Professional Documents
Culture Documents
Objectives
Inspection Process
Headquarters:
Rockville, MD
Regional Office:
Philadelphia, PA
District Office:
D
Detroit,
i MI
10
Site Location
1. Select Site
4. Arrive (482)
2. Contact Site
5. Review Records
3. Schedule Site
6. Interview Staff
7. Present Findings
8. Depart (483)
11
12
FDA Forms
13
14
15
16
Selection Criteria
17
18
19
20
10
21
22
11
23
24
12
25
26
13
27
28
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30
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31
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10/3/2011
BestPracticestoDevelop,Deploy
Best
Practices to Develop Deploy
andMaintainaRiskBasedACE
Program
PresentedbyKarenSGinsbury
For IVTssACEConference
ForIVT
ACE Conference
Amsterdam,Netherlands
October2011
RiskManagement
Startswithphilosophy
Understandingthelawsofnaturehelps:
NaturehasatendencytoDISORDER
Howdoyouperceivewhatisgoingtohappen
tomorrowmorningatyourfacility:
10/3/2011
ItwillbeOK
Whatcouldgowrongtoday
10/3/2011
Letsmakealist
Cleaning
Letsmakealist
Asepticprocessing
10/3/2011
Letsmakealist
Environmentalmonitoring
CleaningValidationcitations
1.Processtanksareroutinelyreusedbeforecleaning,andnocleaning
validationdataareavailabletosupportthispractice.
2.Nodataexisttosupportthemanualcleaningofcentrifugebowls.
3.Approvedcleaningproceduresarenotspecificandarenotvalidatable
4.Inadequatecleaningoflyophilizer,inthatworstcasesamplinglocations
arenotidentified,andsamplingtechniqueshavenotbeenvalidated.
5.Inadequateproductiontankcleaningproceduresexist.Specifically,
validatedholdtimesarenotincludedinthecleaningprocedure;cleaning
validated
hold times are not included in the cleaning procedure; cleaning
SOPslacksufficientdetail;andnoverificationofvisualinspectionfor
cleanliness.
10/3/2011
CleaningWarningLetter
FDAWarningLetter Feb2011
1.Yourfirmhasnotestablishedorfollowedappropriatewritten
proceduresdesignedtopreventmicrobiologicalcontaminationof
drug products purporting to be sterile [21 C F R 211.113(b)].
drugproductspurportingtobesterile[21C.F.R.
211 113(b)] For
For
example,
Forexample,inJune2010,yourfirmfailedtoidentifythe
organismsrecoveredfromasterilitytestforApidra lot
#OF100. Identificationofmicroorganismsrecoveredfroma
sterilitytestisessentialwhenconductingasterilityfailure
investigation.Inaddition,theidentificationoforganismsisalsoa
fundamental part of any investigation of environmental or
fundamentalpartofanyinvestigationofenvironmentalor
personnelmonitoringexcursions.
Yourfirmsfailuretoidentifyorganismsrecoveredfromasterility
testwasalsodiscussedduringtheDecember2008inspection.
10/3/2011
Fromthesameletter
Anadequateenvironmentalmonitoring
programshouldbeestablishedbyyourfirm.
h ld b
t bli h d b
fi
It
It
shouldcapturemeaningfuldataandactasan
earlywarningsystemtodetectpossible
environmentalcontaminantsthatmayimpact
thesterilityofdrugproductsmanufacturedat
yourfacilitythatpurporttobesterile.
October2010
b.Yourasepticprocessingcontrolsystemsandoperationsdonot
provideassurancethattheproductionroomsandequipment
maintain aseptic conditions Additionally your environmental
maintainasepticconditions.Additionally,yourenvironmental
monitoringpracticesdonotincludeadequateroutineexamination
ofthefacilitiesandequipmenttoensurethatpossible
contaminantscanbedetected.
Theinspectiondocumentedmoldcontaminationintheclass100
productionroomandpoorconditionsofawallinthefreezedryer
room,eventhoughmaintenanceisconductedonthefreezedryer
every 6months.Anincidentreport,initiatedinNovember2009,
every
6 months. An incident report, initiated in November 2009,
identifiesholesintheceilingandvisiblelightcomingfromtheroof
neartheventilationsystem,bubblingofthevinyland disintegration
ofthewallundervinylinthefreezedryerroom,visibleblackmold
onthewall,apoordrainsystemforthefreezedryersteamventing
system,andasoft(spongy)wall.
10/3/2011
MHRAFindings
April2008 March2009
WEdwardsDeming
1900 1993
Wehavelearnedtoliveinaworldof
mistakesanddefectiveproductsasifthey
werenecessarytolife
IfIhadtoreducemymessagefor
managementtojustafewwords,Idsayitall
hadtodowithreducingvariation
10/3/2011
CauseandEffect
Allmanufacturingprocessesaredesignedto
f ll
followaseriesofstepswhichareinterlinked
i
f t
hi h
i t li k d
andinterdependent
(causeandeffect)
Variationexistsinallprocesses
Understandingandcontrollingvariationwill
Understanding and controlling variation will
alwaysimproveyourprocess
CauseandEffect
Asepticprocessing:variationcanleadtoNON
sterileproduct
t il
d t
Cleaning:variationcanleadtocross
contaminationorcontamination
EM:variationcanleadtofalserepresentation
of the state of control of a process
ofthestateofcontrolofaprocess
10/3/2011
Uncertainty=Risk
Wherethereisvariability=uncertainty=Risk
Whatcontrolsdoyouhaveinplaceto
stopitgoingwrong?
Riskmanagement:
Riskassessment
Riskmitigation thecontrolsweputinplaceto
stopitgoingwrong
followedby
Riskacceptanceand
Riskcommunication
10/3/2011
Cleaning whatcontrols?
AsepticProcessing whatcontrols?
10
10/3/2011
EnvironmentalMonitoring.
EMisNOTacontrolorariskreduction
measure
EMisthenextstepinourprocess
Riskreview
WeuseEMtomonitorthe
h
STATEOFCONTROLthatwehaveachieved
usingourriskmitigationmeasures
EnvironmentalMonitoring.
WhatinformationwillIusetodeploy
my limited EM resources?
mylimitedEMresources?
Howwillmyriskassessmenttiein
Reassignthemostresourcesto
Highriskactivities
cleaningaconvolutedpiece
ofmultipurposepiping
p p
pp g
Makinganasepticconnection
Machinesetup
Cleaningonthegraveyardshift
11
10/3/2011
FDAWarnedAtLeast43DrugPlantsInRecent
MonthsOverManufacturingPractices
USAToday(5/27,Young)reports
USA
Today (5/27, Young) reports
"Atleast43drugfactoriessupplyingmedicationtothousandsofUS
consumershavereceivedgovernmentwarningsinrecentmonthsfor
failingtocorrectshoddymanufacturingpracticesthatmayhaveexposed
patientstohealthrisks...."
Violations"include:
plantsusingequipmentandingredientscontaminatedwithbacteriaorinsects
failingtodopropertestingtoensuredrugstrengthandpurity,andignoring
consumercomplaintsthatproductsweremakingthemsick."
FFrom2002to2006,"morethanhalfofinspectionsatdomesticdrugplants
2002 t 2006 "
th h lf f i
ti
td
ti d
l t
and62%atforeignplantssupplyingtheUShadviolationsthatdidn't
promptwarningletters,butwereclassifiedasrequiringcorrection,FDA
datapublishedbytheGovernmentAccountabilityOfficeshow."
EstablishingandMaintainingaStateofControl
Whathaschanged?
1)Lessexperiencedinspectorswithmisalignedperceptionsofhow
systemsshouldworkamplifiedbytheresultantpostinspection"
ConsultantCreep"(Actionandreaction)
(
)
2)Downsizingofworkforce,sometimesbelowthelevelrequiredto
operategoodqualitysystems.
3)Lackofleadership/technicalexperienceintheQAstaff.
4)PoororganizationplacementofQA.
5)PoorInspectionmanagementonpartoffirms.
6) Failure to understand validation and its purpose Textbook exercise
6)Failuretounderstandvalidationanditspurpose.Textbookexercise
vs.actualproductandequipmentbasedtestdesign.
7)Increasedagencyemphasisonquickenforcement,sometimes
withoutdialogue
12
10/3/2011
AndKeepasking:
Whatcouldgowrongtoday
TheEnemiesofControl
13
10/3/2011
Deviations
"Everydefectisatreasure,ifthecompany
canuncoveritscause
it
andworktopreventitacrossthe
corporation
KilchiroToyoda,founderofToyota
.oops!
p
Changes
Change
Changemanagementisaboutcontrolling
management is about controlling
changestoensurethatinnovationhappens
withoutunintended/unforeseen
consequences
14
10/3/2011
InConclusion
Riskmanagementisabout:
Identifyingrisks
Id tif i
ik
Investingenergytocontrolandreducethoserisks
Communicatingastheriskmitigationmeasuresto
stakeholdersatalllevelsinthecompany
broadestpossiblecommunication
Eventreviewandmonitoring
Event review and monitoring
Updatingtheassessmentwhenthereare
indicatorsthatitisfailingormovinginthewrong
direction
Thankyouforyourattention
Anyquestions?
Contactme:
pcikaren@netvision.net.il
15
10/3/2011
Lewis Carroll
Alice in Wonderland
If you don't
don t know where you
want to go
You are likely to end up
somewhere else
10/3/2011
Objective of Seminar
y Review
y Refresh
y Renew
y Refine
10/3/2011
10/3/2011
10/3/2011
g
regulations
Aseptic Processing - Sterilization
y Section 211.67(a) Equipment cleaning and
10
10/3/2011
materials
t i l / components
t
12
10/3/2011
13
14
10/3/2011
10/3/2011
17
18
10/3/2011
19
data
y Successful gowning qualification
y From total of six different locations
less than 5 cfu
y On
O exitit less
l
than
th 20????????
y During certification take MORE
location than during routine
monitoring and consider variants in
persons build and age
PCI Pharmaceutical Consulting Israel Ltd
Main Changes
y Particulate Classification
20
10
10/3/2011
Previous
Now
21
11
10/3/2011
Duration of Monitoring
y Grade A: full duration of critical processing, including
Sample Size
24
12
10/3/2011
25
growth
th b
butt a contamination
t i ti rate
t
of less than 0.1% with 95%
confidence limit is acceptable
y The manufacturer should
establish alert and action limits
y Any contamination should be
investigated
PCI Pharmaceutical Consulting Israel Ltd
26
13
10/3/2011
vials
i l should
h ld b
be maintained
i t i d
under Grade A conditions at all
times until the stopper is fully
inserted
NOTE: effective 01 March 2010
28
14
10/3/2011
29
30
15
10/3/2011
previous
y Velocity
y Number of air changes in surrounding room:
31
32
16
10/3/2011
17
10/3/2011
35
36
18
10/3/2011
37
38
19
10/3/2011
y gamma
39
20
10/3/2011
TPP
y Target Product Profile
Ap
prospective
p
and dynamic
y
summary
y of
the quality characteristics of a drug
product that ideally will be achieved to
ensure that the desired quality, and
hence the safety and efficacy, of a drug
product is realised
The
e ta
target
get product
p oduct p
profile
o e forms
o s tthe
e
basis of design for the development of
the product
41
CPPs vs CQAs
Critical Process
P
Parameter
t
Critical Quality
Att ib t
Attribute
y physical, chemical,
21
10/3/2011
I Chart
115
UCL=111.55
Individual Value
110
105
_
X=99.63
100
95
90
LCL=87.71
C 8
60
62
64
66
68
70
72
Observation
74
76
78
80
People
I Chart
115
UCL=112.65
110
Individual Value
105
100
_
X=97.94
95
90
85
LCL=83.23
80
40
44
46
48
50
52
Observation
54
56
58
60
Equipment
I Chart
115
UCL=112.65
110
Individual Value
105
100
_
X=97.94
95
90
85
y = (x)
I Chart
LCL=83.23
80
40
42
44
46
48
50
52
Observation
54
56
58
60
115
Measurement
UCL=116.68
Individual Value
115
110
105
_
X=102.37
100
95
UCL=114.17
110
Individual Value
I Chart
120
105
_
X=99.95
100
95
90
LCL=88
LCL
88.05
05
20
22
24
26
28
30
32
Observation
34
36
38
40
90
Process
11
21
31
41
51
61
Observation
71
81
91
UCL=111.55
110
Individual Value
LCL=85.72
85
1
I Chart
115
105
_
X=99.63
100
95
90
OUTPUT
LCL=87.71
60
62
64
66
68
70
72
Observation
74
76
78
80
Materials
I Chart
UCL=111.17
110
105
Individual Value
I
N
P
U
T
S
(X)
42
_
X=98.76
100
95
90
LCL=86.35
85
80
82
84
86
88
90
92
Observation
94
96
98
100
Environment
44
22
10/3/2011
Control Strategy
y Control Strategy
45
TPP continued
y Considerations for the target product
23
10/3/2011
Severity
SEV
Likelihood of
Occurrence
OCC
Low
Medium
High
There is a
The possibility that
reasonable
the cause occurs
possibility
ibilit that
th t the
th
is rare; unusual
cause may occur
event
from time to time
High possibility of
occurrence;
common / known
event
24
10/3/2011
RPN
< 10 ?
SEV x
OCC X
DET
11 29 ?
30 ?
49
50
25
10/3/2011
Lifecycle Product
Management
Developmen
t
CAPA
Annua
l
Produ
ct
Revie
w
51
Process
validation
Commerci
al
52
Personnel Training
V lid i
Validation,
O
Operation
i and
dE
Environmental
i
l
Controls
CAPA and Control Strategy
Deviation
Change
Control
PCI Pharmaceutical Consulting Israel
Ltd
26
10/3/2011
Control Strategy
y List the items that need to be
controlled
t ll d and
d thi
think
k about
b th
how
to achieve that
y _______________________
y _______________________
y _______________________
53
27
10/3/2011
Validation - KPIs
55
EM - KPIs
56
28
10/3/2011
57
29
21 CFR 211.42
Aseptic processing areas:
Easy to clean and maintain
Temperature
and
T
t
d humidity
h idit controlled
t ll d
HEPA filtered air
Environmental monitoring system
Cleaning and disinfecting procedures
Scheduled equipment maintenance and calibration
21 CFR 211.46
Ventilation, air filtration, air heating and cooling:
Adequate control over microorganisms, dust, humidity and
temperature.
temperature
Air filtration systems including prefilters and particulate
matter air filters for air supplies to production areas.
10
11
Importance of EM program
Personnel training in aseptic processing
Establishment of sampling plans and sites
suggested sampling frequencies
12
13
14
15
16
Viable (CFU)
ft3
m3
Class
100
100
3,530
0.1
3.5
Class
10,000
10,000
,
353,000
,
0.5
18
Class
100,000 3,530,000 2.5
100,000
88
17
Controlled Area
Preparation or manufacturing area where nonsterile
product, in-process materials and product-contact
equipment
containers
and
are
i
t surfaces,
f
t i
d closures
l
exposed to the environment
Control nonviable and viable contaminants to reduce
product /process bioburden
Class 100,000 or Class 10,000
18
Controlled Area
Capping areas are now considered controlled
manufacturing areas
Should
Sh
ld be
b supplied
li d with
i h HEPA filtered
fil
d air
i
Should meet class 100,000 conditions during static
conditions
19
Critical Area
Aseptic processing area where sterile products,
components or in-process products are exposed to the
environment
i
t and
d no further
f th processing
i will
ill occur.
Air quality must be Class 100 during processing
Local Class 100 areas are often utilized during open
processing steps during drug substance manufacture.
