documentation
DPNQMFUFE

"MM
JOWFTUJHBUJPOT
TJPOT
XFSF
EPDVNFOUFE
UP
DMPTF
UIF
PSJHJOBM
GBJMFE

WBMJEBUJPO

%FWFMPQNFOU
PG
UIF
OFX
NBOVGBDUVSJOH


QSPDFTT
JODMVEJOH
USJBM
SVOT
XBT
EPDVNFOUFE
BOE

GJMFE
JO
UIF
WBMJEBUJPO
MJCSBSZ
BT
TVQQPSUJOH
JOGPS
NBUJPO
GPS
UIF
OFX
WBMJEBUJPO
12
SVOT
Process Validation
5IF
JODSFBTFE
CBUDI
TJ[F
NBOVGBDUVSJOH
QSPDFTT

GPS
QSPEVDU
JO
UIF
CBDLVQ
UXPJNQFMMFS
NBOVGBD
UVSJOH
UBOL
XBT
WBMJEBUFE

5ISFF
MPUT
XFSF
UFTUFE


"MM
UFTU
EBUB
QBTTFE
BDDFQUBODF
DSJUFSJB

5IF
OFX

NBOVGBDUVSJOH
QSPDFTT
XBT
TVDDFTTGVM
BOE
UIF

QSPDFTT
XBT
WBMJEBUFE
Post-Validation Monitoring
"EEJUJPOBM
NPOJUPSJOH
PG
NBOVGBDUVSJOH
UIF

JODSFBTFE
CBUDI
TJ[F
QSPEVDU
XBT
DPOEVDUFE
UP
DPO
GJSN
TVDDFTTGVM
QSPDFTT
WBMJEBUJPO
7JTVBM
PCTFS

UIF

WBUJPO
PG
UIF
NJYJOH
BOE
EJTTPMVUJPO
QSPDFTT
XBT

SFRVJSFE
GPS
TVCTFRVFOU
MPUT
NBOVGBDUVSFE
EVSJOH

UIF
OFYU
UISFF
NPOUIT

0OF
MPU
XBT
NBOVGBDUVSFE

FBDI
NPOUI

5IF
NBOVGBDUVSJOH
QSPDFTT
VTJOH
UIF

OFX
QSPDFTT
XBT
TVDDFTTGVM
JO
BMM
CBUDIFT
7JTVBM

PCTFSWBUJPO
PG
UIF
NBOVGBDUVSJOH
QSPDFTT
XBT
EPD
VNFOUFE
BOE
GJMFE
JO
UIF
WBMJEBUJPO
MJCSBSZ
Equipment Qualification and Equivalence
5IF
JOTUBMMBUJPO
RVBMJGJDBUJPO
*2

GPS
UIF
NBOV XFSF
VTFE
BT
TVQQPSUJOH
KVTUJGJDBUJPO
UP
NPEJGZ
UIF

GBDUVSJOH
UBOL
XJUI
UIF
UXP
JNQFMMFST
XBT
SFWJFXFE

UP
CF
TVSF
UIBU
JUT
EPDVNFOUBUJPO
DPSSFDUMZ
TUBUFE

JUT
JNQFMMFS
BSSBOHFNFOU

5IF
*2
EPDVNFOUBUJPO

GPS
BMM
PUIFS
UBOLT
XBT
BMTP
SFWJFXFE

8IJMF
UIF


UIF
BDUJWF
JOHSFEJFOU
XBT
SFBEJMZ

SFTQFDUJWF
*2
EPDVNFOUT
XFSF
BDDVSBUF

FRVJQNFOU
TPMVCMF
JO
QVSJGJFE
XBUFS

.BOVGBDUVSJOH
QSPDFTT
FRVJWBMFODF
EPDVNFOUT
JODPSSFDUMZ
JOEJDBUFE
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were different.
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Paul L. Pluta
GSPN
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Other Similar Products Manufactured at
the Site
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the product of this case study including trial runs
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PROCESS VALIDATION Continued Process Verification 71
Paul L. Pluta

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The Journal of Validation Technology

72 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta

Like-For-Like Changes: Is Validation

Testing Needed?
Validation Case Study #7
Paul L. Pluta

Validation Case Studies discusses validation situ- FRVJQNFOU
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ations useful to practitioners in validation and
compliance. Each case presented deals with a spe-


cific validation problem, elements of which are

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described to demonstrate strategy to solve valida-

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tion problems. We intend this column to be a use-

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ful resource for daily work applications.
Reader comments, questions, and suggestions are
needed to help us fulfill our objective for this col-
umn. Please send your comments and suggestions

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to managing editor Susan Haigney at shaigney@
advanstar.com.

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KEY POINTS DISCUSSED
The following key points are discussed:
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INTRODUCTION
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[
ABOUT THE AUTHORS
For more Author Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive technical and management
information, experience in the pharmaceutical industry. He is also adjunct assistant professor at the University of
go to Illinois at Chicago (UIC) College of Pharmacy in Chicago, Illinois USA. He may be contacted by e-mail
gxpandjvt.com/bios at paul.pluta@comcast.net.

PROCESS VALIDATION Continued Process Verification 73

Paul L. Pluta

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BQQSPWFT
UIF

XPSL WBMJEBUJPO
QSPUPDPM
5IJT
EJTDVTTJPO
BEESFTTFT
TJUVBUJPOT
JO
XIJDI
MJLF 
Validation work.
7BMJEBUJPO
XPSL
JT
QFSGPSNFE

GPSMJLF
DIBOHFT
EJE
OPU
QFSGPSN
BT
FYQFDUFE

4FWFSBM
BDDPSEJOH
UP
UIF
QSPUPDPM
4BNQMJOH
BOE
UFTUJOH

WBMJEBUJPO
NBOBHFST
QSFTFOUFE
FYBNQMFT
PG
TVDI
TJUV BSF
DPNQMFUFE
%BUB
BOE
PUIFS
SFTVMUT
BSF
HFOFS
BUJPOT
BU
JOUFSOBUJPOBM
WBMJEBUJPO
DPOGFSFODFT
5IF
ated and recorded.
PDDVSSFODFT
EFTDSJCFE
BSF
BDUVBM
JODJEFOUT
&YBNQMFT

Validation report.
"
SFQPSU
DPOUBJOJOH
BMM
UFTU

EFTDSJCFE
EFNPOTUSBUF
UIF
CSPBE
TDPQF
BOE
TJHOJGJDBOU
results with discussion and conclusions is pre
NBHOJUVEF
PG
QPUFOUJBM
QSPCMFNT
XJUI
MJLFGPSMJLF
QBSFE
BOE
TVCNJUUFE
UP
UIF
7"$
GPS
BQQSPWBM
5IF

changes. SFQPSU
JT
BQQSPWFE
BOE
UIF
QSPDFTT
PS
FRVJQNFOU

The following discussion includes: DIBOHF
JT
JNQMFNFOUFE
"O
BQQSPQSJBUF
MFWFM
PG

t
Background. 5IF
UZQJDBM
WBMJEBUJPO
PS
RVBMJGJDB QPTUWBMJEBUJPO
NPOJUPSJOH
JT
QSPQPTFE
JO
UIF

UJPO
QSPDFTT
JT
EFTDSJCFE report.
t
Compliance events.
%FTDSJQUJPOT
PG
TFWFSBM

Validation closure. If no other work is need
BDUVBM
MJLFGPSMJLF
WBMJEBUJPO
FWFOUT FE
UIF
WBMJEBUJPO
QSPKFDU
JOJUJBUFE
CZ
UIF
DIBOHF

t
What are the issues?
8IBU
IBQQFOFE
UP
DBVTF
SFRVFTU
JT
DMPTFE
UIFTF
QSPCMFNT 9. Emergency changes.
*O
DBTFT
PG
FNFSHFODZ

t
Corrective action and preventive action DIBOHFT
NBOBHFNFOU
NBZ
BVUIPSJ[F
DIBOHFT

(CAPA).
3FDPNNFOEFE
BDUJPOT
BOE
JNQSPWF UP
CF
DPNQMFUFE
BT
OFFEFE
BQBSU
GSPN
UIF
BCPWF
NFOUT
UP
QSFWFOU
GVUVSF
QSPCMFN
PDDVSSFODFT EFTDSJCFE
QSPDFTT
&NFSHFODZ
DIBOHFT
TIPVME
CF

FWBMVBUFE
CZ
UIF
7"$
BT
TPPO
BT
QPTTJCMF
4VQQPSU
BACKGROUND JOH
EPDVNFOUBUJPO
JT
UIFO
DPNQMFUFE
UP
DPOGJSN

5IF
QSPDFTT
PG
WBMJEBUJPO
PS
RVBMJGJDBUJPO
UZQJDBMMZ
UIF
BDDFQUBCJMJUZ
PG
UIF
DIBOHF
BOE
TVCNJUUFE
UP

DPNQSJTFT
UIF
GPMMPXJOH
TFRVFODF
PG
BDUJWJUJFT UIF
7"$
GPS
BQQSPWBM

74 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta


Documentation.
"MM
SFMFWBOU
EPDVNFOUBUJPO
UJPO
PG
B
MJLFGPSMJLF
SFQMBDFNFOU
CMPXFS
NPUPS
CZ

EFTDSJCFE
BDUJWJUJFT


JODMVEJOH
TVQQPSUJOH
UIF
TJUF
NBJOUFOBODF
TIPQ
TFWFSBM
NPOUIT
QSJPS

QSFXPSL
TIPVME
CF
TUPSFE
JO
UIF
WBMJEBUJPO
MJCSBSZ
)&1"
GJMUSBUJPO
PG
SPPN
BJS
IBE
UIVT
CFFO
DPN
PS
SFBEJMZ
BDDFTTJCMF
UISPVHI
B
LOPXMFEHF
NBO QSPNJTFE
GPS
TFWFSBM
NPOUIT
EVSJOH
XIJDI
UJNF

BHFNFOU
TZTUFN NVMUJQMF
QSPEVDU
MPUT
XFSF
NBOVGBDUVSFE
5IFTF
MPUT

11. Continued verification.
1PTUWBMJEBUJPO
NPO had passed all product testing and were released to
JUPSJOH
DPOGJSNJOH
BDDFQUBCJMJUZ
PG
UIF
DIBOHF
DPNNFSDJBM
EJTUSJCVUJPO
continues throughout the lifecycle. 5IF
64
'PPE
BOE
%SVH
"ENJOJTUSBUJPO
XBT
OPUJ
The issue addressed in this case study occurred GJFE
"MM
MPUT
NBOVGBDUVSFE
EVSJOH
UIF
UJNF
QFSJPE

JO
TUFQ
OVNCFS
UISFF
UIF
WBMJEBUJPO
PS
DIBOHF
XIFO
UIF
CMPXFS
NPUPS
XBT
PQFSBUJOH
JODPSSFDUMZ

SFRVFTU
XIJDI
JOJUJBUFT
UIF
GPSNBM
EPDVNFOUFE
XFSF
SFDBMMFE
"TJEF
GSPN
UIJT
JODJEFOU
CFJOH
IJHIMZ

WBMJEBUJPO
QSPDFTT
&NFSHFODZ
DIBOHFT
NBZ
BMTP
FNCBSSBTTJOH
UP
UIF
PSHBOJ[BUJPO
UIF
SFDBMM
DPTUT

IBWF
BQQMJDBUJPO
JO
UIJT
EJTDVTTJPO
4QFDJGJDBMMZ
JOWPMWFE
XFSF
TJHOJGJDBOU
DIBOHFT
SFRVFTUFE
XFSF
KVEHFE
UP
CF
MJLFGPSMJLF

DIBOHFT
UIBU
TIPVME
IBWF
IBE
OP
JNQBDU
PO
UIF
Milling Solids for Tablet Products
QSPDFTT
PS
FRVJQNFOU
#FDBVTF
OP
JNQBDU
XBT
"OPUIFS
NBOBHFS
EFTDSJCFE
BO
JODJEFOU
JO
XIJDI

FYQFDUFE
OP
UFTUJOH
PS
PUIFS
XPSL
XBT
SFDPN NBKPS
QSPDFTTJOH
QSPCMFNT
XJUI
TFWFSBM
UBCMFU

NFOEFE
CZ
UIF
7"$
PS
CZ
NBOBHFNFOU

BT
QBSU
QSPEVDUT
PDDVSSFE
5IJT
FWFOU
PDDVSSFE
JO
B
MBSHF

PG
UIF
DIBOHF
-JLFGPSMJLF
SFQMBDFNFOU
XPSL
NBOVGBDUVSJOH
GBDJMJUZ
UIBU
QSPEVDFE
NVMUJQMF

XBT
BVUIPSJ[FE
BOE
DPNQMFUFE
8PSL
XBT
EPDV TPMJE
EPTBHF
GPSNT
FH
UBCMFUT
DBQTVMFT
HSBOVMFT

NFOUFE
PO
FRVJQNFOU
IJTUPSZ
MPHT
NBJOUFOBODF
QPXEFST

0DDBTJPOBM
QSPEVDU
QSPDFTTJOH
QSPCMFNT

SFDPSET
PS
PUIFS
TZTUFNT
JO
BDDPSEBODF
XJUI
TJUF
XFSF
PCTFSWFE
XJUI
TFWFSBM
QSPEVDUT
"T
UIFTF
JOEJ
procedures. WJEVBM
JODJEFOUT
CFDBNF
NPSF
GSFRVFOU
JOWFTUJHB
UJPOT
XFSF
JOJUJBUFE
5IF
QSPCMFN
XBT
FWFOUVBMMZ

VALIDATION EVENTS BTTPDJBUFE
XJUI
QBSUJDMF
TJ[F
EJTUSJCVUJPO
DIBOHFT

"
EJTDVTTJPO
XJUI
TFWFSBM
WBMJEBUJPO
NBOBHFST
#MFOEFE
HSBOVMBUJPOT
IBE
TNBMMFS
QBSUJDMF
TJ[F
EJT
SFHBSEJOH
QSPCMFNT
XJUI
WBMJEBUJPO
BDUJWJUJFT
JOEJ USJCVUJPOT
UIBO
FYQFDUFE
XIFO
DPNQBSFE
UP
IJTUPSJ
DBUFE
UIBU
MJLFGPSMJLF
DIBOHFT
XFSF
B
SFDVSSJOH
QSPC DBM
EBUB
&WFOUVBMMZ
UIFTF
QSPCMFNT
XFSF
BTTPDJBUFE

MFN
*O
HFOFSBM
DIBOHFT
BSF
EFGJOFE
BT
MJLFGPSMJLF
UP
XJUI
QSPDFTTJOH
VTJOH
B
TQFDJGJD
JNQBDU
NJMM
8IFO

FMJNJOBUF
BEEJUJPOBM
WBMJEBUJPO
XPSL
5IF
EFGJOJUJPO
PQFSBUJPO
PG
UIF
NJMM
XBT
JOWFTUJHBUFE
JU
XBT
GPVOE

PG
MJLFGPSMJLF
NBZ
CF
CSPBEMZ
JOUFSQSFUFE
JO
UIFTF
UIBU
UIF
NJMM
XBT
SVOOJOH
JO
UIF
SFWFSTF
EJSFDUJPO

DBTFTBOE
JO
TPNF
DBTFT
UPP
CSPBEMZ
JOUFSQSFUFE
DPNQBSFE
UP
PUIFS
NJMMT
BU
UIF
TJUF
5IJT
DBVTFE

0DDBTJPOBMMZ
UIFTF
KVEHNFOUT
BOE
FOTVJOH
QSPC JODPSSFDU
NJMMJOH
PG
TPMJET
BOE
JNQSPQFS
QBSUJDMF

MFNT
IBE
TJHOJGJDBOU
DPOTFRVFODFT
4FWFSBM
BDUVBM
TJ[F
EJTUSJCVUJPOT
FYBNQMFT
EFTDSJCFE
CZ
NBOBHFST
EFNPOTUSBUFE
TVDI
&RVJQNFOU
IJTUPSZ
SFDPSET
XFSF
SFWJFXFE
5IF