20
10
Critical Area
The area just preceding the sterile core should be one
classification higher than the core.
21
22
11
23
24
12
Microbial Monitoring
Airborne viable contaminants
Surface contaminants
walls
ll
equipment surfaces
countertops
floors
Personnel contaminants
25
Microbial Monitoring
Monitoring methods should be capable of detecting
molds and yeasts
Should
Sh ld also
l be
b able
bl to
t detect
d t t anaerobes
b
Most often, this is an issue associated with products filled
anaerobically (with nitrogen overlay)
26
13
Microbial Monitoring
Routine microbial monitoring should take place during
operations (for airborne contaminants) and
i
immediately
di t l following
f ll i operations
ti
(for
(f surfaces
f
and
d
personnel).
Airborne monitoring frequencies:
Each use for aseptic processing areas
Varies from daily to weekly to less frequently for controlled
areas depending on use
27
Microbial Monitoring
Personnel and surface monitoring frequencies vary:
Aseptic processing - after every fill
Other
daily
Oth controlled
t ll d areas - varies
i from
f
d il to
t weekly
kl or less
l
for surfaces
Personnel monitoring often restricted to aseptic area
personnel and personnel working in Class 100 hoods
performing tasks such as inoculation
28
14
Microbial Monitoring
Monitoring of surfaces and airborne contaminants
during rest periods (following cleaning)
IImportant for
f confirming
fi i adequacy
d
off cleaning
l
i procedures
d
Indicates whether HVAC system is operating properly
NOTE: Disinfectant effectiveness studies also required for
cleaning agents used in the facility
29
Microbial Monitoring
Monitoring frequencies and procedures are influenced
by a number of factors:
Stage
off manufacturing
S
f
i
Open or closed manufacturing step
Single or multiple product manufacturing
30
15
Microbial Monitoring
Establishment of monitoring locations should be based
on performance qualification studies during dynamic
conditions
diti
gridding study to determine worst case locations/most
meaningful locations
31
32
16
33
34
17
Exceeding Limits
Alert limits are designed to provide some warning that
environmental quality is approaching action limit and
allow
ll
you time
ti
to
t correct.
t
Exceeding alert limit triggers a warning response - i.e.,
alert affected area personnel
Exceeding multiple alerts - triggers action level
response
35
Investigations
Wyeth Pharmaceuticals
18
Investigations
V review of product & component
sterilization & aseptic filling process
V microbial monitoring history
V media fill record
V equipment & facilities maintenance
documentation
V sanitization record
V training status of the personnel
V level of supervision
37
Wyeth Pharmaceuticals
Exceeding Limits
Action limit excursions require investigations
Speciation of organism(s)
Review
batch
date
R i
b t h records
d from
f
d t off excursion
i
Review other recent EM data (trends)
Review cleaning records
Interview personnel
Product impact - must quarantine until determined
38
19
Exceeding Limits
Excursions from action limits require corrective
actions that may include:
More rigorous
M
i
or additional
ddi i
l monitoring
i i
More rigorous cleaning
Retraining of personnel
Procedural changes - change to or addition of disinfection
procedures, for example
HVAC maintenance
39
40
20
41
Corrective Actions
Wyeth Pharmaceuticals
21
Corrective Actions
43
Wyeth Pharmaceuticals
Trending
Should trend monitoring results (environmental and
water)
Periodic
by
P i di (quarterly
(
l or monthly)
hl ) review
i
b QA and
d others
h
Re-evaluation of action and alert limits on an annual basis
This trending information is generally included in the Annual
Product Review
44
22
45
46
23
Water Requirements
Test
TOC
Conductivity
Micro
Micro.
Purity
EndoToxin
500
CFU/ml
100
CFU/ml
none
none
10 CFU/
100 ml
0.25
EU/ml
47
48
24
Purified Water
Defined in USP
Obtained by a suitable process, usually one of the
f ll i
following:
deionization
reverse osmosis
combination
49
Potable Water
Meets National Drinking Water Regulations
40 CFR Part 141
Periodic
as well
P i di monitoring
it i in-house
i h
ll as periodic
i di
certificates from municipality (if applicable)
50
25
51
52
26
Water Use
WFI
Solvent for preparation of parenteral solutions
F
Formulation
l ti off mammalian
li cell
ll culture
lt
media
di
Formulation of purification buffers
Final product formulation
Vial and stopper washing
Final rinse for product equipment
53
Water Use
Purified Water
Preparation of terminally sterilized microbiological media
Initial
I iti l rinsing/cleaning
i i / l
i
Laboratory use
Feed for WFI system
54
27
Water Use
Potable Water
Non-product contact uses
F d for
Feed
f purified
ifi d water
t system
t
55
56
28
57
58
29
59
Monitoring Considerations
Remote sampling probes - validate use of tubing
Must sample adequate quantity of air to be statistically
meaningful.
i f l
80-100 ft3/min
60
30
Fluids in Motion
Turbulent Flow
Streamline Flow
Q: Have you ever used your thumb to control the water flowing
f
from
th
the endd off a hose?
h ?
Q: Have you ever used your thumb to control the water flowing
f
from
th
the endd off a hose?
h ?
A: When the end of a hose is partially closed off, thus reducing
its cross-sectional area, the fluid velocity increases.
This kind of fluid behavior is described by the equation of
10
continuity.
Equation of Continuity
11
Bernoulli's Equation
12
Bernoullis Equation
13
Bernoullis Equation
14
The tarpaulin that covers the cargo is flat when the truck is
stationary but bulges outward when the truck is moving.
15
Household Plumbing
Curveball Pitch
17
Airplane
18
Turbulent flow
Laminar flow
19
http://www.engineering.uiowa.edu/~cfd/gallery/lim-turb.html
20
10
21
22
11
23
12
Velocity profile
for turbulent flow
Velocity profile
if flow were laminar
everywhere
13
result
esu t in high
g head
ead loss
oss (o
(of course,
cou se, one
o e of
o the
t e
purposes of a valve is to create head loss when
it is not fully open)
Ev are the loss in terms of velocity heads
Ev = K
U2
2
L eq U 2
U2
hv =
= Kv
= 2 f
2g
D g
27
Rounded inlet
Sharp-edged inlet
14
Bends in pipes:
Sharp bends result in
separation downstream of
the bend.
The turbulence in the
separation zone causes
flow resistance.
Greater radius of bend
reduces flow resistance.
29
30
15
31
A1
A2
KE
E E = KE
E E = KE
(U 1 U 2 )
2
U
2
2
2
( 1) 2
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
20
40
60
80
angle ()
A
= 2
A1
32
16
Sudden Contraction
(Orifice Flowmeter)
Orifice flowmeters are used to determine a
liquid or gas flowrate by measuring the
differential pressure P1
P1-P2
P2 across the orifice
plate
2 ( p p ) 1 / 2
1
2
Q = C d A 2
(1 2 )
1
0.95
0.9
0 85
0.85
Cd 0.8
0.75
0.7
0.65
0.6
102
103
P1
P2
Flow
105
104
106
107
Re
33
Pipe
Entrance
34
17
35
36
18
37
38
19
39
40
20
41
42
21
43
44
22
45
46
23
47
48
24
49
50
25
51
52
26
53
54
27
55
56
28
57
58
29
59
60
30
61
62
31
63
64
32
65
66
33
67
Circuit
Size
311
2.5"
311
2"
311
1"
311
.75"
75"
311 2.5" valve
311
2" valve
311
1" valve
311 2" x 1.5"
311 1" x 0.75"
311 2.5" elbow
311 2" elbow
311 1" elbow
311
2.5" T
311
2" T
311
1" T
Length (ft)/#
Common Supply to 311
5.583 Line-2.5"
23.667 Line-2"
27.667 Line-1"
Li 3/4"
0 833 Line-3/4"
0.833
2 ITT DiaV-2.5"/DN50
1 ITT DiaV-2.00"/DN50
2 ITT DiaV-1.00"/DN25
1 Red-contract (2 x 1.5)
1 Red-contract (1 x 3/4)
1 Elbow-2.5"
3 Elbow-2"
18 Elbow-1"
2 2.5" T-Branch (Equal)
2 2" T-Branch (Equal)
4 1" T-Branch (Equal)
SUBTOTAL
in
D, Inch
out
2.37
1.87
0.87
0 62
0.62
2.50
2.00
1.00
1.87
0.87
2.37
1.87
0.87
2.37
1.87
0.87
1.37
0.62
# or L, ft
5.583
23.667
27.667
0 833
0.833
2
1
2
0.245
0.245
1
3
18
2
2
4
Q, GPM
Q, LPM Vmax, ft/s
10.0
37.9
0.7
10.0
37.9
1.2
10.0
37.9
5.4
10 0
10.0
37 9
37.9
10 6
10.6
10.0
37.9
0.7
10.0
37.9
1.0
10.0
37.9
4.1
10.0
37.9
2.2
10.0
37.9
10.6
10.0
37.9
0.7
10.0
37.9
1.2
10.0
37.9
5.4
10.0
37.9
0.7
10.0
37.9
1.2
10.0
37.9
5.4
Nre
13,291
16,844
36,206
50 805
50,805
12,600
15,750
31,499
f ,Cv,or b
0.0287
0.0270
0.0225
0 0209
0.0209
95
70
18.6
0.73
0.71
13,291
0.0287
16,844
0.0270
36,206
0.0225
13,291
0.0287
16,844
0.0270
36,206
0.0225
K
0.8
4.1
8.6
03
0.3
3.9
2.9
2.6
0.2
0.2
0.4
0.4
0.3
1.7
1.6
1.3
DP, ft
0.01
0.09
3.88
0 59
0.59
0.05
0.05
1.33
0.01
0.33
0.00
0.02
2.56
0.03
0.07
2.44
11.46
Volume
L
4.84
12.78
3.23
0 05
0.05
feet
68
34
Vessel 311
Line-2.5"
Line-2"
Line-1"
Line-3/4"
Line-1"
Line-1/2"
Line-1.5"
Line-1"
Line-3/4"
Line-1/2"
Line-1"
Line-1/2"
Line-1"
Line-1/2"
Line-1"
Line-1/2"
Line-1"
Line-1/2"
Line-1"
Line-1/2"
Line-2.5"
Line-1.5"
Length (ft) Flow Rate (LPM) Reynolds Number Velocity (ft/s) Pressure Drop (ft)
Supply Header
5.6
13,291
0.7
23.7
16,844
1.2
37.9
11.46
27.7
36,206
5.4
0.8
50,805
10.6
Path 1
2.7
36,206
5.4
37.9
248.29
8.8
85,133
29.8
Path 2
0.3
22,992
2.2
2.7
36,206
5.4
37.9
757.30
1.1
50,805
10.6
8.8
85,133
29.8
Path 3
1.9
36,206
5.4
37.9
215.88
6.7
85,133
29.8
Path 4
2.7
36,206
5.4
37.9
182.11
5.9
85,133
29.8
Path 5
2.7
36,206
5.4
37.9
162.24
5.4
85,133
29.8
Path 6
2.7
36,206
5.4
37.9
158.01
4.9
85,133
29.8
Path 7
1.9
36,206
5.4
37.9
234.45
8.0
85,133
29.8
Return Header
40.0
13,291
0.7
37.9
0.80
12.6
22,992
2.2
62.64
69
Rule of Thumb
<Cleaning and cleaning validation: A biotechnology perspective, pub PDA, 1996>
Instrument Tee for CIP: L/D <1.5
Bad
Good
Best
ft/sec
5 ft/sec
5 ft/sec
70
35
10/5/2011
WritingSOPsandBatchRecords
Robert Pallo
g Fill and Finish Operations
p
Manager
36 years at Allergan
pallo_robert@allergan.com
Opinions expressed in the presentation are those of the author and in no way represent those of Allergan
10/5/2011
WritingSOPsandBatchRecords
y Doit
WritingSOPsandBatchRecords
y Doit
y Writeit
10/5/2011
WritingSOPsandBatchRecords
y Doit
y Writeit
y Testit
WritingSOPsandBatchRecords
y SOPWritingEssentials
10/5/2011
WritingSOPsandBatchRecords
y SOPWritingEssentials
y Be Brief
WritingSOPsandBatchRecords
y SOPWritingEssentials
y AskemployeesusingtheSOPfortheirinput
10/5/2011
WritingSOPsandBatchRecords
y SOPWritingEssentials
y AskemployeesusingtheSOPfortheirinput
y Prepareafirstdraft
WritingSOPsandBatchRecords
y SOPWritingEssentials
y AskemployeesusingtheSOPfortheirinput
y Prepareafirstdraft
y Runawalkthrough
10/5/2011
WritingSOPsandBatchRecords
y SOPWritingEssentials
y AskemployeesusingtheSOPfortheirinput
y Prepareafirstdraft
y Runawalkthrough
y Solicitfeedbackandmakecorrections
WritingSOPsandBatchRecords
y SOPWritingEssentials
y AskemployeesusingtheSOPfortheirinput
y Prepareafirstdraft
y Runawalkthrough
y Solicitfeedbackandmakecorrections
y Makeitofficial!
10/5/2011
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
10/5/2011
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
y Increaseconsistency
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
y Increaseconsistency
y FulfillCompliancerequirements
10/5/2011
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
y Increaseconsistency
y FulfillCompliancerequirements
y Communicateeffectivenessmeasures
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
y Increaseconsistency
y FulfillCompliancerequirements
y Communicateeffectivenessmeasures
y Retainandtransferknowledge
10/5/2011
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
y Increaseconsistency
y FulfillCompliancerequirements
y Communicateeffectivenessmeasures
y Retainandtransferknowledge
y Documentimprovementandchange
WritingSOPsandBatchRecords
y BenefitsofsolidSOPs
y Decreasetrainingtime
y Increaseconsistency
y FulfillCompliancerequirements
y Communicateeffectivenessmeasures
y Retainandtransferknowledge
y Documentimprovementandchange
y Decreaseerrorrate
10
10/5/2011
WritingSOPsandBatchRecords
y UnderstandingtheProcess
y BallisticProcess
y
y
y
Characteristicofthemotionofobjectsmovingundertheir
ownmomentum
Ifthereisnowaytoprovidefeedbacktochangeoradjusta
process,thisisaballisticprocess
TheBallisticProcessismostcommon
E.g.Anautoclavecycle;amanufacturingprocedure
WritingSOPsandBatchRecords
y UnderstandingtheProcess
y BallisticProcess
y Controlledprocess
y
Monitortheinputsandoutputsandmakecorrectivechanges
totheprocessinordertoachievethedesiredoutput
E.g.afillingmachinewherethefillweightisconstantly
adjusted.
11
10/5/2011
WritingSOPsandBatchRecords
y UnderstandingtheProcess
y BallisticProcess
y Controlledprocess
y AdaptiveProcess
y
y
y
Aprocessthatlearns
Canchangeovertimetoimproveeffectiveness
E.g.allowsausertoidentifyiftheprocessneedsmodification
andtheycanhavetheoptiontoupdatetheprocedure
NotagoodGMPidea
WritingSOPsandBatchRecords
y WritingaProcedure
y Discovery
y Design
y Development
y Deployment
12
10/5/2011
WritingSOPsandBatchRecords
y WritingaProcedure
y Discovery
y
y
Understandtheproblemorprocess
Aprocedureisneededtodescribethestepsofabusiness
process.Sobeforewecanwritethat,weneedtodiscoverwhat
isexpected.
Needtounderstand
y Whoarethesources/resources
y Whataretheinputsandoutputs
y Whoarethecustomers
y Whataretheeffectivenesscriteria
y Whatisthecorrectiveactioniftheprocessdoesntwork
WritingSOPsandBatchRecords
y WritingaProcedure
y Discovery
y Design
y
y
y
y
Thisiswhereyouspendyourtime
Aprocessmapwillhelpcommunicatetheproceduraldesign
andcollectfeedbackbeforewewriteoutthewrittensteps
Performawalkthroughwiththedesign
RememberPDCA(PLAN DO CHECK ACT)
13
10/5/2011
WritingSOPsandBatchRecords
y WritingaProcedure
y Discovery
y Design
y Development
y
Importantquestion:Whoistheaudience?Novices,
occasionalusersorfrequentusers?
WritingSOPsandBatchRecords
y WritingaProcedureforfrequentusers
y Donotrequirealotofexplanation
y Mightonlyneedachecklist
y Priorityisnavigationratherthanexplanation
14
10/5/2011
WritingSOPsandBatchRecords
y WritingaProcedureforoccasionalusers
y Maynotnecessarilybeexperienced
y Mayfillinforsomeonefromtimetotime
y Mayrequiremoreexplanationorsomehowandwhy
y Priorityisexplanation,notnavigation
WritingSOPsandBatchRecords
y WritingaProcedureforthenovice
y Leaveoutthedetail
y Makeitastepbystepprocedure
y Providethedetailsinanaccompanyingtraining
document
y and
15
10/5/2011
WritingSOPsandBatchRecords
y WritingaProcedureforthenovice
y Leaveoutthedetail
y Makeitastepbystepprocedure
y Providethedetailsinanaccompanyingtraining
document
y and
y NoticethattheBESTSOPsarewritteninthisstyle!
WritingSOPsandBatchRecords
y Reviewofthewrittenprocedure
y ThesevenCs
y
y
y
y
y
y
y
Context
Consistency
Completeness
Control
Compliance
Correctness
Clarity
16
10/5/2011
WritingSOPsandBatchRecords
y WritingaProcedure
y Discovery
y Design
y Development
y Deployment
WritingSOPsandBatchRecords
y Deployment
p y
y Training
y Auditing
y Continuousimprovement
17
10/5/2011
Writing
g Essentials
Be Brief
Be Clear and Concise
Writing Essentials
Be Brief
Clear and Concise
The shorter, the better
18
10/5/2011
Writing Essentials
Be Brief
Clear and Concise
The shorter, the better
SOPs should say what to do, not how to
do it
Writing Essentials
Be Brief
Clear and Concise
The shorter, the better
SOPs should say what to do, not how to
do it
Pictures are worth a thousand words
19
10/5/2011
Do I Need SOPs?
Consistency
SOPs Reduce Variation
SOPs facilitate training
People can support SOPs (particularly if
they
y help
p write them))
of SOPs?
20
10/5/2011
of SOPs?
Hierarchical steps
p
This is an extension of Simple Steps.
Works well for more complex steps
1. Start the Mixer
1 1 Ch
1.1
Check
k Safeties
S f i
1.2 Zero the propeller speed
1.3 Press the start button
Writing SOPs and Batch
Records--Robert Pallo
of SOPs?
Annotated Pictures.
Works well when there are language
barriers.
Shortens complex and detailed SOPs
21
10/5/2011
of SOPs?
Annotated Pictures.
to Write an SOP
22
10/5/2011
PARETOCHART(EXCEL)
Count
40
35
30
25
20
Count
15
10
5
0
Machine
Setup
Highplate
counts
Highparticle PoorAirFlow
counts
Gowning
Technique
Supplies
Facility
Disinfection
23
10/5/2011
Format
Standard Operating
g Form
Form
24
10/5/2011
Standard Operating
g Form
Form
Gateway to Excellent SOP
Compliance
Includes the critical parts of a procedure
in a batch record format
Standard Operating
g Form
Form
Gateway to Excellent SOP
Compliance
Includes the critical parts of a procedure
in a batch record format
step
Operator signs off each critical step,
assuring compliance with the SOP.
25
10/5/2011
Format
Tips
26
10/5/2011
Tips
Tips
27
10/5/2011
WritingSOPsandBatchRecords
STEP
OPERATION
C/B
TIME IN
CHECK OPERATIONS
MS
DATE
Room No.:
_____________
P/B
DATA/RESULTS
CT
C
L
AC
MO
EM
OTHER
TIME
OUT
WritingSOPsandBatchRecords
y ExampleSOF
P/B
C/B
DATE
FLEXICON PF6
Description
Volume
Tube Diameter
Setting
Pump RPM
Reverse
Actual Tube
Diameter
Specification
Per BPO
6 mm
As needed
As needed
6 mm
Actual
28
10/5/2011
WritingSOPsandBatchRecords
y ExampleSOF
WritingSOPsandBatchRecords
FinalComments
1. Educate employees about the new SOP.
2. Control procedural drift by ensuring that
the SOP is followed consistently overtime.
3 Establish
3.
E t bli h an evaluation
l ti and
d review
i system
t
to
t
be certain that over time all the steps of an
SOP are still correct and appropriate for the
production system.
Writing SOPs and Batch
Records--Robert Pallo
29
10/5/2011
WritingSOPsandBatchRecords
y FINALCOMMENTS
Phone: 714-246-4413
Email: Pallo_robert@allergan.com
_
g
30
Cleaning Validation
Coverage Studies
Jeff Felker
Sanofi Pasteur, Inc.
Dawn T
D
Tavalsky
l k
Sanofi Pasteur, Inc.
Background Information
Background Information
Background Information
Cleaning Methods
Cleaning Parameters
Cleaning Equipment
10
11
12
13
14
15
16
Cleaning Technology
17
18
Riboflavin
Riboflavin, also known as vitamin B2
Riboflavin
Rib
fl i iis best
b t known
k
visually
i
ll as the
th vitamin
it i which
hi h
imparts the orange color to solid B-vitamin
preparations, the yellow color to vitamin supplement
solutions, and the unusual fluorescent-yellow color to
the urine of persons who supplement with high-dose Bcomplex preparations (no other vitamin imparts any
color to urine).
19
Riboflavin
20
10
Vitamin K Fluorescence
Detecting Riboflavin
* A coverage test also qualifies that a final rinse sample taken during
cleaning validation or cleaning monitoring, is a composite sample from
all surfaces
Procedure:
Note: Care must be taken when working around cleaning systems. Solutions containing
chemicals at high concentrations and temperatures are used in the normal operation of the
system. Good practice is to have the system operator available at all times while this testing is
g performed.
p
being
1. For vessels with sprayballs/wands/bars that have already been tested (for example as part of
FAT), audit the test documentation and verify that the following information is available and has
been recorded for each sprayball/wand/bar:1.1 Vessel Identification
1.2 Sprayball/Wand/Bar Identification
1.3 Date of Test
1.4 Test Method (Riboflavin, Salt, Other)
1.5 Feed Solution Pressure or Flow Rate
1.6 Results
1.7 Conclusion (Pass/Fail)
Wrong
10
11
2. For vessels with sprayballs/wands/bars that have not had coverage testing
performed, perform the following tests for each spray ball/wand/bar:
2.1 Prepare the vessel/equipment item to be tested per normal operational cleaning
procedures.
d
2.2 Prepare a solution of dilute riboflavin in a spray bottle per approved procedures
(0.2 gm/L).
2.3 Spray the product contact surfaces of the vessel/equipment item with the
riboflavin solution being sure to coat all exposed areas - especially those that may
be masked by vessel appurtenances.2.4 Initiate a cleaning cycle using (if
possible) the minimum pressures/flow rates to simulate worst case conditions.
2.5 At the completion of the cleaning cycle, inspect the vessel product contact
surfaces using an ultraviolet light. Look for traces of fluorescence - indications
that the spray ball coverage failed to contact the surface in that location.
2.6 Document the locations of any fluorescence observed.
12
13
Acceptance Criteria:
1. For vessels with sprayballs/wands/bars that have
already
tested,
l
d been
b
t t d the
th test
t t reports
t indicate
i di t
successful sprayball coverage and contain the
following information:
Vessel Identification
Sprayball/Wand/Bar Identification
Date of Test, Test Method (Riboflavin, Salt, Other)
Feed solution pressure or flow rate Results
Conclusion (Pass/Fail)
14
15
Talking Specifics
Riboflavin wet or dry?
What do you do with small spots left?
Full
cycle?
F ll cleaning
l
i cycle
l or just
j t rinse
i
l ?
Bursts or Flow?
16
Impact of Coverage
17
18
19
20
10
10
Cleaning Case
10
11
Effective Strategies
g
to Design a
Aseptic Facility
More Quality is better quality or More money spent to design
in quality the better can cause as many as problems as the
lack of quality in a facility design.
design.
Amjad
Facility Layout that can affect or influence required space or unit operations, defines their
inter--relationships and establishes the flow pattern that best represents the process GMP
inter
and operator requirements
Equipment Layout is developed by defining room sizes, structural grids and access routes
in broad compliance with building and fire regulations
regulations.. Contact surface should be stainless
steel 316
316L
L.product and container closure parts should be made to withstand repeated
cleaning and sterilization.
sterilization.
The equipment must be suitable for delivery the products into the container within the
required accuracy
Moving
parts
in--house
that
M i
t should
h ld be
b contained
t i d iin
h
th t preventt exposure to
t the
th aseptic
ti
environment, and lubricant (pharma grade) should be used outside the filling area
area..
Equipment should be installed in a manner that allows routine intervention and maintenance
from outside the filling area
Equipment should be able to sample the IPC samples without interrupting the operation of
the line
Stoppers bowls and delivery shutes should be readily demountable for sterilization, cleaning
and changeover.
changeover.
Amjad
Amjad
Amjad
2.
3.
4.
5.
Amjad
Amjad
Amjad
Clean area control parameters should be supported by microbiological and particle data
obtained during qualification studies.
studies. Initial cleanroom qualification includes, in part, an
assessment of air quality under as
as--built, static conditions
conditions..
It is important for area qualification and classification to place most emphasis on data
generated under dynamic conditions (i
(i..e. with personnel present, equipment in place, and
operations ongoing)
ongoing)..
An adequate aseptic processing facility monitoring program also will assess conformance
with specified clean area classifications under dynamic conditions.
conditions.
HEPA filtered air should be supplied in critical area at a velocity to sweep particles away
from the filling and closing areas and maintain unidirectional airflow during operation.
operation.
A velocity of 0.45meter/second
45meter/second per 90
90feet
feet per minute has generally been established with a
range of plus or minus 20
20percent
percent around the set point
point..
Proper design and control prevents turbulence and stagnant air in the critical area.
area. Once
relevant parameters are established, it is crucial that airflow patters be evaluated for
turbulence or eddy currents that can act as a channel or reservoir for air contaminants
contaminants..
Amjad
Amjad
Factors associated with the longest permitted run on the processing line that can pose
contamination risk (e.g., operator fatigue)
Representative number, type, and complexity of normal interventions that occur with each
run, as well as non-routine interventions and events (e.g.: maintenance, stoppages,
equipment adjustments)
Lyophilization, when applicable
Aseptic assembly of equipment (e.g.: at start-up,during processing)
Number of personnel and their activities
Representative number of aseptic additions (e.g.,charging containers and closures as well as
sterile ingredients) or transfers
Shift changes
changes, breaks
breaks, and gown changes (when applicable)
Type of aseptic equipment disconnections and connections
Aseptic sample collections
Line speed and configuration
Weight checks
Container closure systems (e.g.: sizes, type, compatibility with equipment)
Amjad
Amjad
Amjad
Amjad
Amjad
Amjad
10
Amjad
Keep
the entire
K
th
ti body
b d outt off the
th path
th off unidirectional
idi ti
l airflow:
i fl
Unidirectional airflow design is used to protect sterile equipment
surfaces, container
container--closures, and product.
11
Amjad
Amjad
12
External Sources:
Use of rere-circulated air from the manufacturing area, provided no cross contamination
risk
Careful selection of filters to match particular application
Careful location of fresh air intakes.
Location of the facility.
Amjad
Amjad
13
Amjad
Amjad
14
Amjad
15
Amjad
Amjad
16
17
Amjad
18
Environmental: Noise
Due to large air handling requirements, sterile
facilities can be serious source of external noise.
noise.
Fans, compressors and other utilities equipment can
generate unacceptable noise levels, in terms both
volume and frequency
frequency.. Site boundary noise levels are
55 dB(A) during daytime operations and 45
45dB(A)
dB(A) at
night time.
time. Suitable attenuation techniques must be
employed to comply
comply..
Amjad
19
HEPA Filters:
Regularly replace terminal HEPA filters
Employ some type of constant air volume control on terminal HEPA
filters.
Install a second main bank of HEPA filters, ensuring two filters in series.
(Note: The first two options given above can result in either expensive
capital or maintenance costs.)
Amjad
20
Container preparation
F
f
i
i
Four
forms
off contamination
Bioburden: Viable microbiological count CFU
Bioburden:
Endotoxins:Pyrogenic cell wall materials resulting from growth and
degradation of microorganism
Extraneous particulates: Solid particulate matter resulting from container
manufacturing, packaging and staging processes glass fragment)
Extraneous chemicals: e.g
e.g:: excess quantities of surface treatment
chemicals
Changing rooms
Designed as airlocks
Effective flushing with filtered air
Separate rooms for entry and exit desirable
Hand washing facilities
Interlocking system for doors
Visual and/or audible warning system
Amjad
21
Examples of contaminants
Amjad
U shaped filling and stoppering line has the advantage of returning the container to the pharmaceutical area
for capping 06. Filling Stoppering Process.pdf
Fill reproducibility rejection( with lock) for no fill and no stopperstopper- fill container &stopper container counter
Change parts design for fitting and removing with minimum use of tooling
Design of ease of cleaning and removing of metallic fragments generated by the crimping process
Amjad
22
Personnel
Facility &
Room
D/M
QA/QC
Media Fills
D= Design
M= Maintenance
Aseptic
Processing
Line
D/M
Daily
Sterility
Assurance
Disinfection
Procedures &
Practices
Process
-personnel flow
-material flow
-layout
HVAC/
Utilities
Response to
Deviations &
Environmental
Control Trends
Amjad
7. Interactive Discussion
Understanding the notion of designing the aseptic facility and
sharing your real life experience thoughts in this field that would
bring the discovery to the field.
Case Study for
Media Fill
Amjad
23
7. Interactive Discussion
Case Study
Media Fill Failure:
A
60% contaminated
i
d
Approx.
Considered spurious. Corrections made to firms satisfaction.
FDA Guideline (and PDA #22): 3 Lots for Revalidation
First Media Fill Batch = No contamination
Second Media Fill Batch = Over 95% contaminated (over 5000 vials)
Third Media Fill Batch = No contamination
If one batch was run, a firm would return to production/release of commercial lots
without knowledge nonnon-sterility problem still existed.
Root Cause:
Personnel / Aseptic Connection
Isolates in both failures were common skinskin-borne microbes
Only Partially Gowned, Skin Exposed, Aseptic Technique questionable.
Corrections to resolve these issues: Full sterile gown donned and enhanced
personnel/environmental monitoring performed in near term. Equipment later
modified to allow for SIP.
Amjad
7. Interactive Discussion
Examples of observations during GMP audits
I d
t environmental
i
t l monitoring
it i programmes.
Inadequate
At one site, management could not find the media preparation area.
No quantitative limits for fertility test. Qualitative limit (growth/no growth is not acceptable)
It is very easy to obtain zero results in all microbiological monitoring, including sterility &
bioburden testing.
If there are find pages & pages of zero results this should ALERT you NOT satisfy you.