FWFOUT
1FSTPOOFM
SFTQPOTJCMF
GPS
UIFTF
MJLFGPSMJLF
POMZ
BDUJWJUZ
QFSGPSNFE
UIBU
DPVME
IBWF
DBVTFE
UIJT

KVEHNFOUT
EJE
OPU
SFBMJ[F
UIF
QPUFOUJBM
QSPCMFNT
FWFOU
XBT
UIF
JOTUBMMBUJPO
PG
B
MJLFGPSMJLF
SFQMBDF
DBVTFE
CZ
UIFJS
KVEHNFOUT NFOU
NPUPS
5IF
NPUPS
DIBOHF
XBT
DPSSFMBUFE
UP
UIF

GJSTU
SFQPSU
PG
QSPDFTT
QSPCMFNT
BU
UIF
TJUF
1SPCMFNT

Laminar Air Flow in XFSF
BTTPDJBUFE
XJUI
NJMMJOH
PG
MBSHF
RVBOUJUJFT
PG

Aseptic Processing Facility ESVH
BOE
JOBDUJWF
JOHSFEJFOUT
GPS
SFTQFDUJWF
MPUT
0OF
NBOBHFS
EFTDSJCFE
BO
JODJEFOU
JO
XIJDI

SPVUJOF
SFWBMJEBUJPO
PG
BO
BTFQUJD
GJMMJOH
MJOF
XBT
Cell Culture Agitation
CFJOH
QFSGPSNFE
"MM
BDUJWJUJFT
BOE
UFTUT
XFSF
QFS "OPUIFS
WBMJEBUJPO
NBOBHFS
EFTDSJCFE
BO
FWFOU
JO

GPSNFE
BDDPSEJOH
UP
QSPDFEVSF
JODMVEJOH
TUFSJM XIJDI
UIF
DFMM
HSPXUI
JO
B
CJPUFDIOPMPHZ
QSPDFTT

J[FS
SFWBMJEBUJPO
NFEJB
SVOT
JOUFSWFOUJPOT
BOE
XBT
TJHOJGJDBOUMZ
MPXFS
UIBO
UIF
IJTUPSJDBM
BWFSBHF

TP
PO
"MM
SFTVMUT
XFSF
BDDFQUBCMF
BOE
BT
FYQFDUFE
XIFO
DVMUVSFT
XFSF
HSPXO
JO
B
TQFDJGJD
NBOV
VOUJM
UIF
GJMMJOH
MJOF
TNPLF
UFTU
XBT
DPOEVDUFE
facturing tank. Because this product was a high
5IF
TNPLF
UFTU
DPOGJSNT
UIF
MBNJOBS
BJSGMPX
EJSFD WPMVNF
QSPEVDU
UIBU
XBT
NBEF
JO
NVMUJQMF
UBOLT

UJPO
JO
UIF
BTFQUJD
TVJUF
"MM
JOWPMWFE
XFSF
TIPDLFE
UIF
MPXFS
HSPXUI
XBT
OPU
JNNFEJBUFMZ
PCWJPVT
"T

XIFO
UIF
BJSGMPX
XBT
TIPXO
UP
CF
VQXBSE
UPXBSE
NPSF
MPX
HSPXUI
CBUDIFT
XFSF
NBOVGBDUVSFE
JU

UIF
)&1"
GJMUFS
JOTUFBE
PG
EPXOXBSE
UISPVHI
UIF
CFDBNF
BQQBSFOU
UIBU
MPX
ZJFMET
XFSF
CFJOH
DPOTJT
filter toward open product. tently produced in a single tank.
3PPN
BOE
FRVJQNFOU
IJTUPSZ
SFDPSET
XFSF
&RVJQNFOU
IJTUPSZ
SFDPSET
GPS
UIF
TVTQFDU
UBOL

DIFDLFE
5IF
POMZ
BDUJWJUZ
QFSGPSNFE
JO
UIF
BSFB
XFSF
SFWJFXFE
5IF
POMZ
XPSL
QFSGPSNFE
PO
UIF

UIBU
DPVME
IBWF
DBVTFE
UIJT
FWFOU
XBT
UIF
JOTUBMMB UBOL
BT
EPDVNFOUFE
JO
UIF
FRVJQNFOU
IJTUPSZ
MPH

PROCESS VALIDATION Continued Process Verification 75

Paul L. Pluta

XBT
UIF
JOTUBMMBUJPO
PG
B
SFQMBDFNFOU
NPUPS
PO
DPOWFZPS
JT
HPJOH
CBDLXBSET
UIF
QSPCMFN
XPVME

UIF
NJYFS

5IF
NPUPS
DIBOHF
XBT
DPSSFMBUFE
UP
CF
FBTJMZ
PCTFSWFE
5IF
POMZ
MJLFGPSMJLF
DIBOHFT

UIF
GJSTU
SFQPSU
PG
MPXFSFE
HSPXUI
BOE
TVCTFRVFOU
SFRVJSJOH
WFSJGJDBUJPO
BSF
UIPTF
JO
XIJDI
JOTUBMMB
CBUDIFT
UIFSFBGUFS

8IFO
PQFSBUJPO
PG
UIF
UBOL
UJPO
FSSPST
XPVME
OPU
CF
PCWJPVT
EVSJOH
PQFSBUJPO

XBT
UIPSPVHIMZ
JOWFTUJHBUFE
JU
XBT
GPVOE
UIBU
FH
SFWFSTFE
MBNJOBS
BJS
GMPX

UIF
JNQFMMFS
XBT
SVOOJOH
JO
UIF
SFWFSTF
EJSFDUJPO
*O
TPNF
PSHBOJ[BUJPOT
NBJOUFOBODF
NBOBHF
DPNQBSFE
UP
UIF
PSJHJOBM
JOTUBMMBUJPO
BOE
DPN NFOU
IBT
UIF
GJOBM
BOE
DPNQMFUF
BVUIPSJUZ
UP
KVEHF

pared to other tanks at the site. This effect signifi XIFUIFS
PS
OPU
WBMJEBUJPO
PG
B
DIBOHF
VOEFS
UIFJS

DBOUMZ
BMUFSFE
UIF
NJYJOH
QSPGJMF
PG
UIF
DFMM
DVM BVTQJDFT
JT
SFRVJSFE
5IJT
QSBDUJDF
TIPVME
CF
MJN
UVSF
SFTVMUJOH
JO
SFEVDFE
DFMM
HSPXUI
BOE
BDUJWF
JUFE
UP
JOJUJBUJPO
PG
FNFSHFODZ
DIBOHFT
POMZ
*G
B

QIBSNBDFVUJDBM
JOHSFEJFOU
ZJFME DIBOHF
JT
MJLFGPSMJLF
JO
UIF
KVEHNFOU
PG
NBJOUF
OBODF
NBOBHFNFOU
UIF
FNFSHFODZ
XPSL
TIPVME

WHAT ARE THE ISSUES? CF
JOJUJBUFE
BT
TPPO
BT
QPTTJCMF
8PSL
TIPVME
UIFO

*O
FBDI
PG
UIF
FWFOUT
QSFTFOUFE
B
MJLFGPSMJLF
CF
EPDVNFOUFE
JO
FRVJQNFOU
IJTUPSZ
MPHT
PS
PUIFS

DIBOHF
XBT
QFSGPSNFE
XJUIPVU
OFFE
GPS
BOZ
DPO TJUF
EPDVNFOUBUJPO
TZTUFNT
$PNQMFUFE
FNFSHFODZ

GJSNBUPSZ
UFTUJOH
*EFOUJDBM
SFQMBDFNFOU
FRVJQNFOU
DIBOHFT
TIPVME
UIFO
CF
FWBMVBUFE
CZ
UIF
TJUF
7"$

XBT
BWBJMBCMF
GPS
FBDI
PG
UIF
DIBOHFT
"MM
QFSTPOOFM
$PNQMFUFE
DIBOHFT
BSF
UIFO
FWBMVBUFE
CBTFE
PO

JOWPMWFE
CFMJFWFE
UIBU
JOTUBMMBUJPO
PG
SFQMBDFNFOU
XPSL
EPOF
BOE
SJTL
UP
QBUJFOU
BOE
PSHBOJ[BUJPO

FRVJQNFOU
XBT
JODPOTFRVFOUJBM
BOE
XPVME
CF
EPOF
"QQSPQSJBUF
DPOGJSNBUPSZ
XPSL
XPVME
UIFO
CF

DPSSFDUMZ
5IF
QSPCMFNT
PCTFSWFE
XFSF
DPNQMFUFMZ
QSFTDSJCFE
.BJOUFOBODF
NBOBHFNFOU
TIPVME
CF

VOFYQFDUFE
*O
FBDI
DBTF
UIF
MJLFGPSMJLF
DIBOHF
QFSNJUUFE
UP
BVUIPSJ[F
FNFSHFODZ
DIBOHFT

"MM

XBT
DPOTJEFSFE
UP
CF
JOTJHOJGJDBOU
"EEJUJPOBM
UFTU DIBOHFT
VMUJNBUFMZ
TIPVME
CF
SFWJFXFE
FWBMVBUFE

JOH
UP
WFSJGZ
BDDFQUBCMF
FRVJQNFOU
JOTUBMMBUJPO
XBT
BOE
KVEHFE
CZ
UIF
TJUF
7"$
5IF
7"$
KVEHNFOUT
BSF

OPU
QSFTDSJCFE
"MUIPVHI
UIF
MJLFGPSMJLF
FRVJQ EPDVNFOUFE
JO
UIF
VTVBM
NBOOFS
"DDFQUBCJMJUZ
PG

NFOU
TFMFDUJPO
XBT
BDDVSBUF
BOE
BDDFQUBCMF
JOTUBM DIBOHFT
JT
UIF
VMUJNBUF
SFTQPOTJCJMJUZ
PG
UIF
7"$
MBUJPO
PG
UIF
FRVJQNFOU
XBT
OPU
'BVMUZ
JOTUBMMBUJPO

SFTVMUFE
JO
TFSJPVT
DPOTFRVFODFT
GPS
UIF
NBOV Validation Documentation Requirements
GBDUVSJOH
TJUF
BOE
UIF
PSHBOJ[BUJPO
*O
UIF
BTFQUJD
1SPUPDPMT
TIPVME
OPU
BMXBZT
CF
SFRVJSFE
UP
DPOGJSN

)&1"
GJMUFS
JODJEFOU
B
TJHOJGJDBOU
SFDBMM
PG
QSPEVDU
BDDFQUBCJMJUZ
PG
B
MJLFGPSMJLF
JOTUBMMBUJPO
"
TJNQMF

SFMFBTFE
UP
UIF
NBSLFUQMBDF
XBT
SFRVJSFE XSJUUFO
NFNP
XJUI
BQQSPQSJBUF
SFWJFX
BOE
BQQSPW
BM
BUUFTUJOH
UP
DPSSFDU
JOTUBMMBUJPO
PG
SFQMBDFNFOU

CORRECTIVE AND FRVJQNFOU
TIPVME
CF
TVGGJDJFOU
UP
DPNQMFUF
UIF

PREVENTIVE ACTIONS XPSL
5IF
NFNP
TIPVME
JODMVEF
B
TUBUFNFOU
UIBU

5IF
JODJEFOUT
QSFTFOUFE
IFSFJO
DBVTFE
FBDI
WBMJ DPSSFDU
FRVJQNFOU
PQFSBUJPO
IBE
CFFO
DPOGJSNFE

EBUJPO
NBOBHFS
UP
NBLF
DIBOHFT
JO
UIF
DIBOHF
CZ
B
TFDPOE
JOEJWJEVBM
.BOBHFNFOU
PG
UIF
SFTQPO
DPOUSPM
SFWJFX
QSPDFTT
BU
UIFJS
SFTQFDUJWF
NBOVGBD TJCMF
HSPVQ
FH
NBJOUFOBODF
FOHJOFFSJOH
PUIFST


UVSJOH
TJUFT
4PNF
PG
UIFJS
DPNNFOUT
BOE
TVHHFTUFE
BOE
UIF
TJUF
RVBMJUZ
BTTVSBODF
2"

EFQBSUNFOU

BQQSPBDIFT
BSF
EFTDSJCFE
BT
GPMMPXT TIPVME
BQQSPWF
UIF
NFNP
5IF
BQQSPWFE
NFNP

XPVME
UIFO
CF
GJMFE
XJUI
UIF
WBMJEBUJPO
SFRVFTU
UP

Validation Approval DMPTF
UIF
MJLFGPSMJLF
BDUJWJUZ
5IJT
EPDVNFOUBUJPO

Committee Review of All Changes BQQSPBDI
BDDPNQMJTIFT
UIF
OFFE
UP
WFSJGZ
IJHISJTL

7BMJEBUJPO
NBOBHFST
BHSFFE
UIBU
BMM
DIBOHFT
JOTUBMMBUJPO
XJUIPVU
UIF
FODVNCSBODF
PG
WBMJEBUJPO

JODMVEJOH
MJLFGPSMJLF
DIBOHFT
TIPVME
VMUJNBUFMZ
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76 PROCESS VALIDATION Continued Process Verification


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tions is properly installed. JVT
PROCESS VALIDATION Continued Process Verification 77
John McConnell, Brian K. Nunnally, and Bernard McGarvey

Understanding and Reducing

Analytical Error
Why Good Science Requires
Operational Excellence
John McConnell, Brian K. Nunnally, and Bernard McGarvey

Analysis and Control of Variation is dedicated to t
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revealing weaknesses in existing approaches to under-
standing, reducing, and controlling variation and to
recommend alternatives that are not only based on
sound science but also that demonstrably work. Case
studies will be used to illustrate both problems and
successful methodologies. The objective of the col-
umn is to combine sound science with proven practical
advice.
Reader comments, questions, and suggestions will
help us fulfil our objective for this column. Case studies
illustrating the successful reduction or control of varia-
tion submitted by readers are most welcome. We need

JO
CJPMPHJDT

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OFFE

your help to make Analysis and Control of Variation
a useful resource. Please send your comments and
suggestions to column coordinator John McConnell at


john@wysowl.com.au or journal coordinating editor
Susan Haigney at shaigney@advanstar.com.

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KEY POINTS DISCUSSED
The following key points are discussed:
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[
ABOUT THE AUTHORS
For more Author John McConnell is owner and director at Wysowl Pty Ltd in Queensland, Australia. He may be
information, reached at john@wysowl.com.au. Brian K. Nunnally, Ph.D., is in charge of process validation
go to at Pfizer in Sanford, NC. He may be reached at brian.nunnally@pfizer.com. Bernard McGarvey,
gxpandjvt.com/bios Ph.D., is process modelling group leader, Process Engineering Center at Eli Lilly and Company in In-
dianapolis, IN. He may be reached at mcgarvey_bernard@lilly.com.

78 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

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PROCESS VALIDATION Continued Process Verification 79

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Figure 1: Results of a plant trial to reduce variation.

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80 PROCESS VALIDATION Continued Process Verification

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PROCESS VALIDATION Continued Process Verification 81

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82 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 4: The first principle; stabilize first.

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PROCESS VALIDATION Continued Process Verification 83

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 5: Unstable laboratory controls (for biologics).

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The Journal of Validation Technology

84 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

Meeting Specifications is Not

Good EnoughThe Taguchi Loss
Function
John McConnell, Brian K. Nunnally, and Bernard McGarvey

Analysis and Control of Variation is dedicated t
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help us fulfill our objective for this column. Please XJUI
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coordinator John McConnell at john@wysowl.com. HPPE
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[
ABOUT THE AUTHORS
For more Author John McConnell is owner and director at Wysowl Pty Ltd in Queensland, Australia. He may be
information, reached at john@wysowl.com.au. Brian K. Nunnally, Ph.D., is in charge of process validation
go to at Pfizer in Sanford, NC. He may be reached at brian.nunnally@pfizer.com. Bernard McGarvey,
gxpandjvt.com/bios Ph.D., is process modelling group leader, Process Engineering Center at Eli Lilly and Company in In-
dianapolis, IN. He may be reached at mcgarvey_bernard@lilly.com.