Amjad
24
7. Interactive Discussion
False zero in clean rooms:
Amjad
7. Interactive Discussion
The microenvironment inside an equipment load cannot be
guaranteed because it relies upon:
adequate air removal
adequate steam penetration
lack of leaks in the autoclave (door seal, valves, pipework)
pipework)
prevention of introduction of non
non-- condensable gases from the steam
supply
prevention of condensate accumulating in equipment
Equilibration time, that is, the time for the penetration thermocouples
to show the same temperature as the chamber.
Equilibration time should be less than 15 seconds for chambers less
than 800L and 30 seconds for larger chambers
If the equilibration time is exceeded it diagnoses:
Inadequate air removal OR
Inadequate steam penetration OR
Excessive nonnon-condensable gases
Amjad
25
The End
Amjad
26
10/10/2011
Agenda
10/10/2011
Equipment
q p
Train Definition
Equipment
Grouping
Cleaning SOP
Definition
Critical Process
Parameters
Product
Characteristics
Cleaning Agent
Use Matrix
Residue
Selection
Hard to Clean
Locations
Sampling Method
Selection
Sampling Sites
Limits
Definition
Hold
H
ld Time
Ti
Definition
Engineering
Runs
Product
Grouping
Hard to Clean
Locations
Worst Case
Definition
Methods
Validation
Recovery
Studies
Cleaning Validation
Documented evidence that an approved cleaning
procedure will consistently reduce active pharmaceutical
ingredients (API), process residues, cleaning agents and
microbial residues from product contact equipment
surfaces to acceptable levels for the processing of drug
products
Reference: FDA; Guide to Inspections Validation of
Cleaning Processes, 1993
10/10/2011
Regulatory Requirements
Worldwide GMPs
EU Annex 15 (Paragraph 36) (2006) & GMP Part II
(formerly Appendix 18) (2005)
US FDA, Guide to Inspections of Validation of
Cleaning Processes (1993)
Pharmaceutical Inspection Convention (PIC/S),
Recommendations onCleaning Validation (2001)
WHO Technical
h
l Report No. 937: WHO Supplementary
l
Guidelines on GMP (Annex 4): Validation (2006)
10/10/2011
10/10/2011
SURFACE
SOIL
CHEMISTRY
9
Cleaning Chemistry
Cleaning depends on process control
Time
Action
Concentration / Chemistry
Temperature
Cleaning also depends on cleaning conditions
Water Quality
Individual Performing Cleaning (esp. in manual cleaning)
Nature of Soil
Surface being cleaned
10
10/10/2011
Cleaning Chemistry
Laboratory experiments and engineering studies will help
to establish the following criteria:
Time
Action
Clean in Place (CIP)
Washer (COP)
Manual
Chemistry / concentration
Temperature
11
Types of Soils
Potential Residues for consideration:
API (Drug substance)
Excipients / Colorants / Dyes / Fragrances / Flavors
Preservatives
Degradants / Impurities
Starting materials / Processing aids
Mother liquors / Solvents
Lubricants
Bioburden
Mycoplasma / Prions / Viral particles
Endotoxin
12
10/10/2011
13
Risk Level
0
Risk Level
1
Risk Level
2
Risk Level
3
Risk Level
4
Risk Level
5
Product
Diffi lt to
Difficulty
t
clean - lab
study or
subjective
Very easy to
clean
l
water
t
effective
Easy to clean
and
d highly
hi hl
mobile in liquid
state
Moderately easy
t clean
to
l
some
viscosity issues
Moderately hard
t clean
to
l
viscous or
gelatinous
residue
Difficult to clean
oily
il substance,
b t
builder or
excipient
Very Difficult to
clean
l
such
h as
denatured
protein,
carbopol,
titanium dioxide
Toxicity
LD50 (oral rat)
2500 mg/kg
>1250 mg/kg
and 500
mg/kg
>500 mg/kg
and 250
mg/kg
>250 mg/kg
and 25 mg/kg
25 mg/kg
Solubility g/100mL of
water
Very soluble
100% in water
Freely Soluble
99.9 % in water
Soluble
99% in water
Slightly Soluble
>10% but
<90% in water
Very Slightly
Soluble < 10%
in water
Practically
Insoluble
< 0.01% in
water
14
10/10/2011
Residue Limits
FDA Guide to Inspection of Cleaning Validation (7/1993)
Rationales should be logical
logical, practical
practical, achievable,
achievable
and verifiable
Sensitivity of analytical methods is critical to
establishing valid limits
Three examples given:
10 ppm
1/1000 of normal therapeutic dose
Organoleptic levels (e.g. visually clean)
15
Residue Limits
Fourmen and Mullen approach for active:
Most stringent of dose calculation and 10 ppm (in
next product)
AND
Visually clean
16
10/10/2011
Residue Limits
PIC/S Approach:
Most stringent of
Dose calculation in next product
10 ppm in next product
Visually clean
17
Residue Limits
Confusion in use of limit
Is 10 ppm
ppm
10 ppm in the next product?
10 ppm in rinse sample?
10 ppm in swab desorption sample?
18
10/10/2011
Residue Limits
Possible uses of limit
Daily amount allowed (ADI or ADE)
Concentration in next product
Absolute amount in manufacturing vessel/train (MAC
or MACO maximum allowable carryover)
Amount per surface area
Amount per swab
Concentration in swab extract solution
Concentration in rinse solution
19
Residue Limits
Need to determine how much product we just cleaned
will be administered to each patient taking the next
product
How much will that represent in the next batch?
How much will that represent on the surface?
Need the residual amount to be safe, add safety
factor
Need to recognize variability in manufacturing process
that may change from lot to lot and incorporate into
the strategy
20
10
10/10/2011
21
11
10/10/2011
Nature Term
How much of the product we just cleaned (Product A)
May be expressed as one of the following:
Toxicity or LD50 (with appropriate safety factor)
Therapeutic Dosage
Allergenic Level
Minimum pharmacological effect level
NOEL (No Observable Effect Level)
Most Conservative Approach
23
Dose Term
Amount that will be administered to each patient taking
the next product (Product B)
The amount of the next product that may be
administered
Always most conservative to over-estimate this term
24
12
10/10/2011
Batch Term
How much of the soil will be present in the next batch?
May be expressed as batch size (L or kg) or in the
number of doses (1,000,000 tablets for example)
Most conservative to work with smallest possible
batch size (worst case)
25
Size Term
How much of the soil may remain on the surface?
Size of the equipment
May represent full shared or maximum surface area
of an equipment train
Conservative approach is to over-estimate surface
area of shared equipment
26
13
10/10/2011
27
28
14
10/10/2011
29
Other Considerations
Route of administration
Topical,
Topical oral
oral, parenteral,
parenteral etc.
etc
Duration of use / term of administration
Type of patient likely to receive product
Adult vs. Child
Position / role of equipment in process
Conservative strategies moves one toward a purer
product as the product is processed to a finished
dosage (e.g. UF/DF skids, fillers)
30
15
10/10/2011
Microbiological Residues
Bioburden and endotoxin contaminants should be
considered when required to be limited in the final
product
Important considerations
Environmental conditions
Cleaning and sanitization/disinfection cannot be
performed in one step
Guidance
d
for
f llimits taken
k from:
f
Product Specifications
Historical data
31
32
16
10/10/2011
Sampling
Sampling locations should be selected based on:
Hard to clean locations or complex geometries (hot
spots)
Locations that might disproportionately contribute
residue to the next
Materials of construction or surface finishes with an
affinity for the soil
The
h role
l in the
h process that
h is likely
l k l to lead
l d to buildb ld
up or difficult to remove soils
Number of locations?
33
34
17
10/10/2011
Sampling Methods
Swab
Rinse
Placebo
Physical Removal
Good
Poor
Moderate
Technique Dependent
Yes
No
No
Poor
Good
Good
Moderate
Good
Moderate
Controlled Area
Yes
No
No
Non-Invasive
No
Yes
Yes
No
Yes
No
Yes
Yes
No
35
Analytical Methods
Analytical methods are preferred to be specific to the
analyte
Non-specific methods may be used provided that all
analyte identified is attributed to the worst case residue
limit
Analytical methods and sampling methods must be
demonstrated to be suitable through methods validation
in conjunction with the sampling method / extraction
system and through recovery studies
36
18
10/10/2011
How?
Scale Up Components
Keys in pilot scale/plant evaluation
Confirm lab performance of cleaning agent
Confirm critical control and quality parameters during
cleaning
Confirm adequate engineering design & control
Optimize time(s), conditions
Determine rinse conditions and acceptance levels
ID sampling locations
Evaluate analytical method and swab method
Define Residue limits for products
Define Analytical Method Capability and Swab
Recovery (Qualify Both)
38
19
10/10/2011
39
Summary
Questions?
Thank You for Your Time!
40
20
10/4/2011
www.foamtecintlwcc.com
Agenda
Introduction
Wiping
Wiping--Past, Present & Future
Wiping Challenges in the Life Science
Industry
Corrosion/Staining & Facility Appearance
Questions and Answers
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10/4/2011
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10/4/2011
Risks
Non Value Steps, Wiping
Uniformity, Fibers & Soils
As Above + Productivity
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Kaizen-2nd Questions
Question
Is Wiping Process Well
Defined & Understood?
Key Issues
Wetting, Work Surface
Contact, Operator To
Operator Uniformity
Cost Control,
Productivity(inspection),
Fibers, Damage
Emotional, ReRe-training,
Trial Builds, Small Teams,
Go Slow
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10/4/2011
Star-shaped
microfiber traps and
removes p
particles;
where standard
Polyester round
fibers push particles
around
Woven Microfiber
A tighter bundle
means better pick
up, greater
absorbency, and
superior abrasion
resistance
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Polyester
Foam
Micro Fiber
Application Driver
Cleaning Acid Benches in
Wafer Fabs/1980
Cleaning Acid Benches in
Wafer Fabs/1988
Removing Fibers &
Silicones In Medical
Device Mfg/1982
Cleaning Process
Chambers In Wafer
Fabs/2002
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10/4/2011
Strengths/Weakness
Strengths
/Weakness
Non-Wovens (Sontara)
(S
)
Polyester
Foam
Micro Fiber
Unit Cost,
C
Absorbency,
b b
Tear,
Chemical Resistance/Fibers,
Wet Strength
Tear Strength, Chemical
Resistance Particles,
NVRs/Cleaning Efficiency
Fiber Control, Pickup,
Bi
Biocompatibility,
tibilit
Conformability/Tear, Unit Cost
Cleanliness, Cleaning, NVRs,
Chemical Resistance/Unit Cost
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Sontara/3 strokes
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10/4/2011
Sontara, 3 Strokes
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Polyester-10X Mag/LFW
Polyester, OutOut-OfOf-Bag
Polyester, 3 Strokes
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10/4/2011
Foam, 3 Strokes
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HD Foam, 3 Strokes
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10/4/2011
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POLYESTER WIPER
MICROFIBER WIPER
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10/4/2011
Coater 1 Z PM ww 35
BASELINE NON-VIABLE
PARTICLE READINGS
.5 um
5 um
BASELINE NON-VIABLE
PARTICLE READINGS
.5 um
5 um
BASELINE 1A
15.4
0.05
BASELINE 1B
4.73
0.03
BASELINE 2A
2.12
BASELINE 2B
185.41
0.21
BASELINE 3A
12.87
BASELINE 3B
9.2
0.05
BASELINE 4A
2.43
BASELINE 4B
2.22
BASELINE 5A
29.06
0.03
BASELINE 5B
5.37
0.03
BASELINE 6A
7.36
BASELINE 6B
22.76
11.54
0.008
38.281
0.0533
POST POLYWIPE
NON-VIABLE PARTICLE READINGS
.5 um
5 um
.5 um
5 um
POST POLYWIPE 1A
0.03
POST MIRAWIPE 1B
0.05
POST POLYWIPE 2A
3.02
POST MIRAWIPE 2B
POST MIRAWIPE 3B
3.1
POST POLYWIPE 3A
POST POLYWIPE 4A
0.03
POST MIRAWIPE 4B
0.21
POST POLYWIPE 5A
2.4
POST MIRAWIPE 5B
POST POLYWIPE 6A
1.42
POST MIRAWIPE 6B
0.21
1.66
.470
% NON-VIABLE
PARTICLE REDUCTION
85.6%
100.00%
% NON-VIABLE
PARTICLE REDUCTION
98.8%
100.00%
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Microfiber
wip
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10/4/2011
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Wiping Sanitization
Sanitization with a
wipe should be
done with
Operators in mind
A minimum
contact time needs
to be achieved
Contact =
Cleaning
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10
10/4/2011
Antimicrobial Effectiveness
3-10 minutes
Organisms in suspension are easier to inactivate
3-10 minutes
Organisms dried on a surface are more difficult to
inactivate (as often found in clean rooms)
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Residues
Sodium Hypochlorite
Phenol
Quaternary Ammonium
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11
10/4/2011
Corrosion Remediation
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Disinfectant activity
vs. residue
id (Plus
(Pl
Corrosion)
Disinfectant activity
vs. cleaning power
Can we remove
residues?
id
?
A clean surface is
more easily
disinfected
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12
10/4/2011
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Disinfection
(kill viable
organisms on a surfaces)
Removal of particulates
and microbes from the
surface
Disinfectants need a
specified Contact Time to
work
k
Particulates, residues &
irregular surfaces must
be factored
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13
10/4/2011
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Why Cleaning?
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14
10/4/2011
Expensive:
-
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Discussion Topics
How do you and your team manage
corrosion today?
How is that remedy viewed by EHS,
Manufacturing, Facilities and Quality?
Is corrosion viewed as an aesthetic issue,
microbiological
g
concern,, quality
q
y issue,, or
something else?
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15
10/4/2011
Steris Vesphene Se
disinfectant
residue cleaned
with MiraWIPE
& 70% alcohol
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A HT4513PDHT4513PD-10
10--1,
HT4520PD--10
HT4520PD
10--1 and
finished with a
HT4540PD--10
HT4540PD
10--1 all used
in conjunction with the
HT4754 UltraSOLV
sponge to remove the
stains. Approximately 5
HT5790S were used to
finish the cleaning
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16
10/4/2011
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17
10/4/2011
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18
10/4/2011
Fiber of Woven
Microfiber
Woven
Microfiber
Woven Microfiber
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19
10/4/2011
Epoxy Surface
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Vinyl Surface
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20
10/4/2011
Plastic Curtains
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Star-shaped micro
fiber traps and
removes p
particles;
where standard
Polyester round
fibers push particles
around.
Woven Microfiber
A tighter bundle
means better pick
up, greater
absorbency, and
superior abrasion
resistance.
www.foamtecintlwcc.com
21
10/4/2011
Mopping Objectives
Mopping creates an
abrasive action
This loosens
particulates and
residues
It removes some of
the contaminants
Appropriate
materials for mops
ceilings
walls
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Mopping/Typical Issues
While loosening
and removing
some, it does NOT
remove all
Surface wetting is
minimal and less
than 2 minutes wet
time can occur
floors
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22
10/4/2011
Remediation Benefits
EHS - Water based solution and not
harsh chemicals.
Facilities Remediation can be a quick
process.
Quality Corrosion can harbor
microorganism and minimize the
effectiveness of disinfectants
disinfectants.
Manufacturing Facility is audit ready.
Purchasing The cost to remediate is far
less than the cost to replace!
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Cleaning/Disinfection Challenges
Heavy Residues
Contact Time
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23
10/4/2011
Aesthetics
Sustainable solution
Green solution
Q lit control
Quality
t l improvement
i
t
www.foamtecintlwcc.com
Wrap Up
Corrosion and rust can be remediated
Residue removal is the key
y
A proper cleaning and disinfecting SOP,
should be based on EM data and a lot of
common sense.
Only if and when carried out correctly,
with a good selection of the parameters
(choice of chemicals and application
methods) longer term success is
attainable
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24
Todays Presenters
Bob Toal
Segment Manager , Informatics, Lonza Wayne
Michael Goetter
Director of Product Strategy, Informatics, Lonza Wayne
Nicole Quinlan
Senior Manager, Laboratory Systems, Auxilium Pharmaceuticals
slide 2
Focus Areas
slide 3
Personnel
Media
Equipment
Islands of Information
Sample Records
Laboratory
Spreadsheets
Management
slide 5
NO
Print sampling
schedule &
labels per EM
SOP
Reconcile
planned
samples with
collected
samples
Assign
sampling
activities to
QC Analysts
All samples
accounted
for?
YES
Close out
sampling
schedule per
EM SOP
Review &
Analyze
Process
Collect
NO
Put on sterile
outer garments
and enter
processing
area
Identify area
to collect
samples from
facility map
Collect sample
and affix label
Record date,
time and initials
on paper
schedule and
media
All samples
collected
Record
sample receipt
Prepare
samples for
testing. Report
media lot,
equipment,
dilution info
Record
incubation
start date and
time
Incubate
samples
Record
incubation
stop date and
time
YES
Deliver
sampling
paperwork to
QC Supervisor
Deliver samples
to Microbiology
or Biochemistry
for processing
Analyze
samples and
record results
Results in
range?
NO
Notification of
Alert or Action
YES
Aggregate
data
Trend results
Trends OK?
NO
Investigate
excursion
Report results
YES
slide 6
Why It Matters
slide 7
Automation Concepts
Todays Cleanroom
cleanroom touch pads or computer terminals that allow for
automated data entry IN THE ROOM.
palm-pilot-type of data collection devices that can directly
download to the computer system and allow for
direct data transfer without risk of contamination.
real time data for many of the chemistry and microbiology
tests that must be performed.
Challenges
slide 13
LIMS/Excel Challenges
2.
3.
4.
5.
6.
7.
8.
9.
10.
slide 15
Life Science
Ingredients
Custom
Manufacturing
Bioscience
Nutrition
Ingredients
Chemical
Manufacturing
Therapeutic
Cell Solutions
Microbial
Control
Biological
Manufacturing
Rapid Testing
Solutions
Performance
Intermediates
Development
Services
Endotoxin Detection
Research
Solutions
Microbiology
Informatics
MODA Solution
Solutions Support
slide 17
slide 18
NO
Print sampling
schedule &
labels per EM
SOP
Reconcile
planned
samples with
collected
samples
Assign
sampling
activities to
QC Analysts
All samples
accounted
for?
YES
Close out
sampling
schedule per
EM SOP
Review &
Analyze
Process
Collect
NO
Put on sterile
outer garments
and enter
processing
area
Identify area
to collect
samples from
facility map
Collect sample
and affix label
Record date,
time and initials
on paper
schedule and
media
All samples
collected
Record
sample receipt
Prepare
samples for
testing. Report
media lot,
equipment,
dilution info
Record
incubation
start date and
time
Incubate
samples
Record
incubation
stop date and
time
YES
Deliver
sampling
paperwork to
QC Supervisor
Deliver samples
to Microbiology
or Biochemistry
for processing
Analyze
samples and
record results
Results in
range?
NO
Notification of
Alert or Action
YES
Aggregate
data
Trend results
Trends OK?
NO
Investigate
excursion
Report results
YES
slide 19
NO
Print sampling
schedule &
labels per EM
SOP
Reconcile
planned
samples with
collected
samples
Assign
sampling
activities to
QC Analysts
All samples
accounted
for?
YES
Close out
sampling
schedule per
EM SOP
Review &
Analyze
Process
Collect
NO
Put on sterile
outer garments
and enter
processing
area
Identify area
to collect
samples from
facility map
Collect sample
and affix label
Record date,
time and initials
on paper
schedule and
media
All samples
collected
Record
sample receipt
Prepare
samples for
testing. Report
media lot,
equipment,
dilution info
Record
incubation
start date and
time
Incubate
samples
Record
incubation
stop date and
time
YES
Deliver
sampling
paperwork to
QC Supervisor
Deliver samples
to Microbiology
or Biochemistry
for processing
Analyze
samples and
record results
Results in
range?
NO
Notification of
Alert or Action
YES
Aggregate
data
Trend results
Trends OK?
NO
Investigate
excursion
Report results
YES
slide 20
Paper
8 hours
Paperless 4 Hours
Savings
4 Hours
slide 21
slide 22
slide 23
slide 24
slide 25
slide 26
Systems
(ERP, LIMS, CAPA)
Flexible Workflow
Devices
Integration
On-Demand Analytics
Improved Compliance
Increased Productivity
Media
slide 27
Nicole Quinlan
Senior Manager, Laboratory Systems
Auxilium Pharmaceuticals
The quality control unit should provide routine oversight of nearterm (e.g., daily, weekly, monthly, quarterly) and long-term trends
in environmental and personnel monitoring data
Trend reports should include data generated by location, shift,
room, operator, or other parameters
The quality control unit should be responsible for producing
specialized data reports (e.g., a search on a particular isolate over a
year period) with the goal of investigating results beyond
established levels and identifying any appropriate follow-up actions.
Significant changes in microbial flora should be considered in the
review of the ongoing environmental monitoring data
Written procedures should define the system whereby the most
responsible managers are regularly informed and updated on trends
and investigations
* Guidance for Industry
Sterile Drug Products Produced by Aseptic Processing
Current Good Manufacturing Practice
Paperless EM lifecycle
39
42
44
Incubation
Plate Reads
Results Entry
Visualization
Trending
Paper-Based System
MODA Solution
Significant number of
documentation errors
Eliminates documentation
errors
Paper-Based System
Spreadsheets for data
reporting is not validated
No control of changes in
spreadsheets
No electronic signature for
changes and approvals
All users have all privileges
Data stored in binders that
are stored on and off site
MODA Solution
Validated system
Audit trail tracks all
changes/records
Electronic signature for all
major steps to enable quick
and clear traceability
Varying levels of access to
system dependent upon job
function
Data stored on servers that are
backed up daily
Paper-Based System
MODA Solution
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
6.
7.
8.
9.
10.
Nicole Quinlan
Sr. Manager, IT Laboratory
Systems
Bob Toal
Segment Manager,
Informatics
nquinlan@auxilium.com
robert.toal@lonza.com
Michael Goetter
Director of Product Strategy,
Informatics
michael.goetter@lonza.com
10/5/2011
Goal
Share
Provide
To
Inside
To
10/5/2011
order to
manage risk one
needs to know
their processes,
know their people
(
(capabilities
bili i and
d
limitations) and
their suppliers.
3
HACCP BASICS
Roots
in food industry
Can effectively cross over many
different industries
Backbone for Quality Management
System
Drills
D ill down
d
to
t the
th individual
i di id l
performing the task (ZAPPED!)
10/5/2011
HACCP BASICS
Identifies
HACCP Basics
Development
D
l
of
f a flow
fl
diagram
d
of
f the
h process
Verification of the flow
Establish and control systems that focus on
PREVENTION
P t ti l activities
Potential
ti iti s
10/5/2011
7 PRINCIPLES of HACCP
Conduct a hazard analysis
Determine
D t
i th
the critical
iti l control
t l points
i t
Establish target levels and critical limit(s)
Establish a system to monitor
Establish corrective actions to be taken
when CCP is not under control
Establish procedures to verify system is
working effectively
Establish documentation and keep
appropriate records
12 STAGES of HACCP
Assemble a HACCP team
Describe the product and process
Identify the intended use
Construct a flow diagram
On-site confirmation of the flow diagram
List all potential hazard with each step
10/5/2011
12 STAGES of HACCP
Determine
PROCESS / DESIGN
OVERVIEW
10
10/5/2011
Swim Lanes..
Type
12
10/5/2011
GENERALs
Starting materials
In-process
Fill / Finish
Packaging
Distribution
MORE?????
13
Group Activity!
14
10/5/2011
In the Beginning
What
15
Media Fills
10/5/2011
Media Fills
media
f , together
fills,
g
with
operational controls, environmental
controls, and product sterility
testing, provide a sufficient level of
assurance that drugs purported to
be sterile are in fact sterile
sterile
17
Media Fills
Rigorous
g
design
g
Environmental
Simulations
FDA
performed
minimum 2x/year
Canada 4x/year
Know who you need to satisfy
(regulatory requirements)
18
10/5/2011
20
10
10/5/2011
21
Warning Letters
failed
f
to design
g and p
perform
f
an
adequate process simulation based
upon the same controls used for
routine production
...the operators at your facility have
repeatly
tl f
failed
il d tto comply
l with
ith your
procedures for aseptic operations
22
11
10/5/2011
Warning Letters
your
y
firm
f
has not established
appropriate written procedures
designed to prevent microbiological
contamination of drug products
purporting to be sterileprocess
simulation (media fill) do not
represent actual production for your
sterile API
23
Warning Letters
your
y
firm
f
has not established
appropriate written procedures
designed to prevent microbiological
contamination of drug products
purporting to be sterileprocess
simulation (media fill) do not
represent actual production for your
sterile API
24
12
10/5/2011
Warning Letters
your
y
Warning Letters
your
y
media fill
f studies suggest
gg
that
your manufacturing process is not
under control. The presence of
contaminated units found in 4 out
the 6 media fills conducted during
2008 and 2009 is an indication of
serious breaches to assure sterility
of the ophthalmic drug products
manufactured at your facility
26
13
10/5/2011
sterility
y assurance
Personnel
Facility
sterility
y assurance
Response
to deviations and
environmental control trends
Disinfection regime and actual practices
Media fills
QA/QC
28
14
10/5/2011
Process Verification
f
Parameters to be monitored
Personnel
/ interventions
Environmental conditions
Sterility of product / product contact
surfaces
f
Conditions of non-product contact
surfaces
Production yields / quality of output
29
Personnel / interventions
Environmental conditions
15
10/5/2011
surfaces
EM
of
f non-product
p
contact
results
Production
Production
31
Got Contamination?
Now
what?
How do you investigate?
What do you focus on?
Processing
Procedures
Personnel
When
16
10/5/2011
Contamination Contributors
Sources
of
f Contamination
Raw
material suppliers
Inadequate cleaning
People
Inadequate procedures
Inadequate
d
processes
Can
Recalls
Thin
glass flakes
Stainless steel particulates
Small white particles (polyethylene
terephthalate polyester)
Cracked glass
34
17
10/5/2011
p
particles
Less
than 10 microns
Current standard 0.2 micron filter
Aggregates and potential impact
Currently
Patient safety
35
36
18
10/5/2011
Vial Technology
gy
Based
37
Vial Technology
gy
advantages
Reduction in contamination
Elimination of the preparation steps for
glass vials and rubber stoppers
Trade off in validation requirements
38
19
10/5/2011
Thank you!
y
Anne M Garstka
agarstka@celgene.com
39
20
10/3/2011
Qualification of an Environmental
Monitoring Program
Presented by: Karen S. Ginsbury
For: IVT
ACE, Amsterdam
October 2011
PCI Pharmaceutical Consulting Israel Ltd.
Workshop Objective
Design a lean but effective EM
qualification and monitoring program
Use RM tools for designing and reviewing
EM program (manage by Risk Review)
To quote Jeanne Moldenhauer:
Your EM program should be:
Meaningful
Manageable
Defendable
PCI Pharmaceutical Consulting Israel Ltd.
10/3/2011
Environmental Controls
KEEP THEM
OUT!
PCI Pharmaceutical Consulting Israel Ltd.
10/3/2011
To be discussed
Regulatory Considerations in Qualification
Environmental Monitoring (EM) Program
To be discussed
Developing a Qualification Protocol
Qualification of viable vs non-viable particles
particles,
Temperature, RH and pressure differential
Installation and Operational Qualification?
Performance Qualification:
Selection of sampling locations
Frequency of sampling
Acceptance criteria
10/3/2011
PCI
Pharm
ti
Previous
Current
PCI
Pharm
ti
10/3/2011
PCI
Pharm
ti
Duration of Monitoring
Grade A: full duration of critical processing, including
equipment assembly except where justified e.g. live
organisms, radiological hazards (then do it prior to
operations and using simulated operations)
Monitor Grade A at frequency and sample size that all
interventions, transient events and system deterioration
would be captured and alarms triggered if alert limits are
exceeded
May not always be possible to demonstrate low levels of
5.0 micron particles at the point of fill during filling
because of particle generation / droplets from product
1
0
PCI
Pharm
ti
10/3/2011
Sample Size
1
1
PCI
Pharm
ti
1
2
PCI
Pharm
ti
10/3/2011
1
3
PCI
Pharm
ti
1
4
PCI
Pharm
ti
10/3/2011
1
5
PCI
Pharm
ti
1
6
PCI
Pharm
ti
10/3/2011
1
7
PCI
Pharm
ti
Inspection Findings
1. Failure of your quality control unit to investigate
thoroughly any unexplained discrepancy or the
failure of a batch or any of its components to meet
any of its specifications, and failure to ensure that
written records of investigations are made and
include conclusions and follow-up (21 CFR
211.192]. For example:
a) Your quality unit failed to adequately identify
trends for numerous environmental excursions
found between July 2007 and November 2007.
10/3/2011
Inspection Findings
iii. Investigation report PR87671 was initiated on November 6,
2006, for non-viable particulate excursions in several class
10000 or class 100000 areas
areas. Corrective actions were not
completed until February 20, 2007.
iv. A sample collected from Room 1627 (1627.5) on May 12,
2007, and documented in investigation report PR117911 was
not sent for microbial identification until June 26, 2007.
v. A sample collected from Room 1624 (R1624.14) on August
30, 2007, and documented in investigation report PR128513
was not submitted for microbial identification until October 5,
2007.
2007
vi. A sample collected from Room 1627 (R1627.18) on August
31, 2007, and documented in investigation report PR131057
was not sent for microbial identification until October 31, 2007
10
10/3/2011
Ask Yourself
Have you seen this situation before ?
Do you have SOP to cover situation ?
Do you already understand the risks ?
Severity, Probability, Detectability
Control Strategy
Control Strategy
A planned set of controls, derived from current
product and process understanding, that assures
process performance and product quality.
The controls can include parameters and
attributes related to drug substance and drug
product materials and components, facility and
equipment operating conditions
conditions, in-process
in process
controls, finished product specifications, and the
associated methods and frequency of monitoring
and control
11
10/3/2011
Analysis of facts
2. Risk Assessment
very low
12
10/3/2011
Product Vs Process
Process
Product
Raw Materials
Active
Inactive
Packaging components
Final Product
Equipment surfaces
Cleaning
Water system
HVAC system
Personnel
Gowning
Hygiene
Bioburden test:
MICROBIAL LIMIT
Laboratory:
false positives
MONITORING PROGRAM
With acceptance LEVELS
Regulatory Commitment
Compliance Requirement
Risk Assessment
Likelihood of occurrence
Likelihood of detection
Severity if the event occurs
13
10/3/2011
Scale 1 10?
Scale 1 5?
Scale 1 -3?
Or use letters (H
Or,
(H.M.L.)?
M L )?
REMEMBER The structured Risk Assessment tools
help you determine COMPARATIVE levels of risk, so the
absolute value of the RPN is not important
PCI Pharmaceutical Consulting Israel Ltd.