PROCESS VALIDATION Continued Process Verification 85

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 1: The original industrial view of variation. IN THE BEGINNING...

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NFBO

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CFGPSF
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NFUIPEPMPHZ
BSF

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TPNFXIBU
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CFDBVTF

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5BHVDIJ
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PG
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CPUI
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MPTT
GVODUJPO

1SJ[F
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UP
EFNPOTUSBUF
UIBU

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-PTT
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5IF
5BHVDIJ
-PTT
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WBSJBUJPO
CFMPX
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BHBJO
EFNPOTUSBUFT
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PG
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CFJOH
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T
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4IFXIBSU
OPUFE
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NFU PG
RVBMJUZ
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FTTFOUJBMMZ
BO
FDPOPNJD
QSPCMFN

.BOZ
NBOBHFST
BOE
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GPVOE
B
5IF
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PG
IJT

CPPL
Economic Control of
SFRVJSFNFOU
GPS
TVDI
EFNBOEJOH
QSFDJTJPO
EJGDVMU
Quality of Manufactured Product
NBLFT
UIJT
DMFBS

UP
VOEFSTUBOE

4PNF
GPVOE
JU
JNQPTTJCMF
UP
CFMJFWF

%S
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5BHVDIJ
GPMMPXFE
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UIJT

5IF
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TFU
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DPNQBOJFT
JT
TVDI
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JG
MJOF
PG
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)F
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PG
QPPS

UIF
DIBSBDUFSJTUJD
NFFUT
TQFDJDBUJPO
PS
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BT
UIF
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MPTT
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CZ
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EVF
UP

OP
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JNQSPWFNFOU
JT
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OPS
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BOE
QPPS
RVBMJUZ

5BHVDIJ
XBT
QBTTJPOBUF

XBSSBOUFE

*O
NPTU
DBTFT
BOZ
SFTVMU
PVUTJEF
PG
B
BCPVU
RVBMJUZ
UP
UIF
QPJOU
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IF
DMBJNFE
UIBU

TQFDJDBUJPO
PS
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JT
USFBUFE
BT
BO
BTTJHOBCMF
UIF
NBOVGBDUVSFS
PG
QPPS
RVBMJUZ
XJUI
QBSUJDVMBS

PS
TQFDJBM
DBVTF
PG
WBSJBUJPO

5IJT
PG
DPVSTF
JT
B
SFGFSFODF
UP
SFXPSL
BOE
SFKFDUT

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GBS
XPSTF
UIBO

NJTUBLF B
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B
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B
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IBT
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UIF
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FDPOPNJD
JNQBDU
PO
TPDJFUZ
JT
OJM

3FHBSEMFTT
PG

86 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

XIP
IPMET
JU
UIF

XJMM
TUJMM
CF
JOWFTUFE
PS
TQFOU

Figure 3: An asymmetrical Taguchi Loss Function Curve.
Taguchi Loss The vertical height between
PO
HPPET
BOE
TFSWJDFT

)PXFWFS
JG
B
NBOVGBDUVSFS
Function Curve the baseline and the curve
is the amount of loss. The
UISPXT
BXBZ

JO
SFKFDUT
BOE
SFXPSL
UIF
DPTU
PG
further one moves from the
Optimum Value, the greater
XBTUFE
SFTPVSDFT
DBO
OFWFS
CF
SFDPWFSFE
CZ
FJUIFS
is the loss.
UIF
DPNQBOZ
PS
CZ
TPDJFUZ

*O
BEEJUJPO
B
QSPDFTT
In this case the loss
XJUI
IJHI
MFWFMT
PG
WBSJBUJPO
JO
QSPDFTT
PX
XJMM
increases faster to the left
of the OV than it does to
IBWF
MPXFS
UISPVHIQVU
UIBU
XPVME
CF
UIF
DBTF
JG
UIF
the right.

WBSJBUJPO
JO
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PX
XBT
MPXFS

5IF
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OV
in throughput translates directly into unit costs. Copyright John McConnell 2011

)JHIFS
WBSJBUJPO
JO
QSPDFTT
PX
DPTUT
NPOFZ
5IJT

MPTT
JT
QFSNBOFOU Figure 4: Finding the area of loss.
"
VTFGVM
XBZ
UP
JOUSPEVDF
UIF
5BHVDIJ
-PTT

'VODUJPO
JT
UP
CFHJO
XJUI
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TVQQPTJUJPO
UIBU

The area of loss
EFTJHO
FOHJOFFST
DIFNJTUT
BOE
CJPMPHJTUT
JOUFOTFMZ
(shaded) is dictated
EJTMJLF
WBSJBUJPO
5IFZ
QSFGFS
QFSGFDU
QSFDJTJPO
BOE
by the steepness of
IBWF
BO
PQUJNVN
WBMVF
JO
NJOE

)PXFWFS
UIFTF
the loss function
TDJFOUJTUT
VOEFSTUBOE
UIBU
QFSGFDUJPO
DBOOPU
CF
curve.
BDIJFWFE
CZ
NFSF
NPSUBMT
BOE
UIF
NBDIJOFT
UIFZ

NBLF
BOE
TP
UIFZ
DSFBUF
TQFDJDBUJPOT
PS
UPMFSBODFT

UP
EFMJOFBUF
UIF
CPVOEBSJFT
PG
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WBSJBUJPO

8IBU
UIF
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BSF
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VT
XIFO

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OV OV
0,
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VT
XIBU
UIFZ
EPOU

SFBMMZ
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CVU
BSF
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UP
UPMFSBUF

3FHBSEMFTT
Figure 5:
3FEVDJOH
WBSJBUJPO
SFEVDFT
UIF
BSFB
PG
MPTT
PG
UIJT
UPMFSBODF
UIFSF
JT
BMXBZT
BO
PQUJNVN

LSL USL LSL USL
WBMVF
07


'PS
UIF
TBLF
PG
TJNQMJDJUZ
BOE
DMBSJUZ

UIPTF
DIBSBDUFSJTUJDT
XIFSF
CJHHFS
JT
BMXBZT
CFUUFS

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IPSTFQPXFS
PG
B
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FOHJOF

BOE
TNBMMFS

JT
BMXBZT
CFUUFS
JF
XFJHIU
PG
B
SPDLFU

XJMM
CF

ignored.

THE OLD GOALPOSTS APPROACH

*NBHJOF
XF
DSFBUF
QSPEVDU
"
XIPTF
NFBTVSFE

DIBSBDUFSJTUJD
GBMMT
POMZ
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VQQFS

TQFDJDBUJPO
BT
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/PX
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OV OV
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#
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JT
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UP
CF
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KVTU
PVUTJEF
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TBNF
VQQFS
TAGUCHIS LOSS FUNCTION CONCEPT
TQFDJDBUJPO
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PG
UIFJS
QIZTJDBM
QSPQFSUJFT
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OPUFE
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'JHVSF

5BHVDIJ
FOWJTJPOFE
B
MPTT

BOE
UIFJS
QFSGPSNBODF
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UXP
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MJLFMZ
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CF
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BMM
QSBDUJDBM
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PG
B
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GVODUJPO
DVSWF

XIJDI

JOUFOUT
JEFOUJDBM
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UIF
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MPTT
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B
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BT

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FSSPS
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XJMM
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HSFBUFS
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BXBZ
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BT
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5IF
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:FU
UIF
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DPNQBOJFT
IFJHIU
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CBTFMJOF
BU
UIF
CBTFMJOF
UIFSF
JT
OP

will generally state that product B is outside MPTT

UP
UIF
MPTT
GVODUJPO
DVSWF
EFTDSJCFE
IPX
UIF

TQFDJDBUJPOT
BOE
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JOWFTUJHBUJPO
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PG
MPTT
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BT
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NPWF
GVSUIFS

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VT
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POF
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UP
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UIF
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WBMVF
VOUJM
FWFOUVBMMZ

QSPEVDU
$
XIJDI
JT
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TQFDJDBUJPO

DPNQMFUF
MPTT
PDDVST


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OPHP
EFOJUJPO
PG
RVBMJUZ
TUBUFT
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UIPTF
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HSBTQ
PG
UIF
DPODFQU
PG

UIBU
BMM
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PVU
PG
TQFDJDBUJPO
BSF
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5BHVDIJT
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TFOTF


CBE
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4VQQPTF
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BQQSPBDI
BOE

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#
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$
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GPS
Q)
GPS
B
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different. QBSBNFUFS
BSF

UP


"
SFBEJOH
PG

XJMM

CF
BDDFQUFE
BT
JO
TQFDJDBUJPO
CVU
POF
PG


XJMM
CF
PVU
PG
TQFDJDBUJPO
FWFO
UIPVHI
UIFSF

PROCESS VALIDATION Continued Process Verification 87

John McConnell, Brian K. Nunnally, and Bernard McGarvey

JT
OP
EJTDFSOBCMF
DIBOHF
JO
UIF
QSPEVDU
PS
JO
JUT
FME
GBJMVSF
JT
JHOPSFE
JT

QFSGPSNBODF
UIF
TBNQMJOH
BOE
BOBMZUJDBM
FSSPS

NBZ
XFMM
CF
HSFBUFS
UIBO
UIF
EJGGFSFODF
CFUXFFO
k
$PTU
PG
GBJMJOH
TQFDJDBUJPO
these data). The Taguchi approach sees these data
"WFSBHF

TQFDJDBUJPO
MJNJU


OPU
TPMFMZ
PO
UIFJS
QPTJUJPO
SFMBUJWF
UP
TQFDJDBUJPOT

CVU
PO
B
DPOUJOVVN

5IF
UBSHFU
PS
PQUJNVN
WBMVF

JT


0VS
MPTT
JODSFBTFT
DPOUJOVBMMZ
UIF
GVSUIFS
UNDERSTANDING
POF
EFQBSUT
GSPN
UIJT
PQUJNVN

/PUF
IPX
BU
UIF

07
UIF
MPTT
JT
NJOJNJ[FE
CVU
JT
OPU
[FSP

"CTPMVUF
LOSSES DUE TO VARIATION
MJNJUT
BSF
TUJMM
OFDFTTBSZ
GPS
SFMFBTF
BOE
DPNQMJBODF
5IF
OFYU
TUFQ
JT
UP
PWFSMBZ
UIF
MPTT
GVODUJPO
DVSWF

SFBTPOT
CVU
JG
MPTT
JT
TFFO
PO
B
DPOUJOVVN
JU
PQFOT
POUP
UIF
SFMFWBOU
EJTUSJCVUJPO
5IF
BSFBPGJOUFSTFDU

OFX
QFSTQFDUJWFT
BOE
PQQPSUVOJUJFT
UP
VOEFSTUBOE
PG
UIFTF
UXP
DVSWFT
SFQSFTFOUT
UIF
BNPVOU
PG
MPTT

BOE
JNQSPWF
UIF
QSPDFTT
BOE
QSPEVDU
IJUIFSUP
XIJDI
DBO
CF
DBMDVMBUFE
GSPN
FRVBUJPO


4PNF

unnoticed. MPTT
GVODUJPO
DVSWFT
BSF
MPX
BOE
BU
BMMPXJOH

5IF
5BHVDIJ
-PTT
'VODUJPO
DVSWF
OFFE
OPU
CF
DPOTJEFSBCMF
NPWFNFOU
BXBZ
GSPN
UIF
PQUJNVN

TZNNFUSJDBM
BMUIPVHI
JU
PGUFO
JT

'JHVSF

TIPXT
WBMVF
CFGPSF
TJHOJDBOU
MPTT
JT
JODVSSFE

0UIFST
BSF

BO
FYBNQMF
XIFSF
UIF
DVSWF
JT
BTZNNFUSJDBM

5IF
UBMM
BOE
TUFFQ
XIFSF
FWFO
B
TNBMM
EFWJBUJPO
GSPN

MPTT
JODSFBTFT
GBTUFS
UP
UIF
SJHIU
PG
UIF
07
UIBO
JU
UIF
PQUJNVN
WBMVF
DBO
JODVS
DPOTJEFSBCMF
MPTT
BT

EPFT
UP
UIF
MFGU

5IF
EFUFSNJOBUJPO
PG
UIF
TIBQF
PG
OPUFE
JO
'JHVSF


5IF
TUFFQOFTT
PG
UIJT
DVSWF
JT

UIF
DVSWF
JT
UFDIOJDBM
JO
OBUVSF
SBUIFS
UIBO
QVSFMZ
ESJWFO
CZ
UIF
NBHOJUVEF
PG
UIF
k factor.
statistical. *O
NPTU
DBTFT
XPSLJOH
PO
UIF
FBSMJFS
TUFQT
JO
UIF

5IF
%FNJOH
5BHVDIJ
BOE
4JY
4JHNB
BQQSPBDIFT
QSPDFTT
XJUI
QBSUJDVMBS
SFHBSE
UP
JOQVUT
BOE
TFUVQ

EFNBOE
BCBOEPONFOU
PG
SFMJBODF
PO
UIF
HP
OPHP
PG
UIF
QSPDFTT
QSPWJEFT
TJHOJDBOU
MFWFSBHF
CFDBVTF

TQFDJDBUJPOT

*U
JT
TUJMM
OFDFTTBSZ
UP
TFU
BCTPMVUF
UIF
MPTT
GVODUJPO
DVSWFT
BSF
OFBSMZ
BMXBZT
TUFFQFS

MJNJUT
CVU
TVDI
MJNJUT
TIPVME
OPU
CF
UIF
TPMF
UIFSF

5IF
JNQPSUBODF
PG
XPSLJOH
VQTUSFBN
JO
UIF

CBTJT
GPS
BTTFTTJOH
UIF
WBSJBUJPO
BU
BOZ
TUBHF
PG
UIF
QSPDFTT
DBOOPU
CF
PWFSTUBUFE

5PP
PGUFO
B
QMBOUT

QSPDFTT
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BEEJUJPO
HP
OPHP
TQFDJDBUJPOT
TIPVME
NPTU
UBMFOUFE
QFPQMF
DBO
CF
GPVOE
XPSLJOH
JO
UIF

OFWFS
CF
VTFE
BT
UIF
CBTJT
GPS
QSPDFTT
DPOUSPM NJEEMF
PS
MBUUFS
TUBHFT
PG
UIF
QSPDFTT
BGUFS
WBSJBUJPO

5IF
5BHVDIJ
MPTT
GVODUJPO
UBLFT
TFWFSBM
GPSNT

JO
UIF
FBSMJFS
FWFOUT
IBT
BMSFBEZ
EFTUBCJMJ[FE
UIF

0OF
RVBESBUJD
GPSN
PG
DBMDVMBUJPO
JT
TIPXO
JO
process and shrouded cause and effect relationships.
FRVBUJPOT

BOE



0UIFS
TUBUJTUJDBM
NFUIPET
TVDI
BT
%0&
XJMM
IFMQ
UP

JTPMBUF
UIPTF
WBSJBCMFT
UIBU
IBWF
UIF
HSFBUFTU
JNQBDU

PO
RVBMJUZ
BOE
DPTUT

"
DPSOVDPQJB
PG
BEWBODFE

'PS
BOZ
HJWFO
QSPEVDU
TUBUJTUJDBM
UFDIOJRVFT
FYJTUT
CVU
JU
JT
CFZPOE
UIF

TDPQF
PG
UIJT
BSUJDMF
UP
DPWFS
UIFN
Lossx = k(x-OV)2 <&RVBUJPO
>
5BHVDIJT
BQQSPBDI
EFNPOTUSBUFT
UXP
JNQPSUBOU

JEFBT

'JSTUMZ
JU
JT
JO
DPODFSU
XJUI
%S
%FNJOHT

8IFSF TUBUFNFOU
UIBU
TPNF
MPTT
XJMM
CF
JODVSSFE
FWFO
JG

BMM
EBUB
NFFU
TQFDJDBUJPOT
BOE
UIBU
CVTJOFTTFT

TIPVME
BMXBZT
CF
BUUFNQUJOH
UP
SFEVDF
WBSJBUJPO


x

WBMVF
PG
RVBMJUZ
DIBSBDUFSJTUJD /PUF
IPX
JO
'JHVSF

UIF
TIBEFE
BSFB
CFUXFFO

OV

0QUJNVN
7BMVF UIF
EJTUSJCVUJPO
BOE
UIF
MPTT
GVODUJPO
DVSWF

k 
"
QSPQPSUJPOBMJUZ
DPOTUBOU
B
GVODUJPO
EFNPOTUSBUFT
UIBU
MPTT
FYJTUT
FWFO
UIPVHI
BMM

of the failure cost structure) PVUDPNFT
NFFU
TQFDJDBUJPOT

4FDPOEMZ
JU

EFNPOTUSBUFT
UIBU
BT
WBSJBUJPO
JT
SFEVDFE
TP
UPP
JT

UIF
BNPVOU
PG
MPTT
JODVSSFE
BT
OPUFE
JO
'JHVSF


*U

'PS
BOZ
HJWFO
QPQVMBUJPO
PG
QSPEVDUT POMZ
SFNBJOT
UP
JTPMBUF
UIPTF
WBSJBCMFT
UIBU
QSPWJEF

HSFBUFTU
MFWFSBHF
Lossx = k(x2 + (Avex - OV )2)
<&RVBUJPO
>
5BHVDIJT
DPODFQUT
MFE
UP
UIF
EFWFMPQNFOU
PG
UIF

NPTU
DPNQMFUF
EFOJUJPO
PG
RVBMJUZ
BT
GPMMPXT
All characteristics should have minimum, stable
"
TJNQMJFE
WFSTJPO
PG
UIF
k factor
variation around an optimum value.
FYJTUT
UIBU
NBLFT
DFSUBJO
BTTVNQUJPOT
%S
5BHVDIJT
DPODFQU
JT
POF
XBZ
UP
JMMVTUSBUF
IPX

JODMVEJOH
UIBU
UIF
TQFDJDBUJPOT
IBWF
WBSJBUJPO
JNQBDUT
PO
QSPDFTTFT
BOE
DPTUT
4JY
4JHNB

CFFO
QSPQFSMZ
TFU
BOE
UIBU
BOZ
DPTU
PG
JT
BOPUIFS
BT
JT
%FNJOHT
BQQSPBDI
BOE
-JUUMFT
-BX

88 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

8IBU
JT
DMFBS
JT
UIBU
TFWFSBM
EJGGFSFOU
BQQSPBDIFT
UP
CONCLUSIONS
UIF
TVCKFDU
BSSJWF
BU
TUSJLJOHMZ
TJNJMBS
DPODMVTJPOT
7BSJBUJPO
JT
OPU
GSFF
OPU
FWFO
XIFO
BMM
PVUDPNFT

as follows: BQQFBS
UP
NFFU
TQFDJDBUJPOT

7BSJBUJPO
DPOTVNFT

t

7BSJBUJPO
DPTUT
NPOFZ
FWFO
XIFO
FWFSZUIJOH
SFTPVSDFT
NPOFZ
BOE
UJNF

8IFSF
B
TJHOJDBOU

BQQFBST
UP
NFFU
TQFDJGJDBUJPOT QSPQPSUJPO
PG
UFDIOJDBM
QFSTPOOFMT
UJNF
JT

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The Journal of Validation Technology

PROCESS VALIDATION Continued Process Verification 89

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Process Modeling:
A Powerful Weapon in the
Fight to Reduce VariationPart 1
John McConnell, Brian K. Nunnally, and Bernard McGarvey

ABSTRACT Q)
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[
ABOUT THE AUTHORS
For more Author John McConnell is the coordinator of Analysis and Control of Variation and is the owner and direc-
information, tor of Wysowl Pty Ltd. in Queensland, Australia. He may be reached at john@wysowl.com.au. Brian K.
go to Nunnally, Ph.D., is associate director, Validation, at Wyeth Research. He may be reached at nunnalb@
gxpandjvt.com/bios wyeth.com. Bernard McGarvey, Ph.D., is process modeling group leader, Process Engineering Cen-
ter, Eli Lilly and Company. He may be reached at mcgarvey_bernard@lilly.com.

90 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

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PROCESS VALIDATION Continued Process Verification 91

John McConnell, Brian K. Nunnally, and Bernard McGarvey

Figure 3: HPW distribution system. occurred.

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CASE STUDYCOMMON CAUSE

VARIABILITY AND PREVENTION
CONTROL "
OFX
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XBT
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EFWFMPQFE
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B

VALVE(S) QPXEFS
UP
CF
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WJBMT
5IF
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GJMMFE
EFQFOET
PO
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PG
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SPUBUJPOT
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UIF

Figure 4: Pressure profile through valve. GJMMJOH
BOE
HJWFO
B
GJYFE
GJMM
UJNF
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CFFO
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PRESSURE VAPOR WBSJBUJPO
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PRESSURE *U
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UIBU
UIJT
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PG
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XPVME

FLUID FLOW THROUGH THE CONTROL VALVE CF
VOBDDFQUBCMF
UP
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UP
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or product design or proposed product or process UP
DMBTTJGZ
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BOE
UIF
SFTVMUT

92 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

TIPXFE
UIBU
B
TVJUBCMF
DPOUSPMMFS
DPVME
CF
EFTJHOFE

Figure 5: Linear to rotating table vial transport system.


'JHVSF

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PG
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TFU
VIAL MOVEMENT
PG
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VIAL MOVEMENT
no control and the lower chart shows what this would
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GUIDE


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Figure 6: Model output showing a vial falling over.
ZPV
HP
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CASE STUDYSPECIAL CAUSE WBMWF
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VARIABILITY AND PREVENTION DJQMF


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on an airplane wing when the shape of the wing causes
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the air on the top of the wing to flow faster than the air
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PROCESS VALIDATION Continued Process Verification 93

John McConnell, Brian K. Nunnally, and Bernard McGarvey

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tion. Then the following options were tested in the TJNVMBUFT
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TFF
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effect his creates a restriction in the line after XPVME
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PQFSBUF
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VARIABILITY AND CORRECTION
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CASE STUDYCOMMON CAUSE BOE
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VARIABILITY AND CORRECTION MJRVJE
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94 PROCESS VALIDATION Continued Process Verification

 John McConnell, Brian K. Nunnally, and Bernard McGarvey

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Figure 7: Force per stopper histogram for batch with defects.
WJBMT
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Simulation Results
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0.13 25000
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Relative Probability
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Vial Height Delta 0.925
on the lowest shelf and the results presented as a histo
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This plot shows the correlation of each input to the
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PROCESS VALIDATION Continued Process Verification 95

John McConnell, Brian K. Nunnally, and Bernard McGarvey

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Identification of Parametric Models from
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CONCLUSION 
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Analysis and Control of Variation
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Understanding Variation, the Key to Managing
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REFERENCES 
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The Journal of Validation Technology

96 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta

White Spots on Tablets

Compliance
IMAGEZOO/GETTY IMAGES Case Study #8
Paul L. Pluta

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The following key points are discussed:
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growth.
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source of the white spots.
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excipient.
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conducted.
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[
ABOUT THE AUTHORS
For more Author Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive technical and management experience
information,
in the pharmaceutical industry. He is editor in chief of the Journal of GXP Compliance and the Journal of
Validation Technology. Dr. Pluta is also adjunct associate professor at the University of Illinois College of
go to
Pharmacy in Chicago, Illinois USA. He is the editor of and contributed chapters to Cleaning and Cleaning
gxpandjvt.com/bios Validation, published by PDA and Davis Healthcare International in 2009. He may be reached by e-mail at
paul.pluta@comcast.net.

PROCESS VALIDATION Continued Process Verification 97

Paul L. Pluta
INTRODUCTION
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Journal of GXP
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growth.

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reported for this or any other products at the site.
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and analysis.
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Corrective action and preventive action (CAPA).
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98 PROCESS VALIDATION Continued Process Verification
WPMVNF
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as follows:
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issues.
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QA Personnel Interviews
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B
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PG
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/P

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PG
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TQPUT
PO
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Technical Personnel Investigation

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UIF
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PG
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pursued.
Microbiological testing.

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GPS

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PG
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HSPXUI

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HSPXUI
XBT

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BT
B
DBVTF
PG
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Elemental analysis.

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TQPUT
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GSPN
UIF
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GPS
NJDSPTDPQJD


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4BNQMFT
PG
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UIF

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GPS

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/P
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PG
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CZ
HSFBTF

XBT
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5IF
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DPNQPTJUJPO
PG
UIF

Paul L. Pluta
XIJUF
TQPUT
XBT
JEFOUJDBM
UP
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GPSNVMBUJPO

DPNQPOFOUT

(SFBTF
TQPUT
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BT
B
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PG
UIF
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Changes in formulation materials. The purchasing
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PG
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5IFSF

XFSF
OP
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5IFSF
XFSF
OP
DIBOHFT

JO
TVQQMJFST
PG
GPSNVMBUJPO
NBUFSJBMT

"MM
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B
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IJTUPSZ

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DIBOHFT
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OPU
B
DBVTF
PG
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FD&C Blue #2 chemistry. Technical personnel
#MVF

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PG
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EZF
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UP
CF
UIF
TPVSDF
PG
UIF

XIJUF
TQPUT
'%$
#MVF

JT
B
XJEFMZ
VTFE
TZOUIFUJD

CMVF
EZF
BOE
JT
VTFE
JO
UIF
EZJOH
PG
CMVF
KFBOT


'%$
#MVF

JT
BMTP
LOPXO
BT
*OEJHPUJO
EZF
DIFNJDBMMZ
SFEVDFE
UP
JOEJHP
XIJUF
PS
MFVDPJOEJDP
XIJDI
JT
XIJUF
JO
DPMPS

5IF
GPSNVMBUJPO
PG
UIF
CMVF

UBCMFU
QSPEVDU
DPOUBJOFE
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UIBU
NBJOUBJOFE

BO
BMLBMJOF
Q)
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Q)
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GPS
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5IF
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PG
UIF
UBCMFU

DPSF
DBVTFE
SFEVDUJPO
PG
UIF
CMVF
EZF
UP
JOEJHPXIJUF
XIJDI
JO
UVSO
DBVTFE
XIJUF
TQPSUT

)PXFWFS
PG
UIF
TVEEFO
DIBOHF
JO
UIF
BQQFBSBODF
PG
UIF
UBCMFU

XIFO
UIFSF
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CFFO
OP
DIBOHFT
JO
UIF
GPSNVMBUJPO
NBUFSJBMT
Manufacturing equipment.
8IFO
QSPCMFNT

XJUI
UIF
CMVF
EZF
XFSF
JEFOUJGJFE
NBOBHFNFOU
GVSUIFS
QSPCFE
'%$

IBOEMJOH
BOE

QSPDFTTJOH
%JTDVTTJPOT
XJUI
NBOVGBDUVSJOH
PQFSBUPST

JOEJDBUFE
UIBU
UIFSF
XBT
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GPS
JNQSPQFSMZ

BTTFNCMFE
NJMMJOH
FRVJQNFOU

*U
XBT
QPTTJCMF
UIBU

UIF
NJMMJOH
TDSFFOT
XFSF
OPU
DPSSFDUMZ
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UIJT

PDDVSSFE
DIBNCFS
BOE
XPVME
OPU
CF
NJMMFE
$PSSFDU
FRVJQNFOU

TFUVQ
XBT
OFDFTTBSZ
GPS
HPPE
NJMMJOH
t
Control milling.

5IF
JNQBDU
NJMM
XBT
BTTFNCMFE

NJMMFE

4JFWF
BOBMZTJT
XBT
DPOEVDUFE
UP

DIBSBDUFSJ[F
UIF
NJMMFE
NBUFSJBM
t
Problem milling.

5IF
JNQBDU
NJMM
XBT
BTTFNCMFE

JODPSSFDUMZ

"MLBMJOF
FYDJQJFOU
XBT
NJMMFE


6ONJMMFE
QPXEFS
XBT
PCTFSWFE
FTDBQJOH
UIF

NJMMJOH
DIBNCFS

4JFWF
BOBMZTJT
XBT
DPOEVDUFE
UP

DIBSBDUFSJ[F
UIF
NJMMFE
NBUFSJBM

%BUB
JOEJDBUFE

UIBU
B
TNBMM
QFSDFOUBHF
PG
QBSUJDMFT
XFSF
OPU

NJMMFE
QBSUJDMFT
JO
UIF
UBCMFU
DPSF

*U
XBT
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UIBU
UIFTF
MBSHF
QBSUJDMFT
SFBDUFE
XJUI
CMVF
EZF
UP

DBVTF
XIJUF
TQPUT
JO
UIF
CMVF
UBCMFUT
PROCESS VALIDATION Continued Process Verification 99
Paul L. Pluta

t
Control tablets.

1SPEVDU
UBCMFUT
XFSF
t
%PDVNFOUBUJPO

NBOVGBDUVSFE
XJUI
DPSSFDUMZ
NJMMFE
NBUFSJBM t
$PNNVOJDBUJPO
UP
PUIFS
TJUFT
t
Problem tablets.

1SPEVDU
UBCMFUT
XFSF
t
0UIFS
TJNJMBS
QSPEVDUT
NBOVGBDUVSFE
BU
UIF
TJUF
NBOVGBDUVSFE
XJUI
JNQSPQFSMZ
NJMMFE
NBUFSJBM
$PNQBSBUJWF
UFTUJOH
PG
DPOUSPM
UBCMFUT
BOE
New Milling Equipment Assembly Procedure
FYQFSJNFOUBM
UBCMFUT
VOEFS
BDDFMFSBUFE
UFNQFSBUVSF
5IF
JNQPSUBODF
PG
FRVJQNFOU
BTTFNCMZ
JO

DPOEJUJPOT
XBT
UIFO
DPOEVDUFE
4BNQMFT
PG
SFTQFDUJWF
UIF
NJMMJOH
QSPDFTT
JOEJDBUFE
UIBU
HSFBUFS

UBCMFUT
XFSF
BMTP
TUPSFE
VOEFS
SFGSJHFSBUJPO
5BCMFUT
DPOUSPM
XBT
SFRVJSFE

"
OFX
BOE
NPSF
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NBOVGBDUVSFE
XJUI
UIF
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NBUFSJBM
BTTFNCMZ
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XBT
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"MTP
UIF

TUPSFE
BU
IJHI
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BOE
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XIJUF
TQPUT
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XBT
DPODMVEFE
UIBU
UIF
MBSHF
QBSUJDMF TJHOBUVSF

UIF
BTTFNCMZ
PG
UIF
NJMM
CZ
UIF

TJ[F
FYDJQJFOU
XBT
UIF
DBVTF
PG
UIF
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XIJUF
TQPUT
NBOVGBDUVSJOH
PQFSBUPS
4JHOPGG
CZ
UIF
TVQFSWJTPS

JO
UIF
UBCMFUT
$PNQBSJTPO
PG
UBCMFUT
TUPSFE
VOEFS
XBT
BEEFE
UP
UIF
NBOVGBDUVSJOH
CBUDI
SFDPSE
BDDFMFSBUFE
DPOEJUJPOT
UP
UIF
SFGSJHFSBUFE
UBCMFUT

JOEJDBUFE
UIBU
UIF
SFGSJHFSBUFE
UBCMFUT
XFSF
TMJHIUMZ
New Milling Process
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JO
DPMPS
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UIF
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5IJT
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OFX
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JOEJDBUFE
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DIFNJDBMMZ
JNQMFNFOUFE
GPS
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XJUI
UIF
BMLBMJOF
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BT
UIBU
XBT
EFUFSNJOFE
UP
CF
UIF
DBVTF
PG
UIF
XIJUF