14
10/3/2011
15
10/3/2011
16
10/3/2011
Contact Details
KAREN GINSBURY
pcikaren@netvision.net.il
PCI Pharmaceutical Consulting Israel Ltd.
17
Preventing
Contamination:
Taking the Mystery out
of Media Fills
Dawn Tavalsky
S
Sanofi
fi Pasteur
P t
TOPICS
Aseptic Processing
Manufacturing Environment
Classification of Clean Areas
Comparison of classifications
WHO GMP
Grade A
Grade B
Grade C
Grade D
US 209E
US Customary
M 3.5
M 3.5
M 5.5
M 6.5
ISO/TC (209)
ISO 14644
ISO 5
ISO 5
ISO 7
ISO 8
Class 100
Class 100
Class 10 000
Class 100 000
EEC GMP
Grade A
Grade B
Grade C
Grade D
Manufacturing Environment
Classification of Clean Areas
At rest
In operation
> 5 m
0.5 - 5.0 m
>5
3 500
3 500
3 500
350 000
2 000
350 000
2 000
3 500 000
20 000
3 500 000
not defined
20 000
not defined
Manufacturing Environment
Four grades of clean areas:
Manufacturing Environment
G d
Grade
A
B
C
D
Air sample
Ai
l
(CFU/m3)
<3
10
100
200
Settle
S
ttl plates
l t
(90mm
(90
Contact
C
t t plates
l t
diameter)
(55mm
(CFU/4hours)
diameter)
(CFU/plate)
<3
5
50
100
<3
5
25
50
Glove print
Gl
i t
(5 fingers)
(CFU/glove)
<3
5
-
10
Manufacturing Environment
Environmental Monitoring
Physical
Particulate
P ti l t matter
tt
Differential pressures
Air changes, airflow patterns
Clean up time/recovery
Temperature and relative humidity
Airflow velocity
y
11
12
Manufacturing Environment
Environmental Monitoring - Physical
Particulate matter
Particles significant because they can contaminate and
also carry organisms
Critical environment should be measured not more than
30cm from worksite, within airflow and during
filling/closing operations
Preferably a remote probe that monitors continuously
Difficulties when process itself generates particles (e.g.
powder filling)
Appropriate alert and action limits should be set and
corrective actions defined if limits exceeded
Manufacturing Environment
Environmental Monitoring - Physical
Differential pressures
Positive pressure differential of 10-15 Pascals should be
maintained between adjacent rooms of different
classification (with door closed)
Most critical area should have the highest pressure
Pressures should be continuously monitored and
frequently recorded.
Alarms should sound if pressures deviate
Any
A d
deviations
i ti
should
h ld be
b investigated
i
ti t d and
d effect
ff t on
environmental quality determined
13
Manufacturing Environment
Environmental Monitoring - Physical
14
Manufacturing Environment
Environmental Monitoring - Physical
15
16
Manufacturing Environment
Personnel
Manufacturing Environment
Personnel (2)
17
18
Manufacturing Environment
Personnel (3)
Manufacturing Environment
Personnel (4)
19
Aseptic Processing
20
10
Aseptic Processing
Preparation and Filtration of Solutions
Solutions to be sterile filtered prepared in a Grade C environment
If not to be filtered,
filtered preparation should be prepared in a Grade A
environment with Grade B background (e.g. ointments, creams,
suspensions and emulsions)
Prepared solutions filtered through a sterile 0.22m (or less)
membrane filter into a previously sterilized container
filters remove bacteria and moulds
do not remove all viruses or mycoplasmas
filtration
filt ti should
h ld b
be carried
i d outt under
d positive
iti pressure
21
Aseptic Processing
Preparation and Filtration of Solutions (2)
consideration should be given to complementing filtration process
with some form of heat treatment
Double filter or second filter at point of fill advisable
Fitlers should not shed particles, asbestos containing filters
should not be used
Same filter should not be used for more than one day unless
validated
If bulk product is stored in sealed vessels, pressure release
outlets should have hydrophobic microbial retentive air filters
22
11
Aseptic Processing
Preparation and Filtration of Solutions (3)
Time limits should be established for each phase of processing,
e.g.
maximum period between start of bulk product
compounding and sterilization (filtration)
maximum permitted holding time of bulk if held after
filtration prior to filling
product exposure on processing line
storage of sterilized containers/components
total
t t l time
ti
for
f product
d t filtration
filt ti to
t preventt organisms
i
from
f
penetrating filter
maximum time for upstream filters used for clarification or
particle removal (can support microbial attachment)
23
Aseptic Processing
Preparation and Filtration of Solutions (4)
Filling of solution may be followed by lyophilization (freeze drying)
stoppers partially seated,
seated product transferred to lyophilizer
(Grade A/B conditions)
Release of air/nitrogen into lyophilizer chamber at
completion of process should be through sterilizing filter
24
12
Aseptic Processing
Prefiltration Bioburden (natural microbial load)
Limits should be stated and testing should be carried out on each
batch
Frequency may be reduced after satisfactory history is established
and biobuden testing performed on components
Should include action and alert limits (usually differ by a factor of
10) and action taken if limits are exceeded
Limits should reasonably reflect bioburden routinely achieved
25
Aseptic Processing
Prefiltation Bioburden (2)
No defined maximum limit but the limit should not exceed the
validated retention capability of the filter
Bioburden controls should also be included in in-process controls
particularly when product supports microbial growth and/or
manufacturing process involves use of culture media
Excessive bioburden can have adverse effect on the quality of the
product and cause excessive levels of endotoxins/pyrogens
26
13
Aseptic Processing
Filter integrity
Filters of 0.22m or less should be used for filtration of liquids and
gasses (if applicable)
filters for gasses that may be used for purging or
overlaying of filled containers or to release vacuum in
lyphilization chamber
filter intergrity shoud be verified before filtration and confirmed
after filtration
bubble point
pressure hold
forward flow
methods are defined by filter manufacturers and limits determined
during filter validation
27
28
Aseptic Processing
Filter Validaton
14
Aseptic Processing
Filter validation (2)
29
Aseptic Processing
Equipment/container preparation and sterilization
30
15
Aseptic Processing
Equipment/container preparation and sterilization (2)
CIP/SIP processes
particular attention to deadlegs - different orientation
requirements for CIP and SIP
heat tunnels often used for sterilization/depyrogenation of glass
vials/bottles
usually high temperature for short period of time
need to consider speed of conveyor
validation of depyrogenation (3 logs endotoxin units)
worst case locations
tunnel supplied with HEPA filtered air
31
32
Aseptic Processing
Equipment/container preparation and sterilization (2)
16
33
34
Aseptic Processing
Media Fill
17
Aseptic Processing
Media Fill (2)
35
Aseptic Processing
Media Fill (3)
36
18
Aseptic Processing
Media Fill (4)
37
Aseptic Processing
Media Fill (5)
Duration
Depends
p
on type
yp of operation
p
BFS, Isolator processes - sufficient time to include
manipulations and interventions
For conventional operations should include the total filling time
Size
5000 - 10000 generally acceptable or batch size if <5000
For manually intensive processes larger numbers should be
filled
Lower numbers can be filled for isolators
38
19
Aseptic Processing
Media Fill (6)
39
Aseptic Processing
Media Fill (7)
Environmental conditions
Media
40
20
Aseptic Processing
Media Fill (8)
Incubation, Examination
g 20-35C.
In the range
If two temperatures are used, lower temperature first
Inspection by qualified personnel.
All integral units should be incubated. Should be
justification for any units not incubated.
Units removed (and not incubated) should be consistent
with routine practices (although incubation would give
information regarding risk of intervention)
Batch reconciliation
41
Aseptic Processing
Media Fill (9)
Interpretation of Results
When filling fewer than 5000 units:
no contaminated units should be detected
One (1) contaminated unit is considered cause for
revalidation, following an investigation
When filling from 5000-10000 units
One (1) contaminated unit should result in an investigation,
including consideration of a repeat media fill
Two (2) contaminated units are considered cause for
revalidation,
lid ti
ffollowing
ll i iinvestigation
ti ti
When filling more than 10000 units
One (1) contaminated unit should result in an investigation
Two (2) contaminated units are considered cause for
revalidation, following investigation
|
42
21
Aseptic Processing
Media Fill (10)
Interpretation of Results
Media fills should be observed by QC and contaminated
units reconcilable with time and activity being simulated
(Video may help)
Ideally - no contamination. Any contamination should be
investigated.
Any organisms isolated should be identified to species
level (genotypic identification)
Invalidation of a media fill run should be rare
43
44
Aseptic Processing
Media Fill (11)
22
Aseptic Processing
45
46
Aseptic Processing
23
Useful Publications
47
48
24
Risk-based approach
Critical Control Points (CCPs)
Sources
S
off Variability
V i bilit
Holistic Facility
Case studies
Recurring problems underscore importance of CCPs
49
[Noble, P., PDA Journal of Pharmaceutical Science and Technology, July/August 2001.]
50
25
Risk-Based Approach
Critical Control Points
Causes of Contamination
Personnel
QA/QC
Media Fills
D= Design
M= Maintenance
Facility &
Room
D/M
Aseptic
Processing
Line
D/M
Daily
Sterility
Assurance
Disinfection
Procedures &
Practices
51
Process
-personnel flow
-material flow
-layout
HVAC/
Utilities
Response to
Deviations &
Environmental
Control Trends
|
52
26
Risk-Based Approach
Design
53
Personnel
Continued
Continued vigilance throughout the
entire manufacturing process
[Avis, K.,Personnel An academic Approach, PDA Journal, Sept-Oct., 1971]
54
27
Environment
Studies have shown that the level of airborne
55
[PDA Technical Report #22 Process Simulation Testing for Aseptically Filled Products, 1996]
56
28
57
Case Study
Media Fill Failure
58
29
59
60
30
61
62
31
63
64
32
65
66
33
67
68
34
69
70
35
71
72
36
73
74
37
75
76
38
77
78
39
79
80
40
81
82
41
83
84
42
85
86
43
87
88
44
89
90
45
91
92
46
93
94
47
95
96
48
97
98
49
99
100
50
101
102
51
103
104
52
105
106
53
Thank you
Questions / Comments?
Feel free to contact me at
dawn.tavalsky@sanofipaseur.com
107
54
OUTLINE / OBJECTIVES
Process Validation General
Residue
Performance
Equipment
Analytical
Documentation
Interactive discussion
PLEASE PARTICIPATE!
2
Equipment #2
Process steps
Equipment #3
Process steps
UO #2
Qualification
HVAC
Utilities
Facilities
Computers
UO #3
Process steps
1987
Development
Performance Maintenance
2008-2011
Development Performance
f
Maintenance
Above based on RISK
Qualification
Equipment
Purified Water
Computer / software
Compressed air
Conductivity
TOC
Qualification
Personnel
Purified Water
Compressed air
10
Pre 2008
Cl
Cleaning
i method
th d d
development
l
t (?)
Development PQ Maintenance
INCREASED SPECIFIC REQUIREMENTS
11
DEVELOPMENT (STAGE 1)
CLEANING PROCESS DEVELOPMENT
Physical and chemical properties of the residue
is basis for cleaning process
Considerations for determination of most
difficult-to-clean residue
Residue solubility and stability in determining
worst-case soils
Residue
R id chemistry
h i t critical
iti l ffor analytical
l ti l method
th d
BASIS FOR CLEANING PROGRAM
BASIS FOR ANALYICAL METHOD
13
Final method: Acid wash, alkaline soap wash, water, PurW, dry
No residues. Unknown peaks determined to be flavors.
DETERMINATION OF
MOST DIFFICULT TO CLEAN RESIDUE
BASIS FOR CLEANING PROGRAM
Water solubility USP Tables
Is this adequate? NO!
pH effect API with ionizable groups?
Solubility in cleaning agent?
y at range
g pH
p 1-12
Determine solubility
Understand solubility at pH of cleaning liquid
Understand solubility in cleaning agent liquid
15
Drug A
Drug B
pH 1
12
16
CLEANING MATRIX
Determine Worst-Case Soil at Site
SOLUBILITY (mg / ml)
pH 1
Water
pH 12
Cleaning
agent
Drug A
25
25
25
25
Drug B
15
15
15
15
Drug
gC
15
50
Drug D
80
10
10
20
Drug E
125
10
100
250
18
Sulfamethoxazole Solubility
Solubility
mg/ml
Note pKa
pH 1
12
19
CLEANING PROCESS
SOURCES OF VARIATION
20
10
CLEANING EQUIPMENT
CIP system must be qualified (IQ/OQ/PQ or
ASTM E2500)
Riboflavin testing
Temperature controls
Flow rates, etc.
PAT systems
y
control rinse for drug
g and
cleaning agent
22
11
EQUIPMENT TO BE CLEANED
Cleaning-related qualification
Product-contact materials
Surface areas
Compatibility with cleaning agents
Equipment equivalence
Highest risk locations (non-uniform contamination)
Most-difficult-to-clean locations on equipment
Sampling methods (swab / rinse)
NON-UNIFORM CONTAMINATION
Typical calculation considers total surface area of all
product contact equipment, and assumes all lot A
residue from total surface area transferred uniformly to
all lot B product
Usually no consideration for residue that is not uniformly
transferred
Examples: Filling needed, encapsulation equipment,
compressing equipment, others post final mixing
Consider and justify non-uniform contamination equipment
24
12
EQUIPMENT TO BE CLEANED
SAMPLING LOCATIONS
UNIFORM AND NON-UNIFORM CONTAMINATION
Product A = X
Product B = X
Product B flushes filling lines with A residue
xxxxxxxxxx x x x x x x x
xxxxxxxxxx
x
xxxxxxxxxx
x
xxxxxxxxxx
xxxxxxx
MANUFACTURING TANK
PRODUCT
25
13
1. Make Product A
2. Clean
3. Make Product B
How long between end of #1 and start #2?
Is residue same?
What can happen to the residue?
28
14
What is DHT?
3 days unless other data available.
29
4.
5.
15
CAMPAIGN LENGTH
How many lots in manufacturing campaign before
cleaning must be done?
What about cleaning between batches?
Equipment should be visually clean
Terminology: Between lot procedure
31
Sampling locations?
Where is equipment likely to be contaminated?
32
16
MANUAL CLEANING
Manual cleaning procedures should be
monitored and maintained with increased
scrutiny
y compared
p
to non-manual p
procedures
More frequent training
Increased supervision
Revalidation batch
33
MANUAL CLEANING
Do you really know what is happening?
Q to operator: Why is there so much foam in the tub?
A: I put in extra soap because the equipment was really dirty.
Q to operator: Why is there powder on the (clean) equipment?
A: No problem -- Well get the residue when we set up.
Q to operator: Why dont you follow the cleaning procedure?
A: The cleaning procedure really doesnt work.
Q to operator: You cleaned the gasket with pure soap this is not the
procedure?
A: That is the only way to get it clean.
Q: So why dont you tell someone to change the procedure?
A: We dont have time.
34
17
MANUAL CLEANING
Do you really know what is happening?
Q to operator: Why is there powder on the clean equipment?
A: Its clean enough.
Q to QA (equipment inspection person): Did you approve that the equipment
is clean?
clean?
A: Its clean enough.
Q to management: Do you know that your equipment is not clean?
A: Its clean enough.
Q to management: Did you finish cleaning the equipment? We are here to
swab for cleaning validation.
A: We cleaned the equipment three times so that we wont have any
problems.
Q to validation person: Did you know that the manufacturing people always
clean the equipment multiple times before it is swabbed?
A: Sure, we knew. But these people are our friends.