MPOH
BT
UIF
BMLBMJOF
FYDJQJFOU
XBT
GJOFMZ
NJMMFE
DPMPS
TQPU
QSPCMFN
XBT
NJMMFE
UXJDF
UISPVHI
UIF
JNQBDU

DIBOHF
XBT
TMPX
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BOE
HFOFSBMMZ
VOOPUJDFBCMF
NJMM

"GUFS
NJMMJOH
UIF
NJMMFE
NBUFSJBM
XBT
TBNQMFE

to the naked or untrained eye. and tested for passage through an appropriate
TDSFFO

"OZ
VONJMMFE
QBSUJDMFT
XPVME
OPU
QBTT

DISCUSSION UISPVHI
UIF
TDSFFO
*G
VONJMMFE
QBSUJDMFT
XFSF

*OGPSNBUJPO
PCUBJOFE
UISPVHI
JOUFSWJFXT
BOE
PCTFSWFE
UIF
QSPDFTT
XBT
TUPQQFE
BOE
B
TVQFSWJTPS

TVCTFRVFOU
FYQFSJNFOUBM
XPSL
FOBCMFE
HPPE
XBT
JNNFEJBUFMZ
OPUJGJFE
VOEFSTUBOEJOH
PG
UIF
QSPCMFN
EFUFSNJOBUJPO
PG
UIF

SPPU
DBVTF
BOE
VMUJNBUF
DPSSFDUJWF
BOE
QSFWFOUJWF
Process Validation
action. Original speculation as to potential causes of 1SPEVDU
NBOVGBDUVSFE
VTJOH
UIF
OFX
NJMMJOH
QSPDFTT

UIF
QSPCMFN
XFSF
UFTUFE
BOE
EJTQSPWFO

*OWFTUJHBUJWF
XBT
WBMJEBUFE
5IF
BNPVOU
PG
BMLBMJOF
FYDJQJFOU

BOE
FYQFSJNFOUBM
XPSL
CZ
UIF
UFDIOJDBM
HSPVQ
DPNQSJTFE
B
WFSZ
MPX
QFSDFOU
PG
UIF
GPSNVMBUJPO

DPODMVTJWFMZ
EFUFSNJOFE
UIF
SPPU
DBVTF
PG
UIF
XIJUF
5IF
BNPVOU
PG
QPUFOUJBMMZ
TNBMMFS
QBSUJDMF
TJ[F

TQPU
QSPCMFN

'%$
#MVF

EZF
JO
UIF
GPSNVMBUJPO
PG
UIJT
JOHSFEJFOU
EJE
OPU
JNQBDU
UIF
QBSUJDMF
TJ[F

XBT
DIFNJDBMMZ
SFEVDFE
UP
JOEJHP
XIJUF
B
XIJUF
EJTUSJCVUJPO
JO
UIF
CMFOEFE
HSBOVMBUJPO
BOE
EJE
OPU

TVCTUBODF

-BSHF
QBSUJDMFT
PG
BMLBMJOF
FYDJQJFOU
XIJDI
BGGFDU
UIF
GMPX
QSPQFSUJFT
PS
DPNQSFTTJOH
QSPDFTT
GPS

IBE
OPU
CFFO
NJMMFE
DBVTFE
UIF
MPDBMJ[FE
DIFNJDBM
the product.
SFBDUJPO
SFTVMUJOH
JO
UIF
GPSNBUJPO
PG
UIF
EJTUJODU

XIJUF
TQPUT
5IF
BMLBMJOF
FYDJQJFOU
JO
UIF
GPSNVMBUJPO
Training
XBT
OPU
NJMMFE
CFDBVTF
UIF
NJMMJOH
TDSFFOT
XFSF
"MM
QFSTPOOFM
XFSF
USBJOFE
PO
UIF
OFX
FRVJQNFOU

JODPSSFDUMZ
JOTUBMMFE
JO
UIF
JNQBDU
NJMM

$PNQBSBUJWF
BTTFNCMZ
QSPDFEVSF
BOE
NJMMJOH
QSPDFTT
QSPDFEVSF

UFTUJOH
DPODMVTJWFMZ
QSPWFE
UIBU
UIF
JNQSPQFSMZ
NJMMFE
5IF
JNQPSUBODF
PG
UIF
NJMMJOH
QSPDFTT
JO

alkaline excipient was the cause of the white spot NBOVGBDUVSJOH
UIJT
QSPEVDU
BOE
UIF
DPSSFMBUJPO
PG

QSPCMFN

$PNQBSJTPO
PG
IFBUFE
UBCMFUT
UP
SFGSJHFSBUFE
JNQSPQFS
NJMMJOH
UP
UIF
XIJUF
TQPU
QSPCMFN
XFSF

UBCMFUT
DPOGJSNFE
UIF
TVTDFQUJCJMJUZ
PG
UIF
'%$
#MVF
XFMM
DPNNVOJDBUFE
5SBJOJOH
PO
QSPQFS
TFUVQ
PG


UP
BMLBMJOF
DIFNJDBM
SFEVDUJPO

"T
MPOH
BT
UIF
NJMMJOH
FRVJQNFOU
XBT
BQQMJDBCMF
UP
BMM
QSPEVDUT

BMLBMJOF
FYDJQJFOU
XBT
GJOFMZ
NJMMFE
MJHIUFOJOH
PG
UIF
NBOVGBDUVSFE
BU
UIF
TJUF

&TTFOUJBMMZ
BMM
QSPEVDUT

CMVF
UBCMFUT
XBT
OPU
OPUJDFBCMF
5IF
JNQPSUBODF
PG
UIF
JODMVEFE
NJMMJOH
BT
QBSU
PG
UIFJS
NBOVGBDUVSJOH

NJMMJOH
QSPDFTT
BOE
FTQFDJBMMZ
PG
DPSSFDU
JOTUBMMBUJPO
PG
process.
TDSFFOT
JO
UIF
JNQBDU
NJMM
XBT
DMFBSMZ
EFNPOTUSBUFE
Documentation
CORRECTIVE AND PREVENTIVE ACTIONS "MM
XPSL
BTTPDJBUFE
XJUI
UIF
PSJHJOBM
WBMJEBUJPO

5IF
GPMMPXJOH
$"1"
BOE
BTTPDJBUFE
BDUJWJUJFT
XBT
DPNQMFUFE
"MM
JOWFTUJHBUJPOT
BOBMZTFT
BOE

were conducted: DPODMVTJPOT
XFSF
EPDVNFOUFE
UP
DMPTF
UIF
$"1"


t
/FX
NJMMJOH
FRVJQNFOU
BTTFNCMZ
QSPDFEVSF %FWFMPQNFOU
PG
UIF
OFX
NBOVGBDUVSJOH
QSPDFTT

t
/FX
NJMMJOH
QSPDFTT JODMVEJOH
USJBM
SVOT
XBT
EPDVNFOUFE
BOE
GJMFE
JO

t
1SPDFTT
WBMJEBUJPO UIF
WBMJEBUJPO
MJCSBSZ
BT
TVQQPSUJOH
JOGPSNBUJPO
GPS

t
Training UIF
WBMJEBUJPO
QSPDFTT
RVBMJGJDBUJPO
12

SVOT

64

100 PROCESS VALIDATION Continued Process Verification

 Paul L. Pluta

'PPE
BOE
%SVH
"ENJOJTUSBUJPO
JOWFTUJHBUPST
WJTJUFE
XBT
DIFNJDBMMZ
JODPNQBUJCMF
XJUI
UIF
BMLBMJOF

UIF
NBOVGBDUVSJOH
TJUF
JO
SFTQPOTF
UP
DVTUPNFS
FYDJQJFOU

)PXFWFS
BT
MPOH
BT
UIF
BMLBMJOF
FYDJQJFOU

DPNQMBJOUT
"MM
JOWFTUJHBUJPO
EPDVNFOUBUJPO
XBT
GJOFMZ
NJMMFE
DPMPS
DIBOHF
XBT
TMPX
EJGGVTF

XBT
SFWJFXFE
CZ
'%"
JOWFTUJHBUPST
/P
'%"

BOE
HFOFSBMMZ
VOOPUJDFBCMF

5IF
JNQPSUBODF

PCTFSWBUJPOT
XFSF
JTTVFE PG
UIF
NJMMJOH
QSPDFTT
BOE
FTQFDJBMMZ
PG
DPSSFDU

JOTUBMMBUJPO
PG
TDSFFOT
JO
UIF
JNQBDU
NJMM
XBT
DMFBSMZ

Communication to Other Sites EFNPOTUSBUFE
5IF
JODJEFOU
EFTDSJCFE
IFSFJO
XBT
DPNNVOJDBUFE
UP
$"1"
BOE
BTTPDJBUFE
BDUJWJUJFT
DPOEVDUFE

PUIFS
HMPCBM
TJUFT
MJDFOTFE
UP
NBOVGBDUVSF
UIJT
QSPEVDU JODMVEFE
B
OFX
NJMMJOH
FRVJQNFOU
BTTFNCMZ

QSPDFEVSF
UP
QSFWFOU
JNQSPQFS
FRVJQNFOU
TFUVQ
B

Other Similar Products Manufactured At The Site OFX
NJMMJOH
QSPDFTT
QSPDFTT
WBMJEBUJPO
PG
UIF
OFX

5IF
NJMMJOH
QSPCMFN
EFTDSJCFE
XBT
VOJRVF
UP
UIF
QSPDFTT
USBJOJOH
PG
NBOVGBDUVSJOH
QFSTPOOFM
BOE

specific product. Other products did not contain EPDVNFOUBUJPO
PG
BMM
BDUJWJUJFT
5IF
EPDVNFOUBUJPO

UIF
TBNF
DPMPSBOUT
PS
GPSNVMBUJPO
DPOUBJOJOH
UIF
XBT
BMNPTU
JNNFEJBUFMZ
VTFGVM
XIFO
'%"
BVEJUFE

alkaline excipient. UIF
TJUF
JO
SFTQPOTF
UP
DVTUPNFS
DPNQMBJOUT
UP

UIF
"HFODZ
5IJT
FWFOU
BOE
JUT
DPSSFDUJWF
BDUJPOT

POST CAPA MONITORING XFSF
DPNNVOJDBUFE
UP
PUIFS
DPSQPSBUF
TJUFT

"EEJUJPOBM
NPOJUPSJOH
PG
NBOVGBDUVSJOH
XBT
NBOVGBDUVSJOH
UIF
TBNF
QSPEVDU
/P
PUIFS
QSPEVDUT

DPOEVDUFE
UP
DPOGJSN
TVDDFTTGVM
DPSSFDUJWF
BDUJPO

NBOVGBDUVSFE
BU
UIF
TJUF
XFSF
TVTDFQUJCMF
UP
UIJT

"
GJOBM
SFQPSU
TVNNBSJ[JOH
BMM
NPOJUPSJOH
EBUB
QSPCMFN
"EEJUJPOBM
NPOJUPSJOH
PG
NBOVGBDUVSJOH

XBT
QSFQBSFE
BGUFS
UISFF
NPOUIT
NBOZ
MPUT

PG
XBT
DPOEVDUFE
/P
JOTUBODFT
PG
JNQSPQFS
NBDIJOF

NBOVGBDUVSJOH

/P
JOTUBODFT
PG
JNQSPQFS
NBDIJOF
TFU
VQ
XFSF
PCTFSWFE

/P
NJMMJOH
EJGGJDVMUJFT
XFSF

TFU
VQ
XFSF
PCTFSWFE

/P
NJMMJOH
EJGGJDVMUJFT
XFSF
SFQPSUFE

/P
DPNQMBJOUT
PO
QSPEVDU
MPUT
UIBU

SFQPSUFE

/P
DVTUPNFS
DPNQMBJOUT
PO
QSPEVDU
MPUT
XFSF
NBOVGBDUVSFE
BGUFS
UIF
QSPDFTT
DIBOHFT
XFSF

UIBU
XFSF
NBOVGBDUVSFE
BGUFS
UIF
QSPDFTT
DIBOHFT
XFSF
SFDFJWFE

$PSSFDUJWF
BDUJPO
XBT
TVDDFTTGVM
SFDFJWFE

$PSSFDUJWF
BDUJPO
XBT
TVDDFTTGVM 5IJT
DBTF
TUVEZ
EFNPOTUSBUFE
IJHIMZ
VOMJLFMZ
DBVTFT

PG
B
TFSJPVT
DPNQMJBODF
QSPCMFN

$IFNJDBM
QSPQFSUJFT

CONCLUSIONS PG
JOBDUJWF
JOHSFEJFOUT
BSF
OPU
B
UZQJDBM
DBVTF
PG

"
DBTF
TUVEZ
EFTDSJCJOH
B
DPNQMJBODF
FWFOU
JO
XIJDI
QSPCMFNT

5IF
NJMMJOH
QSPDFTT
JT
BMTP
OPU
DPOTJEFSFE

B
MBSHF
OVNCFS
PG
QSPEVDU
DPNQMBJOUT
JOWPMWJOH
UP
CF
B
QSPCMFNBUJD
NBOVGBDUVSJOH
QSPDFTT

5IFTF
UXP

EJTUJODU
XIJUF
TQPUT
PO
B
UBCMFU
QSPEVDU
XBT
VOMJLFMZ
DBVTFT
DPNCJOFE
UP
DBVTF
B
WFSZ
TJHOJGJDBOU

EJTDVTTFE
5IF
DBVTF
PG
UIF
QSPCMFN
XBT
OPU
FBTJMZ
QSPCMFN

$PNQMJBODF
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NVTU
CF
BXBSF
UIBU

EFUFSNJOFE

4QFDVMBUJPO
PO
UIF
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TPVSDF
BMM
JOHSFEJFOUT
JO
UIF
GPSNVMBUJPO
OPU
KVTU
UIF
BDUJWF

SBOHFE
GSPN
HSFBTF
TQPUT
UP
NJDSPCJBM
HSPXUI

5IF
ESVH
NBZ
IBWF
TJHOJGJDBOU
OFHBUJWF
FGGFDUT
PO
UIF

QSPEVDU
IBE
CFFO
TVDDFTTGVMMZ
NBOVGBDUVSFE
GPS
QSPEVDU

$PNQMJBODF
QFSTPOOFM
NVTU
OPU
BTTVNF

NBOZ
ZFBST
XJUIPVU
BOZ
JODJEFODF
PG
UIJT
UZQF
PG
TJNQMF
NBOVGBDUVSJOH
QSPDFTTFT
UP
CF
QSPCMFN
GSFF


DPNQMBJOU

5FDIOJDBM
QFSTPOOFM
DPOEVDUFE
QBSBMMFM
5IF
JOBDUJWF
JOHSFEJFOUT
BSF
JNQPSUBOU
DPNQPOFOUT

JOWFTUJHBUJPOT
BEESFTTJOH
QPTTJCMF
DBVTFT
PG
UIF
PG
QSPEVDUT

5IF
QFSGPSNBODF
PG
FWFO
QSFTVNBCMZ

XIJUF
TQPU
QSPCMFN
5IFTF
JODMVEFE
NJDSPCJPMPHJDBM
NVOEBOF
QSPDFTTFT
TVDI
BT
NJMMJOH
NVTU
CF
TFSJPVTMZ

UFTUJOH
FMFNFOUBM
BOBMZTJT
DIBOHFT
JO
GPSNVMBUJPO
DPOTJEFSFE

$PNQMJBODF
QFSTPOOFM
NVTU
LFFQ
BO
PQFO

NBUFSJBMT
BOE
DIFNJTUSZ
PG
'%$
#MVF

UIF
NJOE
XJUIPVU
QSFDPODFJWFE
CFMJFGT
XIFO
JOWFTUJHBUJOH

DPMPSBOU
JO
UIF
GPSNVMBUJPO
$IFNJDBM
DIBOHF
QSPCMFN
TJUVBUJPOT
DIFNJDBM
SFEVDUJPO
JO
BMLBMJOF
Q)

PG
UIF
CMVF
EZF

XBT
EFUFSNJOFE
UP
CF
UIF
TPVSDF
PG
UIF
XIJUF
TQPUT

"MM
PUIFS
QPUFOUJBM
QSPCMFN
DBVTFT
XFSF
EJTQSPWFO REFERENCE
.BOVGBDUVSJOH
QFSTPOOFM
EFUFSNJOFE
UIBU
UIFSF
'%"
$PEF
PG
'FEFSBM
3FHVMBUJPOT
5JUMF

'PPE
BOE
%SVHT

XBT
QPUFOUJBM
GPS
JNQSPQFSMZ
BTTFNCMFE
NJMMJOH
1BSU

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(PPE
.BOVGBDUVSJOH
1SBDUJDF
GPS
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XBT
OPU
NJMMFE

1IBSNBDFVUJDBMT

Federal Register

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5IJT
JO
UVSO
DBVTFE
GPSNBUJPO
PG
UIF
XIJUF
TQPUT

GXP
&YQFSJNFOUBM
USJBMT
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BMTP
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The Journal of GXP Compliance

PROCESS VALIDATION Continued Process Verification 101

D. Wylie McVay, Jr.

Compliance Case Study #5

Secondary Packages With
IMAGEZOO/GETTY IMAGES Defective Glue Joints
D. Wylie McVay, Jr.