35
18
CONCURRENT RELEASE
Equipment concurrent release not same as product
concurrent release
Equipment is clean
Lot #1 RELEASE LOT
Cleaning process
Lot #2 HOLD
Clenaing Process
Lot #3 -- HOLD
Cleaning
gp
process
Next product lot
38
19
DOCUMENTATION
Stages 1, 2, 3
Cleaning process development reports
Equipment qualification
Cleaning equipment
Equipment to be cleaned
Cleaning process records (Cleaning batch records)
PPQ protocol and report
Change control records / validation
Post
P
validation
lid i monitoring
i i results
l
Review of change control records / validation
Periodic review documentation
Management review
39
ANALYTICAL METHODS
Analytical methods must be validated
API residue (?)
Cleaning agent
Analytical instruments qualified
Early development work must be technically sound (not
necessarily validated)
E l d
Early
development
l
t work
k mustt b
be available
il bl ffor audit
dit
FUNDAMENTAL REQUIREMENTS
40
20
ANALYTICAL METHODOLOGY
RESIDUE CONSIDERATIONS
Understand residue
Solubility and stability
Validated analytical method for actual residue
API and cleaning agent
SAMPLING CONSIDERATIONS
Recovery studies from product contact materials
API and cleaning agent
Swab / rinse testing on equipment
Most difficult to clean sampling sites
Use of auxiliary sampling equipment (extension pole)
Swab / rinse training of sampling person
41
RESIDUE PROPERTIES
Solubility and stability
pH / cleaning agent-solubility profile
pH / cleaning agent-stability profile
Oxidation
Hydrolysis
Photolysis
Physical change
Bi t h protein
Biotech
t i residue
id d
degraded
d d iin cleaning
l
i process
21
C d t recovery studies
Conduct
t di (% recovered)
d)
Identical materials desirable
Order coupons when ordering new equipment
Material documentation from vendor
Vendor calculates material surface areas
Retraining considerations
Who does sampling?
Personnel skills
44
22
SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
R&D
Validation
Commercialization
46
23
Lifecycle approach:
Validation is never completed
Validation is always ongoing
47
SUMMARY
VALIDATION -- FUTURE
Development
Stage 1
Performance
Stage 2
Maintenance
Stage 3
48
24
SUMMARY
VALIDATION TRANSITION
1987
Development
Performance Maintenance
2011
Development
p
Performance Maintenance
Above based on RISK
49
SUMMARY
STAGE 1 -- DESIGN AND DEVELOPMENT
Understanding cleaning process
Residue properties
Rational process based on residue
Understand and control sources of
variation
50
25
SUMMARY
STAGE 2 -- PERFORMANCE
g equipment
q p
q
qualified
Cleaning
Equipment to be cleaned qualified
Sampling and testing
Cleaning procedure specified
Manual cleaning high risk
51
SUMMARY
STAGE 3 -- MAINTAINING VALIDATION
Change control -- evaluate impact of change
and validate (test) as necessary
Improve process
Improve control to detect and reduce
variability
Cleaning non-conformances and deviations
P i di M
Periodic
Managementt R
Review
i
52
26
SUMMARY
ANALYTICAL
Understand residue
Solubility and stability
Validated analytical method for actual residue
API and cleaning agent
SUMMARY
DOCUMENTATION
Document everything
Documentation must be readily available
Documentation must be
Scientific and technical
Thorough and clear
Simple sentences, good grammar
54
27
WHAT TO DO NEXT?
1.
2.
3.
4.
Get QA agreement
5.
6.
7
7.
8.
9.
28
REFERENCES
LeBlanc, Destin A.
Validated Cleaning Technologies for Pharmaceutical Manufacturing.
Interpharm/CRC Press, 2000.
Cleaning Validation Practical Compliance Solutions for Pharmaceutical
Manufacturing. PDA and DHI Publishing, 2006.
Cleaning Validation Practical Compliance Solutions for Pharmaceutical
Manufacturing Volume 2
Manufacturing,
2. PDA and DHI Publishing,
Publishing 2010
2010.
www.cleaningvalidation.com
Pluta, editor. Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles. PDA and DHI Publishing, 2009.
Kendrick, Canhuto, and Kreuze. Analysis of Degradation Products of Biopharmaceutical
API Caused by Cleaning Agents and Temperature. Journal of Validation Technology,
V15, #3, Summer 2009.
Cleaning Validation Forum
Forum. Coordinated by Jennifer Carlson
Carlson. Journal of GXP
Compliance.
New Perspectives on Cleaning: Coordinated by Rizwan Sharnez. Journal of
Validation Technology.
Pluta and Sharnez. Avoiding Pitfalls in Cleaning Validation. Journal of GXP
Compliance, V 14, #3, Summer 2010.
57
BENCHMARKING
Comments on identified problems?
A other
Any
th overlooked
l k d cleaning
l
i
problems?
bl
?
Validation and compliance personnel should
evaluate vulnerabilities in their organizations
Lifecycle approach
Risk
58
29
Contact: paul.pluta@comcast.net
59
30
10/5/2011
Robert Pallo
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
CLASSROOM TRAINING
ADVANTAGES
10/5/2011
EASY TO IMPLEMENT
REQUIRES LITTLE OR NO SET UP
FAMILIAR LEARNING MODELS FOR STUDENTS
THE INSTRUCTOR MAKES ALL THE DIFFERENCE
MINIMAL INTERRUPTION OF PRODUCTION OPS
LOTS OF STUDENT FEEDBACK
FEEDBACK, QUESTIONS,
QUESTIONS ETC
CLASSROOM TRAINING
DISADVANTAGES
STILL NEED TO HAVE HANDS ON
REQUIRES EXCEPTIONAL TEACHING SKILL
LIMITED EFFECTIVENESS, BUT ADQUATE FOR
BACKGROUND TRAINING
FOLLOWS THE INSTRUCTORS PACE, NOT THE
STUDENTS
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
VESTIBULAR TRAINING
DISADVANTAGES
VERY EXPENSIVE (especially if you duplicate
equipment)
NEED TO MAINTAIN THE EQUIPMENT!
REQUIRES LOTS OF SPACE
MAY REQUIRE OFF SITE TRAVEL EXPENSE AND
TIME
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
10/5/2011
VIDEOS
DEMONSTRATIONS
SLIDE PRESENTATIONS
LET THE STUDENT PRACTICE OUTSIDE THE AREA
10/5/2011
10/5/2011
10/5/2011
10/5/2011
What is a microbe?
Bacteria are named with
ith ttwo
o names
names. The first
name is the Genus and is always capitalized.
The second name is the species, and is never
capitalized. The names of bacteria are
always written in italics, or underlined.
Escherichia coli or Escherichia coli.
coli.
Microbes
Microbes
bacteria, fungi, yeast, algae, and
virus
10/5/2011
10/5/2011
10/5/2011
Disease producing
bacteria (known as
pathogens) usually
appear as gram
positive and have a
round ((cocci
cocci)) shape.
These are known as
gram positive cocci
cocci..
Examples are
Staphylococcus and
Streptococcus.
10/5/2011
10
10/5/2011
Pyrogens
When bacteria are killed using an autoclave,
their skeletal remains are still present on the
item that was sterilized. These are known as
pyrogens.. When injected into the body,
pyrogens
pyrogens will cause the patient to have a
fever A dry heat oven is used to eliminate
fever.
pyrogens..
pyrogens
10/5/2011
11
10/5/2011
10/5/2011
20 minutes
7 hours
1 million cells
10 hours
1 billion cells
24 hours
10/5/2011
12
10/5/2011
Sources of bacteria
Humans
10/5/2011
10/5/2011
13
10/5/2011
To control bioburden
bioburden::
10/5/2011
10/5/2011
14
10/5/2011
10/5/2011
15
10/5/2011
10/5/2011
Know
o what
a is
s cclean
ea
Know what is contaminated
Know what is sterile
Keep clean and contaminated separate
Keep sterile sites sterile
Resolve any contamination immediately
Learn to recognize when you have broken
t h i
technique.
Th
Thatt iis, if one h
has made
d an aseptic
ti
error, learn to recognize that. This requires a
certain amount of trust for that individual.
10/5/2011
16
10/5/2011
Particle Generators
Machines
10/5/2011
Particle Generators
Machines
Conveyors
10/5/2011
17
10/5/2011
Particle Generators
Machines
Conveyors
People
10/5/2011
Moving
10/5/2011
18
10/5/2011
Moving
Walking
10/5/2011
Moving
Walking
Talking
10/5/2011
19
10/5/2011
Moving
Walking
Talking
Working
10/5/2011
Moving
Walking
Talking
Working
Body Functions
10/5/2011
20
10/5/2011
10/5/2011
Vortices
10/5/2011
21
10/5/2011
Vortices
Operations conducted downstream
10/5/2011
Vortices
Operations conducted downstream
Aerodynamic position
10/5/2011
22
10/5/2011
Vortices
Operations conducted downstream
Aerodynamic position
Slow, deliberate movements
10/5/2011
10/5/2011
23
10/5/2011
Aseptic Gowning
10/5/2011
Pre requisites
10/5/2011
24
10/5/2011
Step One:
Demonstration
Step Two
Practice
Step Three:
Step Four:
More practice
Step Five:
10/5/2011
10/5/2011
25
10/5/2011
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10/5/2011
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10/5/2011
10/5/2011
10/5/2011
27
10/5/2011
10/5/2011
10/5/2011
28
10/5/2011
10/5/2011
Existing
g full time staff?
May be construed as detrimental to career
Contractor?
May lack training or company commitment
10/5/2011
29
10/5/2011
10/5/2011
30
10/5/2011
10/5/2011
DISINFECTOR
DIP THE MOP INTO THE RED BUCKET
WRING THE MOP INTO THE RED BUCKET
DIP THE MOP INTO THE BLUE BUCKET
LET THE MOP DRIP, BUT DO NOT WRING
INTO THE RED BUCKET
10/5/2011
31
10/5/2011
SANITIZER
DIP THE MOP INTO THE WHITE BUCKET
WRING THE MOP INTO THE RED
BUCKET
DIP THE MOP INTO THE BLUE BUCKET
LET THE MOP DRIP
DRIP, BUT DO NOT
WRING INTO THE RED BUCKET
10/5/2011
10/5/2011
32
10/5/2011
10/5/2011
33
10/5/2011
10/5/2011
10/5/2011
34
10/5/2011
DAILY:
10/5/2011
35
10/5/2011
Monday
need
done
Tuesday
need
Wednesday
done need
done
Thursday
need
done
Friday
need
done
101
102
103
104
105
106
107
108
109
110
111
112
Disinfector ID/LOT
QTY Disinfector
10/5/2011
QUALITY ASSURANCE
10/5/2011
36
10/5/2011
10/5/2011
10/5/2011
37
10/5/2011
10/5/2011
10/5/2011
38
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39
10/5/2011
10/5/2011
40
10/5/2011
41
10/5/2011
3
2
42
10/5/2011
FIRST
PASS
DOWN
REVERSE
MOP
DOUBLE
BUCKET
THEN
NEXT
PASS
DOWN
THEN
NEXT
PASS
DOWN
10/5/2011
43
10/5/2011
DOUBLE BUCKET
44
10/5/2011
DAILY:
Monday
need
done
Tuesday
need
Wednesday
done need
done
Thursday
need
done
Friday
need
done
101
102
103
104
105
106
107
108
109
110
111
112
Disinfector ID/LOT
QTY Disinfector
QUALITY ASSURANCE
45
10/5/2011
10/5/2011
Thank You
Phone: +1+1-714
714--246
246--4413
Email: Pallo_robert@allergan.com
Pallo robert@allergan com
10/5/2011
46
9/26/2011
9/26/2011
Objective of Seminar
y
y
y
y
y
Review
Refresh
Renew
Refine and
apply your
knowledge base for aseptic
processing
9/26/2011
y Preparing an assessment
checklist
h kli t
y Risk Management:
focusing on high risk areas
y Key Performance Indicators
y Preparing an assessment report
and recommendations
5
III CAPA
y Prioritizing the findings from the gap
analysis
y Preparing a corrective action
program
y Preparing
p
gap
preventive action
program (proactive) using risk
mitigation strategies
6
9/26/2011
Interactive Bit!
y (to
(t b
be d
done allll along
l
th
the way))
y develop a gap analysis checklist
9/26/2011
Your Bonus.Toolkit
y Template for risk assessment
prioritizing
i iti i audit
dit fifindings
di
(we develop it as we work)
y .to work!
10/68
9/26/2011
11/68
y Under Quality
Quality System
Elements:
y Process Performance and Product
12/68
9/26/2011
y Under CAPA:
13/68
14/68
9/26/2011
15/68
the information ?
16/68
9/26/2011
17
18
9/26/2011
components
t - going
i up / d
down /
static
20
10
9/26/2011
21
22
11
9/26/2011
tunnel
23
12
9/26/2011
25
13
9/26/2011
27
monitoring data
y Successful gowning
qualification
y From total of six different
locations less than 5 cfu
28
14
9/26/2011
Main Changes
y Particulate Classification (Airborne
particles)
y Media Simulations
y Bioburden monitoring
y Capping of (Freeze-Dried)
(Freeze Dried) Vials
29
Existing
New
30
15
9/26/2011
Duration of Monitoring
y Grade A: full duration of critical processing, including
16
9/26/2011
Sample Size
33
34
growth
th b
butt a contamination
t i ti rate
t
of less than 0.1% with 95%
confidence limit is acceptable
y The manufacturer should
establish alert and action limits
y Any contamination should be
investigated
PCI Pharmaceutical Consulting Israel Ltd
17
9/26/2011
35
18
9/26/2011
vials
i l should
h ld b
be maintained
i t i d
under Grade A conditions at all
times until the stopper is fully
inserted
NOTE: effective 01 March 2010
37
38
19
9/26/2011
39
40
previous
y Velocity
y Number of air changes in surrounding room:
compare to previous and compare to design
specification
y Number of particles (total)
y Microbiological monitoring
y HEPA filter integrity
g y test
y Pressure differentials
y Personnel monitoring
y Implementation of cleaning procedures as written
y How are cleaning implements STORED
y Efficacy
ofConsulting
disinfectants
with our isolates
PCI
Pharmaceutical
Israel Ltd
20
9/26/2011
41
21
9/26/2011
44
22
9/26/2011
45
46
23
9/26/2011
47
y gamma
48
24
9/26/2011
PIC/s
49
PIC/s
50
25
9/26/2011
26
9/26/2011
ISO cleanrooms
X Risk Management:
X Focusing on high risk areas
9Key Performance Indicators
X Preparing an assessment report and
recommendations
54
27
9/26/2011
Control Strategy
y Control Strategy
55
56/68
reviewed
y Personnel records can be rapidly
reviewed and give a good overview:
training qualification,
training,
qualification job
descriptions (pick one or two
employees)
BUT is more efficient to do a tour
and then select employees you saw
doing the wrong thing!
PCI Pharmaceutical Consulting Israel
28
9/26/2011
57/68
The Audit
1. Two HEPA filters in
bulk filtration room,
failed integrity and
room air changes
decreased by 25%
from last test
2. In Process
bioburden out of
spec but sterility
test passes
29
9/26/2011
Severity
SEV
Likelihood of
Occurrence
OCC
Low
Medium
High
There is a
The possibility that
reasonable
the cause occurs
possibility
ibilit that
th t the
th
is rare; unusual
cause may occur
event
from time to time
High possibility of
occurrence;
common / known
event
RPN
< 10 ?
SEV x
OCC X
DET
11 29 ?
30 ?