KEY POINTS DISCUSSED PDDVSSFODF

5FDIOPMPHJDBM
BEWBODFT
NBZ
BMUFS
TPNF

The following key points are discussed in this article: EFUBJMT
CVU
OPU
UIF
QSJODJQMFT
SFMBUFE
UP
UIF
DPSSFDUJWF

t
"
DPNQMJBODF
DBTF
TUVEZ
JOWPMWJOH
EFGFDUJWF
BDUJPOT
BOE
QSFWFOUJWF
BDUJPOT
$"1"

packages is discussed 5IJT
EJTDVTTJPO
QSPWJEFT
UIF
GPMMPXJOH
t
"
NVUVBM
USVTUJOH
SFMBUJPOTIJQ
XJUI
UIF
WFOEPS
JT
t
Process descriptions. Background on
LFZ
UP
QSPCMFN
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QSPDFTTFT
JOWPMWFE
t
&NQIBTJT
JT
QMBDFE
PO
UIF
JNQPSUBODF
PG
t
Compliance event.

"
EFTDSJQUJPO
PG
UIF
FWFOU
UIF

VOEFSTUBOEJOH
TVQQMJFS
BOE
DVTUPNFS
DBQBCJMJUJFT LFZ
JTTVFT
UP
CF
BEESFTTFE
BOE

t
5IF
FGGFDUJWFOFTT
PG
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PGUFO
BQQMJDBCMF
DVSSFOU
HPPE
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the result of careful attention to details QSBDUJDF
$(.1

SFRVJSFNFOUT
t
2VBMJUZ
DPOUSPM
PG
B
QSPDFTT
NVTU
CF
QMBDFE
BU
UIF
t
Investigation.

*OUFSWJFXT
BOE
BDUJPOT

critical control step DPOEVDUFE
UP
JOWFTUJHBUF
UIF
FWFOU
t
4BNQMF
JOTQFDUJPO
JT
B
QPPS
EFUFSNJOBOU
PG
UIF
t
Discussion.

,FZ
JOGPSNBUJPO

MFWFM
PG
JODPNJOH
RVBMJUZ BDUJWJUJFT
BOE
BOBMZTJT
t
1SPDFTT
EFGFDUT
BOE
EFGFDUJWF
VOJUT
BSF
NPTU
t
CAPA.

"DUJPOT
BOE
JNQSPWFNFOUT

often generated during startup and shutdown of JNQMFNFOUFE

5IFTF
JODMVEF
OFX
PQFSBUJOH

FRVJQNFOU QSPDFEVSFT
USBJOJOH
OFX
TBNQMJOH
JNQBDU
PO

t
&GGFDUJWF
QSPDFTT
DPOUSPMT
BSF
EFWFMPQFE
XJUIJO
UIF
QBTU
NBOVGBDUVSJOH
BOE
BTTPDJBUFE
BDUJWJUJFT
DPOUFYU
PG
NBOVGBDUVSJOH
QSJODJQMFT t
Post CAPA.

7FSJGZJOH
BOE
NBJOUBJOJOH

t
-FTTPOT
MFBSOFE
GSPN
UIJT
DBTF
TUVEZ
XIJDI
XFSF
QBDLBHJOH
MJOF
QFSGPSNBODF
DSJUJDBM
UP
TPMWJOH
UIF
QSPCMFN
BSF
OPU
UZQJDBMMZ
t
Other activities.

*NQSPWFNFOUT

GPVOE
JO
B
RVBMJUZ
NBOVBM
PS
USBJOJOH
MFDUVSF JNQMFNFOUFE
BT
SFTVMU
PG
LOPXMFEHF
HBJOFE

BOE
BDUJWJUJFT
BTTPDJBUFE
XJUI
UIF
BCPWF

INTRODUCTION JODMVEJOH
UIF
TJUF
BQQSPBDI
UP
TBNQMJOH
5IJT
DBTF
TUVEZ
XBT
QSPWJEFE
UP
UIF
Journal of GXP
Compliance
CZ
B
SFBEFS
XIP
SFRVFTUFE
BOPOZNJUZ

*U
PROCESS DESCRIPTIONS
QSPWJEFT
PUIFST
XJUI
JOTJHIUT
JOUP
IPX
UP
SFDPHOJ[F
5IJT
DPNQMJBODF
FWFOU
JOWPMWFE
UXP
TFQBSBUF
QSPDFTTFT


BOE
SFTPMWF
MPX
MFWFM
RVBMJUZ
QSPCMFNT
UIBU
OFFEMFTTMZ
5IF
GJSTU
XBT
SVO
BU
UIF
DBSUPO
NBOVGBDUVSFS

5IF

JODSFBTF
PQFSBUJOH
DPTU
WJB
NBOVGBDUVSJOH
EPXO
TFDPOE
XBT
SVO
BU
UIF
QIBSNBDFVUJDBM
NBOVGBDUVSFS

UJNF

5IF
DJSDVNTUBODFT
QSPWJEFE
EFTDSJCF
BO
BDUVBM
VTJOH
DBSUPOT
GSPN
UIF
DBSUPO
TVQQMJFS

&BDI
QSPDFTT

[
ABOUT THE AUTHORS
For more Author D. Wylie McVay, Jr. is a consultant in pharmaceutical manufacturing, quality, and regulatory affairs.
information, He is a Certified Quality Engineer, Certified Quality Auditor, and is certified in regulatory affairs. He has
go to published or presented on numerous quality topics including effective implementation of lifecycle control
gxpandjvt.com/bios strategies, aseptic fill, terminal sterilization, dosage form quality including tablets, capsules, liquids, and
other topics. He may be reached by e-mail at dwmcvayjr@gmail.com.

102 PROCESS VALIDATION Continued Process Verification


QSPWJEFE
WJUBM
DMVFT
BCPVU
EFGFDU
GSFRVFODZ
BOE

TPVSDF

5IF
$"1"
MFE
UP
CFUUFS
QSPDFTT
DPOUSPMT
BU
UIF

TVQQMJFST
QMBOU
BOE
CFUUFS
IBOEMJOH
PG
DBSUPOT
CZ
UIF

QIBSNBDFVUJDBM
NBOVGBDUVSFS

5IF
DPNQMJBODF
FWFOU

DPNQSJTFE
MPX
GSFRVFODZ
JOUFSNJUUFOU
DBSUPO
EFGFDUT


5IF
QIBSNBDFVUJDBM
NBOVGBDUVSFS
GJSTU
CFDBNF
BXBSF

PG
UIF
QSPCMFN
GSPN
MPX
FGGJDJFODZ
SBUJOHT
PO
UIF

production line. The carton supplier was unaware that
UIFSF
XBT
B
QSPCMFN
EVF
UP
QPPS
PS
JODPSSFDU
QSPCMFN

EFTDSJQUJPOT

5IF
JOTUJODUJWF
SFTQPOTF
GPS
UIF
TVQQMJFS

BOE
UIF
NBOVGBDUVSFS
XBT
UP
iJOTQFDU
PVU
UIF
EFGFDUJWF

DBSUPOTw

5IF
CFUUFS
TPMVUJPO
XBT
UP
DBSFGVMMZ
FYBNJOF

UIF
QSPCMFN
BOE
iCVJME
RVBMJUZ
JOw
CZ
DPSSFDUJOH
UIF

QSPDFTT
PS
QSPDFTT
DPOUSPMT

"
HFOFSBM
PWFSWJFX
PG

UIFTF
QSPDFTTFT
GPMMPXT
UP
QSPWJEF
UIF
SFBEFS
XJUI
B

general understanding of each process.
Carton Supplier Process
.BOVGBDUVSF
PG
TFDPOEBSZ
QBDLBHJOH
GPMEJOH
DBSUPOT

DBSUPO
CMBOLT

QSFGFSBCMZ
CZ
QSJOUJOH
QPTJUJPO


DPNQSJTFE
UIF
GPMMPXJOH
QSPDFTT
TUFQT


t
Sheet.

1SFQBSF
DBSUPO
DIJQCPBSE
TUPDL

5IF

DBSUPO
TUPDL
JT
QSPWJEFE
CZ
UIF
QBQFS
NJMM
JO


TJNJMBS
UP

KVNCP
SPMMT

XIJDI
JT
UIFO
DVU
JOUP
UIF
QSPQFS
UIF
GFFE
PG
B
QSJOUFS

*OEJWJEVBM
DBSUPOT
BSF
iIFME

GMBU
TIFFU
TJ[F
GPS
QSJOUJOH

5IJT
JT
SFGFSSFE
UP
BT

w
TBOEXJDIFE
CFUXFFO
DPOUJOVPVT

MPPQ

iTIFFUJOHw
Process control alert:

%JSFDUJPOBM
PSJFOUBUJPO


TIBQFE
SBJMT
HFOUMZ
CFOE
UIF
DBSUPO
BU
UIF

PG
UIF
TIFFUT
NVTU
CF
NBJOUBJOFE
GPS
GJCFS

HSBJO
PSJFOUBUJPO
BOE
DPOTJTUFOU
TIFFU
TJ[F

UIF
HMVF
XBT

t
Print.

1SJOU
UIF
GMBU
TIFFUT

.BDIJOF
TFUVQ
GPS

registering and aligning print colors generates

XBUFSCBTFE
HMVF

(MVF
JT

TDSBQ
UIBU
DPOUBJOT
EFGFDUJWF
MBCFMJOH
TVDI
BT

NJTTJOH
QSJOU

5P
BTTVSF
DPOTJTUFOU
QSJOU
MPDBUJPO

PO
BMM
TIFFUT

UIF
TIFFUT
BSF
SFHJTUFSFE
XJUI
B
MBUFSBM
DPOOFDUJPO

$BSUPOT
BSF
IFME
JO
QMBDF
BT
UIF
HMVF

force to a stationary side rail to assure the printing
JT
MPDBUFE
JO
UIF
TBNF
QPTJUJPO
FWFSZ
UJNF
SFMBUJWF

UP
UIJT
FEHF

'MBU
TIFFUT
BSF
GFE
TFRVFOUJBMMZ
BOE


BT
UIFSF
XJMM
CF
EFGFDUT

DPOUJOVPVTMZ
UISPVHI
UIF
QSJOUJOH
QSFTT

&BDI

TIFFU
JT
QSJOUFE
JO
B
iTUFQ
BOE
SFQFBUw
GBTIJPO

BT
TIPXO
JO
UIF
'JHVSF

*G
UIF
SFMBUJWF
QPTJUJPO

SFHJTUSBUJPO
TIJGUT
EVSJOH
QSJOUJOH

UIF
QSJOUUPDVU
JOUFSNJYJOH
PG
HPPE
BOE
EFGFDUJWF
DBSUPOT
UPMFSBODFT
DBO
CF
DPNQSPNJTFE
BOE
DPVME
MFBE
UP

DVU
PGG
DPQZ
PS
NJTTJOH
DPQZ
Process control alert:

4FUVQ
TDSBQF
DPOUBJOT

MBCFMJOH
QSJOU

EFGFDUT
1SJOU
TDSBQ
NBZ
CF
VTFE
Pharmaceutical Manufacturing Process
GPS
DVUUJOH
TFUVQ
BOE
NVTU
CF
DPOUSPMMFE
t
Cut.

1SJOUFE
TIFFUT
BSF
EJFDVU
BOE
TDPSFE
CZ

B
IJHI
QSFDJTJPO
TUBNQJOH
QSPDFTT
TJNJMBS
UP
B

DPPLJF
DVUUFS

5IF
DVUUJOH
EJF
CPBSE
HFOFSBMMZ

DPOTJTUT
PG
B
IJHI
RVBMJUZ
QMZXPPE
iIPMEFSw
UIBU

JT
MBSHFS
UIBO
UIF
QSJOUFE
TIFFU

8JUIJO
UIF
FEHFT

PG
UIF
CPBSE

QSFDJTJPO
MBTFS
DVUT
JO
UIF
TIBQF
PG
t
Blister formation.

5IFSNPGPSNJOH
NBUFSJBM
JO

UIF
GJOBM
GMBU
DBSUPO
IBWF
CFFO
NBEF

5IFTF
DVUT

UIJT
DBTF
JT
QPMZWJOZMDIMPSJEF
17$


5IF
SPMM
JT

PS
DIBOOFMT

BSF
CVSOFE
UISPVHI
UIF
CPBSE
TP
UIBU
NPVOUFE
PO
B
IPMEFS
BU
POF
FOE
PG
UIF
QBDLBHJOH

SB[PS
TIBSQ
DVUUJOH
LOJWFT
BOE
VOTIBSQFOFE
TDPSF

CMBEFT
DBO
CF
NPVOUFE
JOUP
UIF
DIBOOFM

5IF
EJF

JT
NPVOUFE
UP
UIF
DVUUJOH
NBDIJOF
BOE
BEKVTUFE
UP

D. Wylie McVay, Jr.
KVTU
QFOFUSBUF
UIF
FYBDU
UIJDLOFTT
PG
UIF
DIJQCPBSE

TUPDL

5IF
DVUUJOH
LOJGF
JT
BMTP
iOJDLFEw
UP
DSFBUF

JOUFOUJPOBM
NJOPS
EBNBHF
UP
UIF
DVUUJOH
FEHF


5IF
EBNBHFE
BSFB
XJMM
OPU
DPNQMFUFMZ
TFWFS
UIF

QSJOUFE
DIJQCPBSE
TUPDL

5IJT
TNBMM
BNPVOU
PG

DIJQCPBSE
GJCFS
LFFQT
UIF
DBSUPOT
BUUBDIFE
UP

the sheet until the cartons are separated prior to
HMVJOH
4FQBSBUJOH
UIF
DBSUPOT
SFTVMUT
JO
WFSUJDBM

TUBDLT
PG
UIF
TBNF
QSJOU
QPTJUJPO
Process control alert:

4FUVQ
TDSBQ
NVTU
CF

DPOUSPMMFE
CZ
UIF
TVQQMJFS
BOE
NBZ
JODMVEF

QSJOUJOH
EFGFDUT
(MVJOH
CZ
PSEFSFE
QSJOU
QPTJUJPO

FOIBODFT
UIF
DVTUPNFST
BCJMJUZ
UP
USPVCMFTIPPU

BOE
DPOUSPM
QSJOUJOH
QSPCMFNT
UIBU
XFSF
OPU

EJTDPWFSFE
CZ
UIF
TVQQMJFS
t
Gluing.

5IF
HMVJOH
FRVJQNFOU
JT
BQQSPYJNBUFMZ


GFFU
JO
MFOHUI
GSPN
UIF
DBSUPO
GFFE
TJEF

UP
UIF
GJOBM
HMVFE
DBSUPO
UBLF
PGG

4UBDLT
PG

BSF
MPBEFE
JOUP
B
WFSUJDBM
GFFE
NBHB[JOF
PG
UIF

HMVJOH
NBDIJOF

5IF
DBSUPOT
BSF
SFNPWFE
POF
BU

B
UJNF
GSPN
UIF
CPUUPN
PG
UIF
TUBDL
JO
QMBDF
GFFE
UFOTJPO
CFMUT

"T
UIF
DBSUPO
QSPDFFET
EPXO

UIF
CFMU
TDPSF
MJOFT
BOE
QPTJUJPO
UIF
HMVF
KPJOU
GBDF
UP
UIF

HMVF
BQQMJDBUPS

*O
PMEFS
NBDIJOFT
BQQMJFE
CZ
B
TPMJE
NFUBM
XIFFM
UIBU
SFWPMWFE
JO
B

TIBMMPX
QPPM
PG
XIJUF
BQQMJFE
UP
UIF
KPJOU
BOE
GPMEFE
PWFS
UP
DPOUBDU
UIF

PQQPTJUF
GBDF
PG
UIF
DBSUPO
UP
DPNQMFUF
UIF
KPJOU

sets.
Process control alert:

.BDIJOF
TFU
VQ
DBSUPOT

TIPVME
CF
TDSBQQFE
QSFTFOU

(MVF
EFGFDUT
NBZ
CF
DSFBUFE
EVSJOH

TUBSUVQ
PS
TIVUEPXO

&GGFDUJWF
RVBMJUZ
DPOUSPM

TIPVME
CF
DBSFGVMMZ
EFTJHOFE
UP
QSFWFOU

t
Bulk package.

(MVFE
DBSUPOT
BSF
QBDLBHFE
GPS

TIJQNFOU
UP
UIF
QIBSNBDFVUJDBM
NBOVGBDUVSFS
5IF
QSPDFTT
BU
UIF
QIBSNBDFVUJDBM
NBOVGBDUVSFS

JOWPMWFE
GPSNJOH
BOE
GJMMJOH
PG
UIF
CMJTUFS
QBDLBHF

QSJNBSZ
QBDLBHJOH
GPMMPXFE
CZ
JOTFSUJPO
PG
UIF
GJMMFE

CMJTUFST
JOUP
UIF
TFDPOEBSZ
QBDLBHF
DBSUPOT
PCUBJOFE

GSPN
UIF
DBSUPO
NBOVGBDUVSFS
BT
EFTDSJCFE
QSFWJPVTMZ


4QFDJGJDBMMZ
UIJT
QSPDFTT
DPNQSJTFE
UIF
GPMMPXJOH
TUFQT


NBDIJOF

5IF
17$
JT
IFBUFE
UP
NBLF
JU
QMJBCMF


5IF
IFBUFE
17$
JT
GFE
UISPVHI
GPSNJOH
EJFT
UIBU

XJMM
GPSN
UIF
JNQSFTTJPOT
PS
DBWJUJFT
UIBU
XJMM
IPME

PROCESS VALIDATION Continued Process Verification 103
D. Wylie McVay, Jr.
Figure:
Typical printed sheet (dark area is waste
material).

UIF
GJMMFE
DBSUPOT
XFSF
GPVOE


CPUI
PG
XIJDI
SFTVMUFE
JO
NBDIJOF
EBNBHF
BOE



)PXFWFS

FWFO
UIJT
MPX
MFWFM
EFGFDU
SBUF
PG


UIF

UIF
ESVH
QSPEVDU

5IF
17$
JT
IFME
CZ
UIF
FEHFT
UP

transport the product through the processing.

UIF
TJUVBUJPO
QSFTFOUFE

t
Fill blisters with tablets.

%SVH
QSPEVDU
JT
QMBDFE

JOUP
FBDI
DBWJUZ
BDDPSEJOH
UP
UIF
QSPEVDU
EFTJHO


5BCMFUT
UIBU
IBWF
MPX
PS
OP
GSJBCJMJUZ
QSPCMFNT
NBZ

CF
GMPPE
GFE
PWFS
UIF
PQFO
CMJTUFS
DBWJUJFT

4PGUFS

UBCMFUT
NBZ
CF
JOTFSUFE
JOEJWJEVBMMZ
UP
QSFWFOU


BT

EBNBHF
t
Seal blisters.

-JEEJOH
TUPDL
TVDI
BT
BMVNJOVN

GPJM
JT
VOSPMMFE
PWFS
UIF
17$
CMJTUFS
DPOUBJOJOH

UBCMFUT
JO
B
DPOUJOVPVT
GFFE
NBOOFS

1SFTTVSF
BOE

DPOUBDU
XJUI
IFBUJOH
XIFFMT
PS
QMBUFOT
XJMM
XBSN

UIF
QBDLBHF
BOE
BDUJWBUF
UIF
TFBM
CFUXFFO
UIF
CBDL

MJEEJOH
BOE
UIF
GJMMFE
CMJTUFS
DBWJUZ
t
Cut blisters.

5IF
TFBMFE
QBDLBHF
JT
EJFDVU
BOE

TFQBSBUFE
GSPN
UIF
17$
XFC
t
Insert blister into carton.

5IF
DVU
CMJTUFS
TUSJQT

BSF
MPBEFE
UP
B
GFFE
NBHB[JOF

5IF
GPMEJOH
DBSUPOT

GSPN
UIF
TVQQMJFS
BSF
MPBEFE
JOUP
B
TFQBSBUF

NBHB[JOF

5IF
QBDLBHJOH
NBDIJOF
XJMM
PQFO

the carton and seal one end. The carton is then
GJMMFE
XJUI
UXP
CMJTUFS
TUSJQT

*O
UIJT
DBTF

UIF
CGMP Requirements
DBSUPOT
XFSF
GJMMFE
XJUI
CMJTUFS
TUSJQT
XIJMF
JO

UIF
IPSJ[POUBM
QPTJUJPO

5IF
DBSUPOT
IBWF
UP
CF

QFSGFDUMZ
HMVFE
CZ
UIF
TVQQMJFS
PUIFSXJTF

UIF
t

$'3
E

4VCQBSU
&

$POUSPM

NBDIJOF
XJMM
KBN
EVSJOH
PQFOJOH
BOE
DSFBUF

EPXOUJNF

5IJT
QSPDFTT
TUFQ
JT
TJHOJGJDBOUMZ

BGGFDUFE
CZ
EFGFDUJWF
DBSUPOT


t
Shipping case packaging. The filled cartons are

BOE
DMPTVSFT
QBDLBHFE
JOUP
CVML
DBSUPOT
GPS
TIJQQJOH
COMPLIANCE EVENT
5IF
DPNQMJBODF
FWFOU
PDDVSSFE
BU
UIF
QIBSNBDFVUJDBM

NBOVGBDUVSFS
VTJOH
TFDPOEBSZ
DBSUPOT
PCUBJOFE
GSPN

UIF
DBSUPO
TVQQMJFS

5IF
FWFOU
JOWPMWFE
EFGFDUJWF

TFDPOEBSZ
DPOUBJOFST
VTFE
UP
QBDLBHF
QIBSNBDFVUJDBM

UBCMFUT
PO
BO
JOUFHSBUFE
IJHITQFFE
CMJTUFS
GPSNJOH
TFBMJOH
BOE
DBSUPO
GJMMJOH
QBDLBHJOH
MJOF

5IF
PCTFSWFE


FOHJOFFSJOH
TVQQPSU

QVSDIBTJOH


EFGFDU
XBT
PWFSHMVFE
PS
VOHMVFE
DBSUPOT
CFJOH
GFE
JOUP

104 PROCESS VALIDATION Continued Process Verification
UIF
NBDIJOF

5IF
TFDPOEBSZ
QBDLBHFT
XFSF
UIFO
GJMMFE

XJUI
UXP
CMJTUFS
TUSJQT
PG
QIBSNBDFVUJDBM
UBCMFUT

"T

UIF
QSPDFTT
QSPHSFTTFE
UP
IBWF
FJUIFS
OP
HMVF
PS
FYDFTTJWF
BNPVOUT
PG
ESJFE

HMVF
QSPEVDUJPO
EPXOUJNF

5IF
QSPCMFN
XBT
JOUFSNJUUFOU

BOE
B
MPXMFWFM
EFGFDU
SBUFEFGFDUT
PDDVSSFE
JO
QBSUT

QFS

DBSUPO
RVBMJUZ
MFE
UP
DPTUMZ
EPXO
UJNF
BOE
TJHOJGJDBOU

FYDFTT
JOWFOUPSZ
PG
QBDLBHJOH
NBUFSJBMT
KVTU
UP
BTTVSF

UIBU
BEFRVBUF
GPMEJOH
DBSUPOT
XFSF
BMXBZT
BWBJMBCMF

GPS
TDIFEVMFE
QSPEVDUJPO
SVOT

"EEJUJPOBMMZ
RVBMJUZ
DPOUSPM
MBCPSBUPSZ
TQFOU
TJHOJGJDBOU
BNPVOUT
PG

OPOWBMVF
BEEJOH
UJNF
PO
BEEJUJPOBM
JOTQFDUJPO

5IF

JODSFBTFE
JOTQFDUJPO
SBSFMZ
JEFOUJGJFE
QSPCMFNT
CFGPSF

UIF
DBSUPOT
XFSF
OFFEFE
GPS
QSPEVDUJPO

.BOVGBDUVSJOH

PQFSBUJPOT
QFSTPOOFM
XFSF
GSVTUSBUFE
CZ
NJTTJOH
LFZ

EFMJWFSZ
UBSHFUT

*O
TVNNBSZ
BO
PQQPSUVOJUZ
UP
TJHOJGJDBOUMZ
JNQSPWF
UIF
PWFSBMM

CVTJOFTT
QFSGPSNBODF
What Were The Issues?
5IFSF
XFSF
TFWFSBM
DSJUJDBM
JTTVFT
UP
CF
JOWFTUJHBUFE
follows:
t
8IZ
EJE
TPNF
CPYFT
IBWF
OP
HMVF

8IBU

XBT
UIF
GSFRVFODZ
PG
UIJT
PDDVSSFODF
t
8IZ
EJE
TPNF
CPYFT
IBWF
FYDFTTJWF
BOE
ESJFE

HMVF

8IBU
XBT
UIF
GSFRVFODZ
PG
UIJT
PDDVSSFODF
t
8FSF
UIF
UXP
PDDVSSFODFT
DPOOFDUFE

PS
TFQBSBUF
FWFOUT
t
8IZ
XFSF
UIFTF
QBDLBHFT
OPU
EFUFDUFE

JO
RVBMJUZ
VOJU
TBNQMJOH
t
8IZ
XBT
UIJT
IBQQFOJOH
PO
B
WBMJEBUFE
QSPDFTT

VTJOH
WBMJEBUFE
BOE
RVBMJGJFE
FRVJQNFOU
t
8BT
UIF
QSPCMFN
B
TVQQMJFS
QSPCMFN
PS
B
NBOVGBDUVSJOH
QSPCMFN
3FMFWBOU
(.1
SFRVJSFNFOUT
BQQMJDBCMF
UP
UIF
BCPWF

FWFOU
BSF
MJTUFE
BT
GPMMPXT
PS
$PNQPOFOUT
BOE
%SVH
1SPEVDU

$POUBJOFST
BOE
$MPTVSFT

5FTUJOH
BOE

BQQSPWBM
PS
SFKFDUJPO
PG
DPNQPOFOUT
ESVH
QSPEVDU
DPOUBJOFST
t

$'3
B

4VCQBSU
(

1BDLBHJOH

BOE
-BCFMJOH
$POUSPM

.BUFSJBMT

FYBNJOBUJPO
BOE
VTBHF
DSJUFSJB
INVESTIGATION
*OWFTUJHBUJPO
BOE
VMUJNBUF
SFTPMVUJPO
PG
UIJT
FWFOU

SFRVJSFE
JOWPMWFNFOU
PG
TFWFSBM
HSPVQT
UISPVHI

B
TVQQMJFS
DFSUJGJDBUJPO
JOJUJBUJWF

1BDLBHJOH

FOHJOFFSJOH
NBOVGBDUVSJOH
QFSTPOOFM
BOE
RVBMJUZ
BTTVSBODF

 D. Wylie McVay, Jr.

QFSTPOOFM
UFBNFE
UP
BTTFTT
UIF
TVQQMJFS
DPOUSPMT
BT
DIBOHFT
UIBU
DPVME
BGGFDU
GVODUJPOJOH
PG
UIF
BQQSPWFE

XFMM
BT
BTTFTT
UIF
USVF
TQFDJGJFE
OFFET
PG
UIF
UBCMFU
EFTJHO

5IF
DPNQBOZ
XBT
BCMF
UP
TIFE
BQQSPYJNBUFMZ

packaging process.  
PG
FYDFTT
JOWFOUPSZ
CZ
FMJNJOBUJOH
FYDFTT

6OEFS
UIF
VNCSFMMB
PG
UIF
TVQQMJFS
DFSUJGJDBUJPO
safety stock.
QSPDFTT
B
NVUVBMMZ
BHSFFBCMF
EBUF
GPS
B
TJUF
BVEJU

XBT
EFUFSNJOFE

5IF
RVBMJUZ
BTTVSBODF
2"

DISCUSSION
NFNCFST
QSPWJEFE
UIF
MPHJTUJDBM
TVQQPSU
BOE
*OGPSNBUJPO
PCUBJOFE
UISPVHI
JOUFSWJFXT
BOE

DPNNVOJDBUFE
BT
B
TJOHMF
QPJOU
PG
DPOUBDU
UP
UIF
TVCTFRVFOU
GPMMPXVQ
BVEJUT
BOE
TJUF
NFFUJOHT
FOBCMFE

supplier. The intent of the audit was clearly stated: HPPE
VOEFSTUBOEJOH
PG
UIF
QSPCMFN
BOE
MFE
UP
UIF

to learn the folding carton process in order to GJOBM
TPMVUJPO

.PTU
RVBMJUZ
QSPCMFNT
EP
OPU
SFRVJSF

VOEFSTUBOE
UIF
LFZ
GBDUPST
PG
RVBMJUZ
DPOUSPM

5IF
BEWBODFE
NBUIFNBUJDBM
UFDIOJRVFT
CVU
SBUIFS
DBSFGVM

UFBNT
IPQF
XBT
UP
MFBSO
BOTXFST
UP
UIF
QSFDFEJOH
BOE
JOTJHIUGVM
PCTFSWBUJPO

5IJT
TJUVBUJPO
XBT
OP

RVFTUJPOT
GSPN
UIF
TVQQMJFST
QFSTQFDUJWF*O
FYDFQUJPO

*U
XBT
POMZ
UISPVHI
B
TFU
PG
iGSFTI
FZFTw
BOE

PUIFS
XPSET
EFWFMPQ
VOEFSTUBOEJOH
CFUXFFO
UXP
B
NVUVBM
VOEFSTUBOEJOH
PG
FBDI
PUIFST
OFFET
UIBU
UIF

CVTJOFTT
QBSUOFST UFBN
XBT
BCMF
UP
EFWFMPQ
B
DMFBS
DPOUFYU
PG
UIF
SPPU

'PMMPXJOH
TUBOEBSE
BVEJUJOH
QSPUPDPM
BEWBODF
cause.
DPNNVOJDBUJPO
DMBSJGJFE
UIF
PCKFDUJWFT
BOE
MPHJTUJDT
PG
4JNQMZ
QVU
UIF
SPPU
DBVTF
PG
VOHMVFE
PS
PWFSHMVFE