60
30
9/26/2011
MED
HIGH
HIGH
V. HIGH
Med
MED
MED
HIGH
Med
Low
LOW
LOW
MED LOW
Low
Seve
erity
Occurrrence
61
High
Med
High
Low
(Risk)
Report Writing
y Concise and Precise and
TIMELY:
y Overview / Summary
y What was audited
y List best practices
y Overall impression
y Major items from this one (two or
three)
62/68
yPCI
Detailed
List of Findings:
Pharmaceutical Consulting Israel
31
9/26/2011
Report Writing
y Provide time frames
y The detailed audit observations
63/68
III CAPA
y Prioritizing the findings from the gap
analysis
y Preparing a corrective action
program
y Preparing
P
i a preventive
ti action
ti
program (proactive) using risk
mitigation strategies
64
32
9/26/2011
the audit
th
dit
y Prevent them from happening
again by corrective action
y The above already addressed in
the responses to the audit - just
needs follow up
65
Preventive Actions
y Are proactive i.e. acknowledge that
66
33
9/26/2011
68
34
9/26/2011
Validation - KPIs
70
35
9/26/2011
EM - KPIs
71
72
36
10/3/2011
10/3/2011
Objective of Seminar
y Be able to audit a sterile
processing
y Annex 1: EU GMPs on aseptic
processing:
p
g
y FDA Aseptic Processing Guide
y PIC/s Guidance
y ISO guidance
y Inspectional Observations
PCI Pharmaceutical Consulting Israel Ltd
10/3/2011
y Preparing an assessment
checklist
y Risk Management:
focusing on high risk areas
y Key Performance Indicators
y Preparing an assessment report
and recommendations
5
III CAPA
y Prioritizing the findings from the gap
analysis
y Preparing a corrective action
program
y Preparing
P
i a preventive
ti action
ti
program (proactive) using risk
mitigation strategies
6
10/3/2011
Interactive Bit!
y (to be done all along the way)
y develop a gap analysis checklist
10/3/2011
Your Bonus.Toolkit
y Template for conducting risk
10/68
10/3/2011
11/68
y Under Quality
Quality System
Elements:
y Process Performance and Product
12/68
10/3/2011
y Under CAPA:
13/68
14/68
10/3/2011
15/68
the information ?
16/68
10/3/2011
17
18
10/3/2011
components
t - going
i up / d
down /
static
20
10
10/3/2011
21
tunnel
22
11
10/3/2011
24
12
10/3/2011
26
13
10/3/2011
monitoring data
y Successful gowning
qualification
y From total of six different
locations less than 5 cfu???
27
Main Changes
y Particulate Classification (Airborne
particles)
y Media Simulations
y Bioburden monitoring
y Capping of (Freeze-Dried)
(Freeze Dried) Vials
28
14
10/3/2011
Particulate Classes
29
15
10/3/2011
Duration of Monitoring
y Grade A: full duration of critical processing, including
32
16
10/3/2011
vials
i l should
h ld b
be maintained
i t i d
under Grade A conditions at all
times until the stopper is fully
inserted
NOTE: effective 01 March 2010
34
17
10/3/2011
35
36
18
10/3/2011
previous
y Velocity
y Number of air changes in surrounding room:
37
38
19
10/3/2011
20
10/3/2011
41
42
21
10/3/2011
43
44
22
10/3/2011
y gamma
45
PIC/s
46
23
10/3/2011
PIC/s
47
24
10/3/2011
ISO cleanrooms
25
10/3/2011
X Risk Management:
X Focusing on high risk areas
9Key Performance Indicators
X Preparing an assessment report and
recommendations
51
Control Strategy
y Control Strategy
52
26
10/3/2011
53/68
reviewed
y Personnel records can be rapidly
reviewed and give a good overview:
training qualification,
training,
qualification job
descriptions (pick one or two
employees)
BUT is more efficient to do a tour
and then select employees you saw
doing the wrong thing!
PCI Pharmaceutical Consulting Israel
54/68
27
10/3/2011
The Audit
1. Two HEPA filters in
bulk filtration room,
failed integrity and
room air changes
decreased by 25%
from last test
2. In Process
bioburden out of
spec but sterility
test passes
Severity
SEV
Likelihood of
Occurrence
OCC
Low
Medium
High
There is a
The possibility that
reasonable
the cause occurs
possibility
ibilit that
th t the
th
is rare; unusual
cause may occur
event
from time to time
High possibility of
occurrence;
common / known
event
28
10/3/2011
RPN
< 10 ?
SEV x
OCC X
DET
11 29 ?
30 ?
57
Report Writing
y Concise and Precise and
TIMELY:
y Overview / Summary
y What was audited
y List best practices
y Overall impression
y Major items from this one (two or
three)
58/68
yPCI
Detailed
List of Findings:
Pharmaceutical Consulting Israel
29
10/3/2011
Report Writing
y Provide time frames
y The detailed audit observations are
59/68
III CAPA
y Prioritizing the findings from the gap
analysis
y Preparing a corrective action
program
y Preparing
P
i a preventive
ti action
ti
program (proactive) using risk
mitigation strategies
60
30
10/3/2011
the audit
th
dit
y Prevent them from happening
again by corrective action
y The above already addressed in
the responses to the audit - just
needs follow up
61
Preventive Actions
y Are proactive i.e. acknowledge that
62
31
10/3/2011
64
32
OUTLINE / OBJECTIVES
Overview
FDA Process Validation Guidance 2011
Cleaning Validation Policy
Cleaning Validation Master Plan
Stage 1 Documents -- Cleaning Process Development
Stage 2 Documents
Qualification
Equipment #1
UO #1
Equipment #2
UO #2
Equipment #3
UO #3
Qualification
HVAC
Utilities
Facilities
Computers
Designed experiments
Lab scale and pilot scale experiments
9
12
Procedures
Validation plans
Protocols (PPQ)
Sampling
Testing
Results
Plan to maintain validation
alidation
ALL EQUIPMENT, ANALYTICAL, AND SUPPORTING
SYSTEMS MUST BE QUALIFIED.
13
17
2008-2011
Lifecycle approach
Continuum of understanding validation maintenance
20
10
VALIDATION PHILOSOPHY
11
VALIDATION DOCUMENTS
Written for the reader US vs. Europe focus
Objective: Understanding
Clarity much more important than brevity
Stand-alone document
Potential for review in 10+ years
Author / Management not available
12
13
STAGE 2 DOCUMENTS
PROCESS QUALIFICATION
Cleaning Validation Request / Plan
Cleaning
Cl
i Validation
V lid ti P
Protocol
t
l
Cleaning Validation Results / Report
Document continuity:
Plan Protocol Results
If Plan well written, Protocol easy to write, Results easy to
compile and discuss.
28
14
What?
Why needed?
Wh acceptable?
Why
t bl ?
Impact of validation risk analysis
Approach to accomplish Cleaning validation plan
Approval
15
Prematurelyy written
Written to meet individual or business goals
Written to demonstrate future intent
Written in advance of regulatory audit
16
Introduction
Technical information
References
33
34
17
Experimental studies
Past data or related product data
Validation protocols
New procedures
Residue limits calculation
18
CLEANING PROCEDURE
Cleaning procedure is being validated.
Document description
p
General description
Cleaning batch record
Specific critical procedure steps must have
sign/date
Non-critical procedure steps may be grouped for
signature/date
CLEANING SOP NOT ACCEPTABLE
CLEANING PROCEDURE MAY BE INCLUDED IN PLAN
OR PROTOCOL
37
CLEANING PROCEDURE
SOP
Fill tank half full
Add half scoop of soap
Scrub as needed
Rinse
Ri
until
til clean
l
Re-scrub and re-rinse if needed
CLEANING PROCEDURE RECORD
Fill tank with 500 L water. Sign/date __________
Add 20 kg soap. Sign/date __________
Disassemble Part A. Steps 1,2,3,4,5
Scrub for 20 minutes. Sign/date __________
Disassemble
Di
bl Part
P t B.
B Steps
St
1,2,3,4,5
12345
Soak Part B in cleaning liquid for 10 minutes. Sign/date __________
Rinse Part A and Part B with 50 L water. Sign/date __________
Rinse with 50 L Purified Water. Sign/date __________
Dry with compressed air
38
19
Data treatment
Acceptance criteria general
DETAILS OF ABOVE PROVIDED IN PROTOCOLS
39
Title
Date closed
01
02
03
04
Cleaning Procedure
05
06
07
08
20
41
21
TECHNICAL REPORTS
Readily available
Stored in validation library?
Approved by management
Linked to original data
Observe / store original data
Do not assume integrity of printed report
43
22
46
23
47
ENGINEERING STUDY
48
24
DATA SHEETS
Designed sheet with space for expected data
Signature and data of person supplying data
Highly recommended for operators or persons not
familiar with sampling
Prevents missing data in complex protocols
Record sampling and / or testing
49
Acceptance Limit
__________
__________
__________
__________
__________
__________
Actual Data
__________
__________
__________
__________
__________
__________
50
25
51
26
27
28
No validation statement
Results indicate that the cleaning process is validated.
P l written
Poorly
itt
WRITTEN FOR THE READER
57
58
29
Introduction
Key information from Validation Plan
Supporting information
Protocol #1 results Cut and paste
Protocol #2 results Cut and paste
Protocol #3 results Cut and paste
Protocol #n results Cut and paste
Write transitional narrative
Project conclusions (for Validation Plan)
V lid ti statement
Validation
t t
t
Results indicate that the cleaning process is validated.
HAVE MODEL DOCUMENTS AVAILABLE
59
CLEANING PERSONNEL
Personnel operating cleaning equipment or
performing cleaning must be trained.
Manual cleaning is high risk activity.
Training / qualification of cleaning personnel must
be appropriate and documented.
Routine revalidation of manual cleaning processes
must be considered.
60
30
EQUIPMENT TO BE CLEANED
31
EQUIPMENT TO BE CLEANED
SURFACE AREA DOCUMENTS
1.
2.
3.
4.
5.
6.
Disassemble equipment
Separate pages for equipment product-contact components
Pictures / drawings of components and parts
Calculations of components and respective parts surface areas
Identification of associated product-contact materials
Use simple geometry to calculate surface areas. Reasonable
assumptions adequate
7. Summary page:
Material A
Material B
Material C
Equipment total surface area
EQUIPMENT TO BE CLEANED
PRODUCT-CONTACT MATERIALS
1.
2
2.
3.
4.
64
32
EQUIPMENT TO BE CLEANED
EQUIVALENT EQUIPMENT
List all identical or equivalent equipment
Cleaning validation on one or more equipment will serve
for all equipment
q p
Equivalent equipment includes materials, sizes,
disassembly procedures, and cleaning procedure
Document with tables providing dimensions, materials,
etc. justify equipment equivalence.
Document approved by Validation Approval Committee
E i l t equipment
Equivalent
i
t stated
t t d iin manufacturing
f t i b
batch
t h
record as options for manufacturing.
ANALYTICAL METHOD
Residue chemistry understanding
Method must measure actual residue
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ANALYTICAL METHOD
RESIDUE UNDERSTANDING
Analytical method must measure actual residue
Residue may degrade before initiation of cleaning or during
cleaning process
Hydrolysis, oxidation, photolysis, physical change
Non-specific analytical methods may be appropriate
Biotech residues are degraded to protein fragments during
cleaning process use non-specific methods (TOC)
DOCUMENTATION OF ABOVE MUST BE READILY
AVAILABLE FOR AUDIT
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STAGE 3 DOCUMENTS
CONTINUED PROCESS VERIFICATION
Two categories
1 Special requirements based on PPQ results
1.
2. Routine monitoring.
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STAGE 3 DOCUMENTS
MAINTAINING CLEANING VALDIATAION
Compilation of
36
QA
Validation
Production
Production
QA
Production
Validation
___
QA
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74
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75
Suggested approach
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IMPLEMENTATION
Plan implementation strategy
Deliberate strategy must be successful
Meet with affected groups Engineering, Technical Support, others
Meet with Validation Approval Committee
SUMMARY
WHERE WE ARE -- CURRENT PRACTICE
CLEANING VALIDATION
R&D
Validation
Commercialization
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SUMMARY -- VALIDATION
CURRENT PRACTICE
Emphasis on repeatability (3x)
One-time effort
Documentation important
Last step in development basis?
Hope we can pass validation
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SUMMARY
PROCESS VALIDATION HISTORY
1978
CGMP iincludes
l d V
Validation
lid ti
1987
Development -- VALIDATION -- Control
2008-2011
Lifecycle approach
Continuum of understanding validation maintenance
UNDERSTANDING -- VALIDATION -- MAINTENANCE
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SUMMARY
CLEANING VALIDATION -- FUTURE
Development
Stage 1
Performance
Stage 2
Maintenance
Stage 3
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SUMMARY
EFFECTIVE CLEANING VALIDATION DOCUMENTS
HIGH LEVEL DOCUMENTS
Corporate Policies
Company-wide requirements
Site requirements
Reference to validation documents
Cleaning
g matrix
Equivalent equipment
Cleaning project commitments
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SUMMARY
CLEANING VALIDATION DOCUMENTS
Validation documents consistent with validation guidelines and
expectations
Validation g
guidelines specify
p
y details
Validation is confirmation -- Acceptable results are expected
Validation is not R&D, optimization, fine-tuning
New guidance requirements
Stage 1 -- Emphasis on development work supporting Stage 2
Scientific and technical basis
CQA and CPP, sources of variation, variation control plan
Reference and quickly retrieve R&D reports
Stage 2 -- Work should consider validation guidance recommendations
Stage 3 Emphasis on maintaining validated state through lifecycle
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SUMMARY
CLEANING VALIDATION DOCUMENTS
STAGE 1 DOCUMENTS
Cleaning process development reports
Residue chemistry
Cleaning agent selection
Process development
Analytical method development
Residue chemistry
Recovery studies
Sampling training
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SUMMARY STAGE 2
VALIDATION REQUEST / PLAN
Initiates validation
Provides basis and details of future work
Lists all specific requirements to complete
validation
Administrative importance
Most important document all subsequent
p
documents based on validation plan
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SUMMARY -- STAGE 2
VALIDATION PROTOCOLS
Specific guidance requirements
Strategy and approach
Impact of change
Risk analysis
Testing and sampling rationale
Acceptance criteria
Statistical data treatment
Data sheets
Post-validation monitoring plan
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SUMMARY STAGE 2
VALIDATION RESULTS
Data sheets
Discussion of results Evaluate results
Additional post-validation testing if necessary
SUMMARY STAGE 2
CLEANING VALIDATION DOCUMENTS
Operator
p
cleaning
g training
g
Manual cleaning requires appropriate training (not read
and sign)
Retraining (annual?) must be considered.
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SUMMARY STAGE 3
CLEANING VALIDATION DOCUMENTS
Specific Post-PPQ requirements
Compilation of Stage 3 post-validation maintenance
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DOCUMENT SUMMARY
CORPORATE POLICY
CLEANING VALIDATION MASTER PLAN
STAGE 1 DOCUMENTS
R&D Reports
Cleaning process development
Analytical (Assay, Recovery, Sampling training)
STAGE 2 DOCUMENTS
Request/Plan, Protocol, Results/Report
Cleaning equipment qualification
Equipment to be cleaned (Product-contact materials, Surface areas,
Sampling, Equivalent equipment)
Operator training
STAGE 3 DOCUMENTS
Monitoring documents (Non-conformances, deviations, changes)
Change control
Improvement projects
Management Review
ASSOCIATED DOCUMENTS
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IMPLEMENTATION
Plan implementation strategy
Deliberate strategy must be successful
Meet with affected groups and with Validation Approval Committee
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Contact: paul.pluta@comcast.net
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