UIF
USJQ

5IF
QVSQPTF
XBT
FTUBCMJTIFE
BT
JEFOUJGJDBUJPO
DBSUPOT
XBT
QBSUJBM
PS
DPNQMFUF
ESZJOH
PG
HMVF
XIFO

PG
TPVSDFT
PG
MPX
MFWFM
BOE
JOUFSNJUUFOU
DBSUPO
HMVF
UIF
NBDIJOF
XBT
TIVU
EPXO
GPS
CSFBLT
BOE
MVODI


KPJOU
GBJMVSFT

5IF
JNQBDU
PG
JNQSPQFSMZ
HMVFE
DBSUPOT
5IF
TPMVUJPO
JOWPMWFE
UXP
BDUJPOT
CZ
UIF
DBSUPO

XBT
EFTDSJCFE
JO
UFSNT
PG
EPXOUJNF
NBDIJOF
NBOVGBDUVSFS

'JSTU
UIF
NBDIJOF
PQFSBUPST
XPVME

EBNBHF
BOE
BTTPDJBUFE
EJTSVQUJPO
UP
POUJNF
EFMJWFSZ DBSSZ
UIF
HMVJOH
DZDMF
UP
B
MPHJDBM
QSPDFTTIPMEJOH
QPJOU

5IF
TJUF
BTTFTTNFOU
EBZ
BSSJWFE
BOE
PVS
UFBN
NFU
CFGPSF
TUPQQJOH
UIF
NBDIJOF
UP
UBLF
B
CSFBL

4FDPOE

XJUI
UIF
TVQQMJFS
FBSMZ
JO
UIF
NPSOJOH

*OJUJBM
EJBMPHVF
B
GJYFE
BNPVOU
PG
DBSUPOT
XFSF
SFNPWFE
GSPN
UIF

CFUXFFO
UIF
QBSUJFT
DFOUFSFE
PO
CFUUFS
VOEFSTUBOEJOH
NBDIJOF
VQPO
TUBSUVQ

5IF
FOE
PG
UIF
HMVF
DZDMF
XBT

UIF
TVQQMJFST
QSPDFTT
BOE
DPOUSPMT
FTUBCMJTIJOH
MJOFT
iGMBHHFEw
TP
UIBU
TVTQFDU
DBSUPOT
GSPN
UIF
OFYU
TUBSUVQ

PG
EJSFDU
DPNNVOJDBUJPO
GPS
DMFBS
BOE
UJNFMZ
GPMMPX XFSF
SFNPWFE
GSPN
UIF
QBDLBHJOH
MJOF
FGGFDUJWF
RVBMJUZ

VQ
PO
JTTVFT
BOE
EFWFMPQJOH
B
SFQPSU
DBSE
UP
HBVHF
control).
QSPHSFTT

0G
DPVSTF
QBSUOFSTIJQT
BSF
B
UXPXBZ
TUSFFU

-PPLJOH
CBDL
UIF
TUBSUVQ
UIBU
GPMMPXFE
CSFBLT
PS

5IF
UFBN
XBT
HMBE
UP
IPTU
UIF
DBSUPO
TVQQMJFS
UP
TIPX
MVODI
JO
NBOZ
SFTQFDUT
XBT
BNVTJOH
UP
PCTFSWF

5IF

IPX
UIF
UFBN
IBOEMFE
PS
NJTIBOEMFE

UIF
DBSUPOT
BQQMJDBUPS
XIFFM
XIJDI
SFWPMWFE
JO
B
TIBMMPX
SFTFSWPJS

JO
TUPSBHF
BOE
PO
UIF
QSPEVDUJPO
MJOF

5IJT
NVUVBM
PG
HMVF
EFWFMPQFE
B
ESJFE
TLJO
PG
HMVF
EVSJOH
UIF

VOEFSTUBOEJOH
QSPWFE
UP
CF
UIF
LFZ
UP
DBOEJE
BOE
TIPSU
CSFBL
UJNF
XIFO
SPUBUJPO
DFBTFE

5IF
SFTVMU
XBT

FGGFDUJWF
EJBMPHVF
PG
UIF
JTTVFT
SBUIFS
UIBO
iQPJOUJOH
PG
EFGFDUJWF
DBSUPOT

4PNFUJNFT
PO
TUBSUVQ
UIF
XIFFM

GJOHFST
PG
CMBNFw TMVOH
UIF
CMPC
PG
HMVF
JOUP
UIF
DBSUPO
BOE
TFBMFE
JU

4VDDFTT
SFRVJSFE
UJNF
QBUJFODF
BOE
QFSTJTUFOU
TIVU

"U
PUIFS
UJNFT
UIF
HMVF
PO
UIF
XIFFM
IBE
ESJFE

QVSTVJU
PG
FYDFMMFODF
PO
UIF
QBSU
PG
CPUI
QBSUOFST
UP
BOE
UIF
GJSTU
DBSUPO
PS
UXP
EJE
OPU
SFDFJWF
XFU
HMVF

EFWFMPQ
BO
PQFO
BOE
BMJHOFE
WJFX
PG
UIF
QSPCMFN

PO
UIF
KPJOU

0OMZ
DBSFGVM
PCTFSWBUJPO
DPODMVTJWFMZ

5IF
GJSTU
TFWFSBM
NPOUIT
DPVME
CF
UFSNFE
B
QFSJPE
PG
identified this critical control point.
iCVJMEJOH
USVTUw
XIFSF
POMZ
TVTQJDJPO
IBE
QSFWJPVTMZ

FYJTUFE

.BOZ
PG
UIF
BTTVNQUJPOT
UIF
DVTUPNFS
IFME
Sampling Procedure
UVSOFE
PVU
UP
CF
JODPSSFDU

'PS
FYBNQMF
UIF
QBDLBHJOH
0OF
PG
UIF
LFZ
QPJOUT
UP
CF
MFBSOFE
JT
BMNPTU
BMM

engineers were certain precision die cutting was the QSPDFTTFT
EP
OPU
HFOFSBUF
EFGFDUT
SBOEPNMZ

"T
UIJT

SPPU
DBVTF
PG
UIF
QSPCMFNT

5IJT
BTTVNFE
DPODMVTJPO
DBTF
TIPXT
EFGFDUT
XFSF
DSFBUFE
BU
DMFBSMZ
EFGJOFE

BDUVBMMZ
EFMBZFE
JEFOUJGJDBUJPO
PG
UIF
LFZ
RVBMJUZ
UJNFT
EVSJOH
UIF
NBOVGBDUVSJOH
QSPDFTT
TVDI
BT
TUBSU
BUUSJCVUF

"O
JNQPSUBOU
MFTTPO
XBT
MFBSOFE

5IFSF
JT
VQ
PS
TIVU
EPXO

$POUSPM
BOE
DBQUVSF
PG
EFGFDUJWF

OP
TVCTUJUVUF
GPS
DBSFGVM
TUVEZ
PG
B
QSPCMFN

VOJUT
JT
B
DSJUJDBM
FMFNFOU
PG
B
TVDDFTTGVM
RVBMJUZ
DPOUSPM

"GUFS
OFBSMZ
B
ZFBS
PG
DBSFGVM
SFWJFX
UIF
FGGPSUT
QBJE
TUSBUFHZ

3PUF
JOTQFDUJPO
RVBMJUZ
TZTUFNT
XIJDI

PGG

5IF
TVQQMJFS
EFWFMPQFE
CFUUFS
QSPDFTT
DPOUSPMT
UIF
USFBU
BMM
UIF
GJOJTIFE
DBSUPOT
BT
B
IPNPHFOFPVT
MPU

UFBN
MFBSOFE
IPX
UP
QSPQFSMZ
TUPSF
DBSUPOT
UP
QSFWFOU
MBDL
UIF
TFOTJUJWJUZ
UP
QSPQFSMZ
JOWFTUJHBUF
UIJT
LJOE

EBNBHF
:FT
DBSUPOT
EFGPSN
XIFO
UPQMPBEFE
XJUI
PG
RVBMJUZ
QSPCMFN

*U
JT
FBTZ
UP
TFF
UIBU
B
SBOEPN

GPVS
GVMM
IFBWZ
QBMMFUT

%FGPSNFE
DBSUPOT
EP
OPU
XPSL
TBNQMF
BQQSPBDI
BTTVSFT
EFGFDUT
XJMM
CF
EFMJWFSFE
UP

QSPQFSMZ


#PUI
QBSUJFT
EJTDPWFSFE
UIF
JNQPSUBODF
UIF
DVTUPNFS

%PFT
JU
OPU
NBLF
CFUUFS
QSPDFTT
DPOUSPM

PG
BO
FGGFDUJWF
XFMMDSBGUFE
RVBMJUZ
BHSFFNFOU
XJUI
TFOTF
UP
SFNPWF
LOPXO
EFGFDUT
XIFO
UIFZ
PDDVS


SFTQPOTJCJMJUZ
GPS
CPUI
UIF
DVTUPNFS
BOE
TVQQMJFS
5IF
DVTUPNFST
XJMM
BQQSFDJBUF
UIJT
UP
LFFQ
UIF
PUIFS
JOGPSNFE
PG
NBKPS
UFDIOPMPHZ

PROCESS VALIDATION Continued Process Verification 105

D. Wylie McVay, Jr.
CORRECTIVE ACTIONS AND PREVENTIVE
ACTIONS
$"1"
BDUJWJUJFT
XFSF
TQFDJGJFE
BU
CPUI
UIF
DBSUPO


TUBSUVQ
TDSBQ
XBT
XFMM
DPOUSPMMFE
EVSJOH

NBOVGBDUVSFS
BOE
BU
UIF
QIBSNBDFVUJDBM
QBDLBHJOH

PQFSBUJPO

5IFTF
BDUJWJUJFT
DPSSFDUFE
UIF
QSPCMFN
BU

UIF
SPPU
DBVTF
BOE
WFSJGJFE
TVDDFTTGVM
DPSSFDUJPO
BU
UIF

point of use.
5IF
GPMMPXJOH
$"1"
DIBOHFT
UP
UIF
QSPDFTT
XFSF

NBEF
BU
UIF
DBSUPO
NBOVGBDUVSFS
t
New equipment operating procedure. The
TVQQMJFS
JOWFTUFE
JO
BO
BVUPNBUJD
SFKFDU
BSN
UP

iGMBHw
UIF
TUBSU
PG
B
TIVUEPXO
BT
XFMM
BT
UIF
FOEJOH

PG
B
TUBSUVQ

$BQUVSF
PG
UIF
EFGFDUT
JNQSPWFE
UIF

CMJTUFS
QBDLBHJOH
NBDIJOF
FGGJDJFODZ
BOE
ZJFME

t
Training.

5IF
NVUVBM
JOWFTUNFOU
JO
TJUF
BVEJUT

XJUI
PQFSBUPS
MFWFM
FNQMPZFFT
PQFOFE
UIF
EPPS
GPS

DBSUPO
EFTJHO
JNQSPWFNFOUT
BT
OFX
FRVJQNFOU


SPVUJOF
NPOJUPSJOH
BOE
TBNQMJOH

was purchased.
t
New sampling procedure.

4BNQMJOH
XBT
OP


B
NBKPS
UJNF
BOE
MBCPS
TBWFS
MPOHFS
WJFXFE
BT
B
SBOEPNJ[FE
QVMM
GSPN
BMM
PG
UIF

DBSUPOT

CVU
SBUIFS

BT
B
NFBOT
UP
DPOGJSN
DPOUSPMT
CONCLUSIONS
are working properly.
t
Impact on past manufacturing.

1SFWJPVT
MPUT

XFSF
OPU
DPOTJEFSFE
UP
CF
BU
SJTL

5IF
SFBTPO
GPS

UIJT
JT
UIBU
DBSUPOT
XFSF
EBNBHFE
CFZPOE
UIF
QPJOU

PG
CFJOH
VTBCMF
BOE
DPVME
OPU
CF
TPME
t
Validation.

#FDBVTF
UIF
QSPCMFN
XBT
EFUFSNJOFE


DBSUPOT
DPOUBJOJOH
UBCMFUT
JO

UP
CF
B
TFUVQ
BOE
PQFSBUJPOBM
QSPCMFN

BOE
OP
CMJTUFS
QBDLBHFT

BU
B
QIBSNBDFVUJDBM
NBOVGBDUVSJOH

FRVJQNFOU
PQFSBUJOH
QBSBNFUFST
XFSF
DIBOHFE

QMBOU

$BSUPOT
XFSF
GPVOE
UP
IBWF
FJUIFS
OP
HMVF

WBMJEBUJPO
XBT
OPU
OFDFTTBSZ

)PXFWFS

DPOUSPMT
PS
FYDFTTJWF
BNPVOUT
PG
ESJFE
HMVF

CPUI
PG
XIJDI

XFSF
BEEFE
UP
DMPTFS
BMJHO
NPOJUPSJOH
EBUB
UP
UIF

DSJUJDBM
QPJOUT
PG
DPOUSPM
BT
UIF
QSPDFTT
XBT
CVJMU

CVU
IBE
TJHOJGJDBOU
SBNJGJDBUJPOT
5IF
GPMMPXJOH
DIBOHFT
XFSF
NBEF
BU
UIF



QIBSNBDFVUJDBM
QBDLBHF
NBOVGBDUVSFS

BOE

Carton storage.

*NQSPWFNFOUT
JO
DBSUPO
TUPSBHF

XFSF
JNQMFNFOUFE

-JNJUBUJPOT
PO
QBMMFU
TUBDLJOH
JO

UIF
XBSFIPVTF
QSFWFOUFE
FYDFTTJWF
QSFTTVSF
PO
TUPSFE

DBSUPOT

5IJT
FMJNJOBUFE
UIF
QPUFOUJBM
GPS
CPY
CFOEJOH

BOE
DVSMJOH
UIBU
DPVME
JNQBDU
TFDPOEBSZ
QBDLBHF

NBDIJOF
PQFSBUJPO
Verification of corrective action.

8F
UPPL
B

OPWFM
BQQSPBDI
UP
WFSJGZJOH
UIF
TVDDFTT
PG
$"1"

BDUJWJUJFT
BU
UIF
DBSUPO
NBOVGBDUVSFS

5IF
RVBMJUZ
VOJU

BVUIPSJ[FE
TIPSUUFSN
EFQBSUVSFT
GSPN
GJSTUJOGJSTU
PVU
'*'0

DPOUSPMT
UP
QSPWJEF
JNNFEJBUF
GFFECBDL
iCVJMEJOH
USVTUw
XIFSF
POMZ
TVTQJDJPO
IBE
QSFWJPVTMZ

UP
UIF
TVQQMJFS

8JUI
B
MBSHF
FYJTUJOH
JOWFOUPSZ

BOZ
FYJTUFE

.BOZ
PG
UIF
BTTVNQUJPOT
UIF
DVTUPNFS
IFME

JNQSPWFNFOUT
NBEF
CZ
UIF
TVQQMJFS
XPVME
SFRVJSF
B

XBJU
PG
BQQSPYJNBUFMZ
GPVS
NPOUIT

5IJT
XBT
UPP
MPOH

UP
EFUFSNJOF
UIF
FGGFDUJWFOFTT
PG
UIF
QSPDFTT
DIBOHFT


(MVJOH
EFGFDUT
XFSF
BMM
CVU
FMJNJOBUFE
CARTON MANUFACTURER APPROACH TO
SAMPLING

BU
TIVUEPXO
BOE
TUBSUVQ
SFTVMUJOH

5IJT
FWFOU
VMUJNBUFMZ
SFTVMUFE
JO
B
TJHOJGJDBOUMZ

JNQSPWFE
BQQSPBDI
UP
QSPDFTT
TBNQMJOH

5IF
GJSTU

106 PROCESS VALIDATION Continued Process Verification
JNQSPWFNFOU
XBT
CFUUFS
EFGFDU
DBQUVSF
EVSJOH

NBDIJOF
TUBSUVQ
BGUFS
CSFBLT
BOE
BGUFS
MVODI


*OUFSFTUJOHMZ
UIF
NPSOJOH
TUBSUVQ
TJNQMZ
CFDBVTF
FWFSZPOF
LOFX

UIBU
UIF
GJSTU
TUBSUVQ
BMXBZT
QSPEVDFE
EFGFDUJWFT


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The Journal of GXP Compliance

PROCESS VALIDATION Continued Process Verification 107